CADTH Reimbursement Review

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

Sponsor: Vertex Pharmaceuticals (Canada) Incorporated

Therapeutic area: Cystic fibrosis, F508del CFTR mutation, 2 to 5 years

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Abbreviations

AE

adverse event

ALT

alanine transaminase

AST

aspartate transaminase

BMI

body mass index

CF

cystic fibrosis

CF CanACT

Cystic Fibrosis Canada’s Accelerating Clinical Trials Network

CF Canada

Cystic Fibrosis Canada

CFQ-R

Cystic Fibrosis Questionnaire–Revised

CI

confidence interval

ELX

elexacaftor

ELX-TEZ-IVA

elexacaftor-tezacaftor-ivacaftor and ivacaftor

FAS

full analysis set

FEV1

forced expiratory volume in the first second

F/F

homozygous for F508del mutation in the CFTR gene

F/G

1F508del mutation and 1 gating mutation in the CFTR gene

F/MF

1 F508del mutation and 1 minimal function mutation in the CFTR gene

F/R117H

1 F508del mutation and 1 R117H mutation in the CFTR gene

F/RF

1 F508del mutation and 1 residual function mutation in the CFTR gene

ITC

indirect treatment comparison

IVA

ivacaftor

MMRM

mixed-effects model for repeated measures

LCI

lung clearance index

LS

least squares

LUM-IVA

lumacaftor-ivacaftor

ppFEV1

percent predicted forced expiratory volume in the first second

RCT

randomized controlled trial

SAE

serious adverse event

SD

standard deviation

SwCl

sweat chloride

TEZ

tezacaftor

TEZ-IVA

tezacaftor-ivacaftor and ivacaftor

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

Item

Description

Drug product

Elexacaftor-tezacaftor-ivacaftor and ivacaftor (Trikafta):

  • Elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg (granules) and ivacaftor 75 mg (granules), oral

  • Elexacaftor 80 mg–tezacaftor 40 mg–ivacaftor 60 mg (granules) and ivacaftor 59.5 mg (granules), oral

Patients aged 6 years and older:

  • Elexacaftor 50 mg–tezacaftor 25 mg–ivacaftor 37.5 mg (combination tablet) and ivacaftor 75 mg (tablet), oral

  • Elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg (combination tablet) and ivacaftor 150 mg (tablet), oral

Sponsor

Vertex Pharmaceuticals (Canada) Incorporated

Indication

For the treatment of cystic fibrosis (CF) in patients aged 2 years and oldera who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Reimbursement request

Initiation criteria:

  • Confirmed diagnosis with cystic fibrosis with at least 1 F508del mutation in the CFTR gene

  • Aged 2 to 5 years

Initial renewal criteria:

  • For the initial renewal criteria, at least 1 of the following must be demonstrated after 12 months of treatment:

    • a reduction in sweat chloride as defined by a sweat chloride concentration less than 60 mmol/L OR a reduction in sweat chloride of at least 30% from baseline

    • a decrease in the number of pulmonary exacerbations OR in the number of days antibiotics needed to be taken for pulmonary exacerbations OR in the number of courses of antibiotics needed to be taken for pulmonary exacerbations

    • no decline in body mass index percentile

    • a clinical benefit as determined by a physician specializing in the treatment of cystic fibrosis.

Timing for initial renewal assessment: Sponsor requests that the initial renewal criteria be extended from 6 months to 12 months

Subsequent renewals annually: The physician must provide evidence of continued treatment benefit with elexacaftor-tezacaftor-ivacaftor and ivacaftor for subsequent renewal of reimbursement

Health Canada approval status

NOC

Health Canada review pathway

Priority review

NOC date

October 16, 2023

Recommended dose

Patients aged 2 to < 6 years:

  • < 14 kg: 1 packet of elexacaftor 80 mg–tezacaftor 40 mg–ivacaftor 60 mg granules in the morning; 1 packet of ivacaftor 59.5 mg granules in the evening

  • ≥ 14 kg: 1 packet of elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg granules in the morning; 1 packet of ivacaftor 75 mg granules in the evening

NOC = Notice of Compliance.

aThis review focuses on patients aged 2 to 5 years.

Introduction

Trikafta is a fixed-dose combination product containing elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) co-packaged with IVA (ELX-TEZ-IVA). ELX-TEZ-IVA is available as both oral tablets and oral granules in the following dosing strengths:

ELX-TEZ-IVA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least 1 F508del mutation in the CFTR gene. A deletion of phenylalanine 508 in the first nucleotide-binding domain (F508del) is the most common mutation in the CFTR gene that results in CF.1 The Canadian Cystic Fibrosis Registry reported 4,344 patients in Canada living with CF in 2019. Of these patients, 87.8% carried at least 1 F508del mutation (47.1% were homozygous, and 40.7% were heterozygous).

This is the third submission to CADTH for ELX-TEZ-IVA. CADTH has previously reviewed ELX-TEZ-IVA for the treatment of CF in patients who have at least 1 F508del mutation in the CFTR gene for those aged 12 years and older (final recommendation issued in August 2021) and those aged 6 years and older (final recommendation issued in June 2022). For both of the previous reviews, the CADTH Canadian Drug Expert Committee recommended that ELX-TEZ-IVA be reimbursed with conditions.2,3 All the indications for ELX-TEZ-IVA were accepted as priority reviews by Health Canada.

The sponsor has requested that the current submission for ELX-TEZ-IVA focus only on those patients aged 2 to 5 years using the new dosage format (i.e., orally administered granules).

The objective of this review is to evaluate the beneficial and harmful effects of ELX-TEZ-IVA at recommended dosages for the treatment of patients aged 2 to 5 years with CF who have at least 1 F508del mutation in the CFTR gene.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review. Complete patient and clinician input received for the current review of ELX-TEZ-IVA is reported in the appendix of this report. The complete input received for the previous CADTH reviews of ELX-TEZ-IVA is available on the CADTH website (refer to reviews for ELX-TEZ-IVA for patients aged 6 to 11 years and 12 years and older).

Patient Input

One patient group, Cystic Fibrosis Canada (CF Canada), responded to CADTH’s call for patient input for the current review of ELX-TEZ-IVA, which is focused on patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene.

The patient group emphasized that CF tremendously impacts those living with the condition, their loved ones, health systems, and society. The most significant clinical impact is in the lungs, where patients experience progressive scarring of their airways and a progressive decline in lung function. Young children who grow older with CF may experience pulmonary exacerbations requiring weeks to months of hospitalization and IV antibiotics. Malnutrition and low body mass index (BMI) are also common consequences of CF among children aged 2 to 5 years. Patients may also experience CF-related comorbidities, such as CF-related diabetes and CF-related liver disease. In addition, CF has a significant impact on socialization, mental health, and isolation among patients and caregivers.

The patient input stated that managing CF requires a demanding treatment routine. As the disease progresses, more time and effort and frequent clinic visits and hospital stays are needed to manage the progressive and debilitating symptoms. This condition has a significant impact on patients’ and caregivers’ day-to-day activities and quality of life, in addition to creating a huge financial burden for families.

According to the patient group input, an ideal treatment for CF would fully address the basic molecular defect in CF and restore normal chloride transport on the cell surface. Patients with CF and their loved ones are seeking treatments that can change the trajectory of the disease, reduce disease symptoms, improve sleep quality and energy levels, and improve both life expectancy and quality of life.

In the patient group input, CF Canada’s Accelerating Clinical Trials Network (CF CanACT) emphasized the importance of early treatment of CF to prevent disease progression and irreversible damage. Extending access to ELX-TEZ-IVA for patients with CF aged 2 to 5 years would be congruent with the secondary prevention paradigm of CF care and would decrease the long-term burden of the disease.

Clinician Input

Input From Clinical Experts Consulted by CADTH
Unmet Needs

Similar to the input from the patient group, the clinical experts consulted by CADTH indicated that there are significant unmet therapeutic needs for patients living with CF. There are no treatments currently available that can meet the most important goals of therapy, which include prolonging survival, preventing the need for lung transplant, slowing the decline in lung function over time, and reversing the course of the disease. In addition, the clinical experts noted that the current standard treatments for CF are burdensome for patients and their caregivers.

Place in Therapy

The clinical experts anticipate that ELX-TEZ-IVA would be used as a preventive therapy, with the goal of initiating treatment before the patient develops significant lung disease. The current treatment paradigm would be significantly altered if ELX-TEZ-IVA can successfully prevent or delay progression to end organ disease (e.g., lung transplant). The clinical experts consulted by CADTH and those who responded to the call for clinician input noted that children aged between 2 and 5 years will often have structural lung disease (e.g., bronchial wall thickening, mucus plugging, or bronchiectasis) but that detection is challenging using the tools available to evaluate lung function in clinical practice (i.e., spirometry) or as part of a research protocol (e.g., lung clearance index [LCI]). These early stages of lung abnormalities can be visualized using CT; therefore, despite younger patients with CF often demonstrating normal lung function, the underlying disease will continue to progress.

All the clinicians who provided input for this review recommended initiating treatment with ELX-TEZ-IVA as soon as possible. This recommendation is aligned with the previously published Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients With Cystic Fibrosis, which also recommends that CFTR modulators be initiated at the youngest age possible, with the goal of attenuating disease progression and improving clinical status. All stakeholders agreed that there are no data to support withholding the initiation of CFTR modulator treatment until clinical symptoms of CF have developed.

Patient Population

For the expanded indication (i.e., patients aged 2 to 5 years), the clinical experts consulted by CADTH noted that nearly all patients would initiate therapy with ELX-TEZ-IVA as soon as possible, provided it is safe to start to treatment. The clinical experts emphasized that ELX-TEZ-IVA has been a transformative and disease-modifying therapy for CF and that it would not be appropriate to wait until the patient shows worsening symptoms, more frequent exacerbations, or a decline in lung function to initiate treatment with ELX-TEZ-IVA.

Applicability of Existing Reimbursement Criteria to Pediatric Patients

In discussions with CADTH, the sponsor noted that nearly all patients aged 12 years and older living in Canada who are eligible for treatment have begun therapy with ELX-TEZ-IVA (some may have elected to discontinue, but all who are interested have been given the opportunity to access the drug). The sponsor similarly stated that all patients aged 6 to 11 years living in Canada who wish to initiate treatment will have begun treatment with ELX-TEZ-IVA by the end of 2023. For those who have initiated treatment with ELX-TEZ-IVA, the sponsor noted that initial renewal criteria had been met for all patients living in Canada who had started the therapy and wanted to continue (i.e., 100% of patients met the renewal criteria recommended by CADTH and/or applied by the public drug programs). The clinical experts consulted expressed general agreement with the sponsor’s position, noting that rates of initial access and renewal are very high within their individual clinics. With nearly all patients aged 6 years or older having now met the initiation and renewal criteria, newly issued CADTH reimbursement criteria focusing exclusively on patients aged 2 to 5 years would effectively replace the previous criteria (i.e., although limited to patients aged 2 to 5 years, all older patients would have already qualified for initiation and renewal).

The clinical experts consulted by CADTH reviewed the existing criteria recommended for patients aged 6 years and older and noted the following:

Clinician Group Input

Three groups of clinicians responded to CADTH’s call for input: CF CanACT, the CF Canada Healthcare Advisory Council, and the Canadian Cystic Fibrosis Clinician groups. The input from the clinician groups identified the same unmet medical needs for patients with CF and potential place in therapy for the drug under review as the clinical experts consulted by CADTH.

According to the clinician groups’ input, the treatment paradigm for CF in children aged 2 to 5 years is lifelong. All clinician groups noted that available treatments address the symptoms and complications of CF and attempt to slow down the eventual fatal progression of the disease without effectively addressing the root cause or reversing the course of the disease. The treatments also have significant side effects and numerous drug interactions. The clinician groups emphasized that ELX-TEZ-IVA is the most effective improvement of the existing CFTR modulators as it addresses the underlying disease process, which helps in delaying disease progression and the need for other therapies, including lung transplant. Therefore, any patient with CF who has at least 1 copy of F508del could potentially benefit from ELX-TEZ-IVA.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could impact the implementation of a CADTH recommendation for ELX-TEZ-IVA for patients aged 2 to 5 years:

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs (refer to the Drug Program Input section).

Clinical Evidence

Systematic Review

Description of Study

The evidence identified in the current review of ELX-TEZ-IVA that addressed the expanded patient population (i.e., those aged 2 to 5 years) included Study 111, a 24-week, open-label, phase III, nonrandomized, single-arm, 2-part (A and B) study. Study 111 was conducted in 2 parts:

Patients were eligible to be included in Study 111 if they had received a diagnosis of CF and were aged 2 to 5 years (inclusive). All patients had an F508del-CFTR mutation and 1 of the following genotypes: 1 F508del mutation and 1 minimal function mutation in the CFTR gene (F/MF) (69.3%) or homozygous for F508del mutation in the CFTR gene (F/F) (30.7%). Patients were excluded from the study if they had any comorbidities that could impact treatment outcomes or if they had received a prior hematological or solid organ transplant. The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus. Patients were also considered to be ineligible if they reported an acute upper or lower respiratory infection, a pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of the study drug. Patients with a history of solid organ or hematological transplant were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.

Safety and tolerability were the primary end points in Study 111. The secondary end points were absolute change from baseline in SwCl through 24 weeks and absolute change from baseline in LCI2.5. Changes from baseline in growth parameters (BMI, BMI z score, weight, weight z score, height, and height z score) were evaluated as additional efficacy end points, but no statistical analyses were conducted. Descriptive statistics were provided for pulmonary exacerbations and CF-related hospitalizations in Study 111. LCI2.5 was only evaluated in patients aged at least 3 years at the time of screening (n = 50).

Efficacy Results

Treatment with ELX-TEZ-IVA resulted in a within-group improvement (reduction) in SwCl from baseline through 24 weeks. The least squares (LS) mean absolute change was –57.9 mmol/L (95% confidence interval [CI], –61.3 mmol/L to –54.6 mmol/L; nominal P < 0.0001). The reduction from baseline was observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). The results for the subgroup analyses based on CFTR genotype were –70.0 mmol/L (95% CI, –75.4 mmol/L to –64.5 mmol/L) and –52.6 mmol/L (95% CI, –56.9 mmol/L to –48.4 mmol/L) in the F/F and F/MF groups, respectively.

Among those patients who were assessed, treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in LCI2.5 through 24 weeks. The within-group LS mean absolute change from baseline was –0.83 (95% CI, –1.01 to –0.66; nominal P < 0.0001). The reduction from baseline was observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). The results were similar in the F/F and F/MF genotype subgroups: the LS mean change was –0.89 (95% CI, –1.15 to –0.63) and –0.82 (95% CI, –1.06 to –0.57), respectively.

Sixteen percent of patients experienced a pulmonary exacerbation event through 24 weeks (1 event each), with an annualized event rate of 0.32 per year. One patient experienced a pulmonary exacerbation that required hospitalization. There were no CF-related hospitalizations in Study 111.

The absolute change from baseline in growth end points at 24 weeks was 0.10 (95% CI, 0.00 to 0.20) for BMI z score, 0.02 (95% CI, –0.04 to 0.09) for body weight z score, and –0.06 (95% CI, –0.11 to 0.00) for height z score.

Harms Results

The overall percentage of patients who experienced at least 1 adverse event (AE) was 98.7% (nearly all were mild [62.7%] or moderate [36.0%] in severity), including cough (61.3%); increased alanine aminotransferase (ALT) (10.7%); rhinorrhea (33.3%); increased aspartate aminotransferase (AST) (5.3%); rash (16.0%); pyrexia (34.7%); vomiting (28.0%); COVID-19 (18.7%); nasal congestion (17.3%); upper respiratory tract infection (14.7%); decreased appetite (12.0%); and infective pulmonary exacerbation of CF (10.7%). Two patients (2.7%) experienced serious AEs (SAEs): 1 patient with anal incontinence, urinary incontinence, and abnormal behaviour, and 1 patient with an SAE of infective pulmonary exacerbation of CF. One patient (1.3%) discontinued treatment due to an SAE, and 5 patients (6.7%) had AEs leading to treatment interruption. For AEs of special interest were that 8 patients (10.7%) experienced elevated transaminase events and 15 patients (20.0%) experienced rash events (all events were mild or moderate in severity). Two patients experienced rash events leading to treatment interruption. There were no study discontinuations due to rash events or elevated transaminase events.

Critical Appraisal
Internal Validity

Study 111 was conducted in a manner similar to all other pivotal studies for the use of CFTR modulators in patients aged between 2 and 5 years (i.e., expansion of approval indications for Orkambi4,5 and Kalydeco6,7). Each of these studies was conducted in 2 parts, with Part A involving a small number of patients (n = 18 for Study 111), with a primary objective of evaluating pharmacokinetics, and Part B enrolling more patients (n = 75 for Study 111), with the primary objective of evaluating safety and tolerability. As with the other trials for CFTR modulators in patients aged 2 to 5 years, ELX-TEZ-IVA was administered in an open-label manner in Study 111, and there was no comparator group in either Part A or Part B. The limited number of secondary efficacy end points evaluated in the study were objective and unlikely to be influenced by the open-label administration of a CFTR modulator (i.e., change from baseline in SwCl concentration and change from baseline in LCI2.5).

Pulmonary exacerbations were only evaluated with descriptive statistics, and there were no prebaseline or postbaseline comparisons of event rates. In response to an inquiry from CADTH regarding why pulmonary exacerbations were not included as an efficacy end point, the sponsor reported that, as had been noted in relation to the pediatric trial for patients aged 6 to 11 years, exacerbations occur less frequently in younger patients than in older patients. As Study 111 was a single-arm trial without a defined pretreatment evaluation period, and due to the low pulmonary exacerbation rates in the study population, comparison to a pretreatment event rate was not possible.

External Validity

The eligibility and diagnostic criteria used to screen patients for Study 111 were similar to those used in the other phases of the ELX-TEZ-IVA clinical development program (i.e., Studies 106 and 116 for patients aged 6 to 11 years and Studies 102, 103, 104, and 109 for patients aged 12 years and older). As noted in the previous CADTH review of ELX-TEZ-IVA, these criteria are generally consistent with Canadian clinical practice for diagnosing patients with CF. As all Canadian provinces and territories have instituted newborn screening, diagnosis of CF and confirmation of genotyping would typically occur early in the child’s life (an average of 1 month after birth). As such, no changes would be needed in diagnostic testing requirements to establish patient eligibility based on CF diagnosis and genotype for the revised age range for ELX-TEZ-IVA.

The clinical experts consulted by CADTH noted that the baseline growth parameters for the patients in Study 111 were a reasonable reflection of the typical patient in Canadian practice.

Changes from baseline in lung function were evaluated as a secondary efficacy end point in Study 111 using LCI2.5. This is reflective of regulatory guidance, which has noted that spirometry may not be sensitive enough to detect treatment differences in children with CF. In addition, spirometry is not typically performed in patients younger than 6 years in Canada, and FEV1 has not been used as a clinical trial end point in any CFTR modulator studies for those younger than 6 years. LCI is used in CF clinical trials as it may be more sensitive in identifying early underlying structural deficiencies within the lungs of patients with CF that cannot be detected using spirometry.8,9 Similar to spirometry assessments, the LCI test can be challenging to accurately perform with young children. In Study 111, the sponsor noted the LCI test was only performed on patients who were at least aged 3 years at the time of screening. Although LCI is used as an end point in clinical studies, as noted previously it is not routinely used in Canadian clinical practice, and the clinical relevance of differences in this end point have not been characterized.9,10 The clinical experts consulted by CADTH indicated that LCI is not reliably correlated with FEV1. A literature review conducted by CADTH found that variable correlation was observed between FEV1 and LCI in children.

ELX-TEZ-IVA was added to the existing therapeutic regimens used by the patients, which is reflective of how ELX-TEZ-IVA would be administered in clinical practice. The clinical experts consulted by CADTH indicated that the background therapies used in Study 111 were similar to what would be anticipated in Canadian clinical practice, with the following exceptions: all patients in Canadian practice would be supplementing with vitamins, and the use of mucolytics (i.e., dornase alfa and inhaled hypertonic saline) could be slightly lower for patients aged 2 to 5 years in Canada.

The 24-week study treatment periods were sufficient for observing change from baseline in SwCl and LCI2.5 in Study 111; however, the clinical experts consulted by CADTH suggested that 24 weeks is unlikely to be enough time to observe meaningful changes in BMI for a younger patient population that is relatively healthy. In addition, the absence of a control group in Study 111 limits the ability to interpret the results of change from baseline in the growth parameters.

Table 2: Summary of Key Results From Study 111 Part B

End points

ELX-TEZ-IVA (N = 75)

Change from baseline in SwCl (mmol/L) (n = 69)

Baseline, mean (SD)

100.7 (11.2)

Change from baseline, mean (95% CI)

–57.9 (–61.3 to –54.6)

P value

< 0.0001

Change from baseline in LCI2.5 (n = 50)

Baseline, mean (SD)

8.41 (1.48)

Change from baseline, mean (95% CI)

–0.83 (–1.01 to –0.66)

P value

< 0.0001

Pulmonary exacerbations (n = 75)

Patients with events, n (%)

12 (16.0)

Number of events

12

Observed event rate per year

0.32

P value

NR

CF-related hospitalizations (n = 75)

Patients with events, n (%)

|| || ||||

P value

NR

Change from baseline in BMI z score (n = 75)

Baseline, mean (SD)

0.09 (0.85)

Change from baseline, mean (95% CI)

0.10 (0.00 to 0.20)

P value

NR

Summary of AEs, n (%)

≥ 1 AE

74 (98.7)

≥ 1 SAE

2 (2.7)

AE leading to treatment discontinuation

1 (1.3)

AE leading to interruption of treatment

5 (6.7)

AEs of special interest, n (%)

Elevated transaminase levels

8 (10.7)

Rash

15 (20.0)

AE = adverse event; BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; LCI2.5 = lung clearance index 2.5; NR = not reported; SAE = serious adverse event; SD = standard deviation; SwCl = sweat chloride.

Source: Sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

Patients who completed Study 111 were eligible to enrol in an open-label extension study. However, the sponsor reported that the interim results of the extension study were not available at the time of filing the application with CADTH.

Indirect Comparisons

Feasibility of Indirect Treatment Comparison in Patients Aged 2 to 5 Years

The sponsor conducted an indirect treatment comparison (ITC) to compare the clinical efficacy of ELX-TEZ-IVA in Study 111 with other CFTR modulators in patients with F/F and F/MF mutations to generate the inputs needed for the cost-effectiveness analysis. A meta-analysis approach via mixed-effects model for repeated measures (MMRM) was used with individual patient-level data from relevant trials; data from all comparators were included in 1 model for each genotype. The sponsor concluded that the ITC was not feasible due to the small number of patients in this age group, which reduced the power to detect differences between ELX-TEZ-IVA, lumacaftor-ivacaftor (LUM-IVA), and/or placebo. As such, the sponsor did not include the ITC comparison in its submission to CADTH and used estimates from the previous CADTH submission for patients aged 6 to 11 years to use as assumptions within its economic model.

ITCs in Patients Aged 6 to 11 Years and 12 Years and Older

To inform the pharmacoeconomic model, the sponsor submitted estimates of clinical efficacy of ELX-TEZ-IVA compared to placebo derived from ITCs previously conducted for patients aged 6 to 11 years and 12 years and older using individual patient data from relevant phase III randomized controlled clinical trials.

The sponsor conducted a single indirect comparison for patients aged 6 to 11 years with an F/F genotype to derive relative estimates of clinical efficacy for ELX-TEZ-IVA versus LUM-IVA, ELX-TEZ-IVA versus placebo, and ELX-TEZ-IVA versus tezacaftor-ivacaftor and ivacaftor (TEZ-IVA). TEZ-IVA is not currently approved by Health Canada or reimbursed by the Canadian public drug programs for use in patients aged 6 to 11 years. To conduct the primary indirect comparisons, the sponsor extracted 24-week individual patient data for those with an F/F genotype from the following studies: Study 106B for ELX-TEZ-IVA (N = 29); pooled data from Study 809-109 and Study 809-011B for LUM-IVA (N = 160); and Study 661-113B for TEZ-IVA (N = 61). Additional sensitivity analyses were performed using 8-week data. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo for absolute change from baseline through 24 weeks: || || |||||| || |||||| || |||| for percent predicted FEV1 (ppFEV1). The primary limitations of the ITC were the differences in study design across the included studies (Studies 106B, 809-011B, and 661-113B were single-arm, open-label trials, and Studies 809-109 and 661-115 were double-blind placebo-controlled trials) and the differences in the baseline characteristics.

Studies Addressing Gaps in the Evidence From the Systematic Review

The sponsor did not include any additional studies to address gaps in the pivotal trial evidence.

Conclusions

For patients aged 2 to 5 years, a 24-week, open-label, uncontrolled trial (Study 111 Part B; N = 75) suggested that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function (decrease in LCI2.5 from baseline) and CF biomarkers (reduction in SwCl). Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA, as the regulatory submission is based on the extrapolation of efficacy data from the studies conducted in older patients with CF (i.e., those showing some measurable level of disease manifestations at baseline). The clinical experts consulted by CADTH noted that, given the mechanism of action and compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA would be expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. There is consensus across clinicians and patients that treatment with ELX-TEZ-IVA should be initiated as soon as possible given the clinically meaningful benefits observed in patients who can currently access the treatment. Uncertainty remains regarding the magnitude of the beneficial effect of ELX-TEZ-IVA in very young patients with CF, and future real-world evidence may help address this uncertainty.

Study 111 was limited to patients with an F/F or F/MF genotype. There were no clinical studies conducted with ELX-TEZ-IVA in pediatric patients with 1 F508del mutation and 1 residual function mutation in the CFTR gene (F/RF) or 1 F508del mutation and 1 gating mutation in the CFTR gene (F/G) genotypes; however, the clinical experts noted that ELX-TEZ-IVA would result in clinically meaningful improvements for these patients, based on the evidence reported for ELX-TEZ-IVA in adult patients with F/RF and F/G genotypes and the results in F/F and F/MF pediatric studies. This is consistent with the input from patient and clinician groups, who have indicated that all patients with at least 1 F508del mutation are likely to benefit from treatment with ELX-TEZ-IVA.

ELX-TEZ-IVA was well tolerated in the target patient population (i.e., patients aged 2 to 5 years with at least 1 F508del mutation). SAEs and withdrawals due to AEs were rare in Study 111. The product monograph notes that elevated transaminases have been observed in patients treated with ELX-TEZ-IVA and recommends that ALT and AST be assessed prior to initiating treatment with ELX-TEZ-IVA, every 3 months during the first year of treatment, and annually thereafter. The clinical experts consulted by CADTH noted that the recommendations for monitoring with ELX-TEZ-IVA were not anticipated to result in a substantial increase in the number of clinic visits for patients with CF (particularly after the first year of treatment).

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of ELX-TEZ-IVA (Trikafta; oral granules) at recommended dosages for the treatment of patients aged 2 to 5 years with CF who have at least 1 F508del mutation in the CFTR gene.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

CF, an autosomal recessive condition, is the most common fatal genetic disease affecting children and young adults in Canada. It is caused by mutations in the CFTR gene, which is located on chromosome 7. The CFTR gene encodes a chloride channel that regulates ion and fluid transport across cell membranes. When CFTR is dysfunctional, secretions become tenacious and sticky, resulting in pathology in multiple organs, including the lungs, the large and small intestines, the pancreatic and bile ducts, and the vas deferens. A deletion of phenylalanine 508 in the first nucleotide-binding domain (F508del) is the most common mutation that results in CF.1 The Canadian Cystic Fibrosis Registry reported 4,344 patients in Canada living with CF in 2019. Of these patients, 87.8% carried at least 1 F508del mutation (47.1% were homozygous, and 40.7% were heterozygous).1

More than 2,090 CFTR variants have been identified among patients with CF.1 The CFTR variants have been classified as impaired biosynthesis (class I), defective protein maturation and accelerated degradation (class II), defective regulation of CFTR at the plasma membrane (class III), defective chloride conductance (class IV), diminished CFTR transcription (class V), and accelerated turnover at the cell surface (class VI).11 CFTR variants within classes I to III are associated with severe CF as they are considered nonfunctional, while CFTR variants in classes IV to VI may retain CFTR function.11,12 The F508del mutation is typically considered a class II CFTR mutation and is a severe mutation resulting in significant loss of function of the CFTR protein. A F508del defect causes CFTR to misfold, and thus most of the protein is removed before it can reach the cell membrane. In addition, the F508del mutation in the CFTR gene presents a defect in channel gating as well as being unstable and having more rapid turnover at the cell membrane.13,14 Genotyping for mutations in the CFTR gene is performed routinely on almost all patients with CF in Canada and is also part of the newborn screening process.1

CF results in airway obstruction, chronic endobronchial infection, and inflammation, which ultimately lead to destruction of lung tissue through the development of bronchiectasis and to loss of lung function.15 Although chronic pulmonary therapies instituted early in the disease have reduced the decline in lung function over time, patients who are homozygous for the F508del mutation will develop chronic infection with Pseudomonas and progressive bronchiectasis and airway obstruction. In a cohort of approximately 1,000 healthy young children with CF who did not have Pseudomonas infection at enrolment, there was a greater annual decline in FEV1 over the following 4 years in those who were homozygous for the F508del mutation.16 Chronic endobronchial infection of the airways with bacterial pathogens, such as Pseudomonas aeruginosa (reported in 38% of patients with CF living in Canada in 2019),1 is associated with a more rapid loss of lung function.17 Acute or chronic endobronchial infections result in further destruction of lung tissue and are associated with respiratory morbidity. Lung disease accounts for the vast majority of deaths in patients with CF (over 80%).1,18

Pulmonary exacerbations are associated with lung function decline and mortality and may require treatment with IV antibiotics and hospitalization. The Cystic Fibrosis Foundation has reported that approximately a third of patients with CF will have at least 1 pulmonary exacerbation per year requiring IV antibiotics.19

Maintenance of pulmonary function (FEV1) and fewer respiratory exacerbations are associated with increased survival.20 Pulmonary management of CF therefore aims to clear the airways of secretions and treat lung pathogens to minimize inflammation.

Patients who are homozygous or heterozygous for the F508del mutation typically have pancreatic, gastrointestinal, and nutritional disease as well as progressive pulmonary damage. Gastrointestinal and pancreatic involvement results in pancreatic exocrine insufficiency in most individuals with CF, causing malabsorption of fats and fat-soluble vitamins, which leads to malnutrition. Maintaining adequate nutrition is associated with improved clinical outcomes and longevity for patients with CF.21 Virtually all these patients will have insufficient pancreatic function and will need to take lifelong pancreatic enzyme replacement with every meal as well as fat-soluble vitamin therapy. With increasing age, these patients will develop CF-related diabetes and require therapy with insulin. In 2019, CF-related diabetes was reported in 22.0% of patients with CF living in Canada (33.5% of adults and 3.3% of children).1

The median age of survival in Canada for a child born with CF in 2019 is estimated to be 53.4 years.1 The Canadian Cystic Fibrosis Registry has reported an increase in the median age of death for patients with CF in Canada since the year 2000.1 In 2019 the median age of death was 42.1 years, compared with 27.7 years in 2000, 35.1 years in 2013, and 38.9 years in 2016.1,22,23 There is a clear unmet need for better CF therapies (refer to Patient Group Input and Clinician Input).

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

The goals of CF therapy include preservation of lung function by minimizing pulmonary infection and inflammation; restoration of baseline pulmonary function, symptoms, and level of inflammation after acute respiratory exacerbations; and maintenance of adequate nutrition. The choice of a therapeutic regimen for CF depends on organ involvement. The severity of lung function impairment and the presence of bacterial pathogens are deterministic factors when selecting chronic pulmonary therapy.

Treatments that are approved and/or available can be broadly classified either as therapies used to manage symptoms, complications, and comorbidities of CF or as therapies that aim to correct the underlying defects of the CFTR protein, known as CFTR modulators.

Management of Symptoms, Complications, and Comorbidities

Respiratory treatments consist of physiotherapy and pharmacologic agents, such as inhaled antibiotics (e.g., tobramycin, aztreonam, or colistin), anti-inflammatory agents, or mucolytics (e.g., hypertonic saline and/or dornase alfa).24 Nutritional treatments consist of high-calorie and high-fat diets and pancreatic enzyme replacement for patients with pancreatic insufficiency.18,24 Pulmonary exacerbations are treated with oral or IV antibiotics.25 These treatments do not halt, but only slow, the decline in lung function and the progression of disease.

CFTR Modulators

CFTR modulators are a class of medications that aim to correct the underlying defects of the CFTR protein. The CFTR modulators currently marketed in Canada or other jurisdictions are classified as follows:

Table 6 provides a summary of the CFTR modulators currently marketed or under review in Canada, the CFTR mutations and age ranges for which they have been approved by Health Canada, and their reimbursement status within the public drug programs. The currently available CFTR modulators are not approved for use in all patients with at least 1 F508del mutation. The approved indications currently cover patients who are homozygous for F508del mutations (Orkambi and Symdeko), patients who are heterozygous for the 508del mutation and have a residual function mutation (Symdeko), or patients who have a non-F508del gating mutation (Kalydeco). Hence, there is a subset of individuals who are heterozygous for the F508del mutation who will not be covered by the existing indications. In addition, the clinical benefit of some of the existing treatments (e.g., Orkambi) has been described as modest; therefore, there remains an unmet medical need for treatments with the potential to offer greater treatment effects and benefits.26 In 2019, CF Canada reported that 658 individuals (216 children and 442 adults) were receiving treatment with CFTR modulators. The number of patients receiving each treatment were 146 receiving Kalydeco, 368 receiving Orkambi, and 186 receiving Symdeko.1

Drug Under Review

Trikafta is a fixed-dose combination product containing ELX, TEZ, and IVA co-packaged with IVA. ELX-TEZ-IVA is available as both oral tablets and oral granules in the following dosing strengths:

ELX-TEZ-IVA is indicated for the treatment of CF in patients aged 2 years and older who have at least 1 F508del mutation in the CFTR gene. The sponsor has requested that the current submission for ELX-TEZ-IVA focus only on those patients aged 2 to 5 years using the new dosage format (i.e., orally administered granules). The sponsor has requested the reimbursement criteria presented in Table 3.

Table 3: Sponsor Requested Reimbursement Criteria

Category

Requested reimbursement criteria

Initiation criteria

  • Confirmed diagnosis with CF with at least 1 F508del mutation in the CFTR gene

  • Aged 2 to 5 years

Renewal criteria

  • For the initial renewal criteria, at least 1 of the following must be demonstrated after 12 months of treatment with ELX-TEZ-IVA:

    • A reduction in sweat chloride as defined by a sweat chloride concentration less than 60 mmol/L OR a reduction in sweat chloride of at least 30% from baseline

    • A decrease in the number of pulmonary exacerbations OR in the number of days that antibiotics need to be taken for pulmonary exacerbations OR in the number of courses of antibiotics that need to be taken for pulmonary exacerbations

    • No decline in BMI percentile

    • A clinical benefit as determined by a physician specializing in the treatment of CF

  • The sponsor requests that the initial renewal criteria be extended to 12 months from the current 6 months, which is consistent with the latest INESSS recommendation (August 5, 2022)27 and aligned with the recommendation from CF experts28

  • The physician must provide evidence of continued treatment benefit with ELX-TEZ-IVA for subsequent renewal of reimbursement

BMI = body mass index; CF = cystic fibrosis; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; INESSS = Institut national d’excellence en santé et services sociaux.

Source: Sponsor Summary of Clinical Evidence.

Mechanism of Action

ELX-TEZ-IVA is the third treatment specifically indicated for the treatment of patients with CF who have F508del mutation(s) in the CFTR gene. This mutation is believed to be associated with misfolding of the CFTR protein, which results in a lower quantity of CFTR expression at the cell surface. In addition to the reduced quantity of the protein, the mutation results in CFTR that is less stable and has defective channel gating compared with wild-type CFTR. Treatment with ELX-TEZ-IVA results in an increased quantity and improved function of the F508del-CFTR protein at the cell surface, through the following mechanisms:26,29,30

Recommended Dosage

The recommended dosing of ELX-TEZ-IVA is summarized in Table 4. For patients aged 2 to younger than 6 years who weigh less than 14 kg, the recommended dosage regimen is 1 packet of ELX 80 mg–TEZ 40 mg–IVA 60 mg granules in the morning and 1 packet of IVA 59.5 mg granules in the evening. For those who weigh at least 14 kg, the recommended dosage is 1 packet of ELX 100 mg–TEZ 50 mg–IVA 75 mg granules in the morning and 1 packet of IVA 75 mg granules in the evening.

Both tablets and granules are administered orally and should be taken approximately 12 hours apart with fat-containing food. Table 5 provides a summary of the recommended dosage adjustments for patients with hepatic insufficiency or those receiving concomitant treatment with moderate CYP3A inhibitors (e.g., fluconazole or erythromycin) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, or clarithromycin).

Table 4: Recommended Dosage

Age (weight)

Morning dose

Evening dose

2 to < 6 years (< 14 kg)

1 packet granules: ELX 80 mg–TEZ 40 mg–IVA 60 mg

1 packet granules: IVA 59.5 mg

2 to < 6 years (≥ 14 kg)

1 packet granules: ELX 100 mg–TEZ 50 mg–IVA 75 mg

1 packet granules: IVA 75 mg

6 to < 12 years (< 30 kg)

2 tablets: ELX 50 mg–TEZ 25 mg–IVA 37.5 mg

1 tablet: IVA 75 mg

6 to < 12 years (≥ 30 kg)

2 tablets: ELX 100 mg–TEZ 50 mg–IVA 75 mg

1 tablet: IVA 150 mg

≥ 12 years

2 tablets: ELX 100 mg–TEZ 50 mg–IVA 75 mg

1 tablet: IVA 150 mg

ELX = elexacaftor; IVA = ivacaftor; TEZ = tezacaftor.

Source: Product monograph.29

Table 5: Recommended Dosage Adjustments

Age

Condition

Dosage adjustment

Hepatic insufficiency

2 to < 6 years

Mild (Child-Pugh Class A)

No dose adjustments

Moderate (Child-Pugh Class B)

Use not recommended: Treatment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ELX-TEZ-IVA should be used with caution at a reduced dose, as follows:

  • Days 1 to 3: 1 packet of ELX-TEZ-IVA granules each day

  • Day 4: No dose

  • Days 5 to 6: 1 packet of ELX-TEZ-IVA granules each day

  • Day 7: No dose

Repeat dosing schedule each week. The evening dose of IVA should not be taken.

Severe (Child-Pugh Class C)

Should not be used

6 years and older

Mild (Child-Pugh Class A)

No dose adjustments

Moderate (Child-Pugh Class B)

Use not recommended: Treatment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, ELX-TEZ-IVA should be used with caution at a reduced dose, as follows: 2 ELX-TEZ-IVA tablets alternating with 1 ELX-TEZ-IVA tablet, taken in the morning on alternate days. The evening dose of IVA should not be taken.

Severe (Child-Pugh Class C)

Should not be used

CYP3A inhibitors

2 to < 6 years

Moderate CYP3A inhibitors

Morning: 1 packet ELX-TEZ-IVA granules (day 1); 1 packet IVA granules (day 2)

Evening: No dose

Strong CYP3A inhibitors

Morning: 1 packet ELX-TEZ-IVA granules (twice weekly; 3 to 4 days apart)

Evening: No dose

6 years and older

Moderate CYP3A inhibitors

Morning: 2 ELX-TEZ-IVA tablets (day 1); 1 IVA tablet (day 2)

Evening: No dose

Strong CYP3A inhibitors

Morning: 2 ELX-TEZ-IVA tablets (twice weekly; 3 to 4 days apart)

Evening: No dose

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; IVA = ivacaftor.

Source: Product monograph.29

Previous CADTH Reviews

This is the third submission to CADTH for ELX-TEZ-IVA. CADTH has previously reviewed ELX-TEZ-IVA for the treatment of CF in patients who have at least 1 F508del mutation in the CFTR gene for patients aged 12 years and older (final recommendation issued in August 2021) and patients aged 6 years and older (final recommendation issued in June 2022). For both of the previous reviews, the CADTH Canadian Drug Expert Committee recommended that ELX-TEZ-IVA be reimbursed with conditions.2,3 All the indications for ELX-TEZ-IVA were accepted as priority reviews by Health Canada.

CADTH has previously reviewed IVA alone for the following indications: patients aged 6 years and older who have a G551D mutation in the CFTR gene; patients aged 6 years and older who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R; and patients aged 18 years and older who have an R117H mutation in the CFTR gene.31-33 For each of these indications, the CADTH Canadian Drug Expert Committee recommended that IVA be reimbursed with conditions. LUM-IVA was previously reviewed for the treatment of CF in patients who are homozygous for the F508del mutation in the CFTR gene, and it received do not reimburse recommendations in 2016 and 2018.34,35 CADTH was unable to recommend reimbursement for TEZ-IVA as a submission was not filed by the sponsor.36

Key characteristics of ELX-TEZ-IVA and other CFTR modulators approved in Canada are summarized in Table 6.

Table 6: Key Characteristics of CFTR Modulators

Characteristic

Trikafta

(ELX-TEZ-IVA)

Orkambi

(LUM-IVA)

Symdeko

(TEZ-IVA)

Kalydeco

(IVA)

Mechanism of action

CFTR potentiator (IVA) and correctors (ELX and TEZ)

CFTR potentiator (IVA) and corrector (LUM)

CFTR potentiator (IVA) and corrector (TEZ)

CFTR potentiator

Indicationa

Patients aged ≥ 2 years who have at least 1 F508del mutation in the CFTR gene

Patients aged ≥ 1 year who are homozygous for the F508del mutation in the CFTR gene

Patients aged ≥ 12 years who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have 1 of the following CFTR mutations: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711 + 3A → G, S945L, S977F, R1070W, D1152H, 2789 + 5G → A, 3272-26A → G, and 3849 + 10kbC → T

Granules (25 mg, 50 mg, and 75 mg) are indicated for the treatment of patients with CF aged 4 months and older and weighing 5 kg to < 25 kg who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H

Tablets (150 mg) are indicated for the treatment of patients with CF aged 6 years and older and weighing 25 kg or more who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H

Route of administration

Oral tablets and granules

Oral tablets and granules

Oral tablets

Oral tablets and granules

Recommended dose

Granules:

  • 2 to < 6 years (< 14 kg): ELX 80 mg–TEZ 40 mg–IVA 60 mg (morning); IVA 59.5 mg (evening)

  • 2 to < 6 years (≥ 14 kg): ELX 100 mg–TEZ 50 mg–IVA 75 mg (morning); IVA 75 mg (evening)

Tablets:

  • 6 to < 12 years (< 30 kg): ELX 100 mg–TEZ 50 mg–IVA 75 mg (morning); IVA 75 mg (evening)

  • 6 to < 12 years (≥ 30 kg) or ≥ 12 years: ELX 200 mg–TEZ 100 mg–IVA 150 mg (morning); IVA 150 mg (evening)

Tablets:

  • 6 to 11 years: LUM 200 mg–VA 250 mg q.12.h.

  • ≥ 12 years: LUM 400 mg/IVA 250 mg q.12.h.

Granules

  • 2 to 5 years (< 14 kg): LUM 100 mg–IVA 125 mg q.12.h.

  • 2 to 5 years (≥ 14 kg): LUM 150 mg–IVA 188 mg q.12.h.

Morning: TEZ 100 mg–IVA 150 mg

Evening: IVA 150 mg

Tablets: IVA 150 mg q.12.h.

Granules:

  • 7 kg to < 14 kg: IVA 50 mg q.12.h.

  • 14 kg to < 25 kg: IVA 75 mg q.12.h.

Serious adverse effects or safety issues

Product monographs of each of the products include a warning about the risk of elevated transaminases (ALT and AST), and monitoring of liver function is recommended prior to initiating treatment, every 3 months during the first year of treatment, and annually thereafter.29,37-39

Product monograph recommends that ELX-TEZ-IVA not be used in patients with severe hepatic impairment; dosage reduction scenarios are provided in the product monographs for IVA, TEZ-IVA, and LUM-IVA.29,37-39

CADTH reviews

Aged ≥ 6 years: Reimburse with conditions3

Aged ≥ 12 years: Reimburse with conditions2

Do not reimburse34,35

Nonsubmission36

Reimburse with conditions31-33

ALT = alanine transaminase; AST = aspartate transaminase; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ELX = elexacaftor; IVA = ivacaftor; LUM = lumacaftor; LUM-IVA = lumacaftor-ivacaftor; q.12.h. = every 12 hours; TEZ = tezacaftor; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

aHealth Canada–approved indications.

Source: Product monographs for Trikafta, Orkambi, Symdeko, and Kalydeco.29,37-39

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH have been included in the Stakeholder section of this report.

One patient group, CF Canada, responded to CADTH’s call for patient input for the current review of ELX-TEZ-IVA, which is focused on patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene. CF Canada is a national not-for-profit corporation committed to improving and lengthening the lives of people living with CF through treatments, research, information, and support.

Information from CF Canada was based on focus groups with 6 parents of children younger than 5 years who have at least 1 copy of the F508del mutation; a survey of patients and caregivers with access to ELX-TEZ-IVA, which was conducted in 2021; medical and scientific publications; and the Canadian Cystic Fibrosis Registry. In addition, CF Canada used preliminary findings from phase I of the Global Burden of Disease study, which measures the burden of CF at the individual, family, health system, and societal levels and is considered one of the most comprehensive studies of the burden of CF in the world.

The patient group emphasized that CF has a tremendous impact on those living with the condition, their loved ones, health systems, and society. The most significant clinical impact is on the digestive system and the lungs. Patients experience progressive scarring of their airways and a progressive decline in lung function. Young children who grow older with CF may experience pulmonary exacerbations requiring weeks to months of hospitalization and IV antibiotics. Malnutrition and low BMI are also common consequences of CF among children aged 2 to 5 years. Patients may also experience CF-related comorbidities, such as CF-related diabetes and CF-related liver disease. In addition, CF has a significant impact on socialization, mental health, and isolation among patients and caregivers.

The patient input stated that managing CF requires a demanding treatment routine. As the disease progresses, more time and effort and frequent clinic visits and hospital stays are needed to manage the progressive and debilitating symptoms. This condition has a significant impact on patients’ and caregivers’ day-to-day activities and quality of life, affecting sleep quality, education, career, travel, relationships, and family dynamics and planning, and creates a huge financial burden for families.

According to the patient group input, an ideal treatment in CF would fully address the basic molecular defect in CF and restore normal chloride transport on the cell surface. Patients with CF and their loved ones are seeking treatments that can change the trajectory of the disease, reduce disease symptoms, improve sleep quality and energy levels, and improve both life expectancy and quality of life. Caregivers want their children to have a normal life with better lung function, fewer hospital stays and invasive medical procedures, and a reduction in the treatment burden of daily therapies.

In the patient group input, CF Canada’s clinical trials network (CF CanACT) emphasized the importance of early treatment of CF to prevent disease progression and irreversible damage. Extending access to ELX-TEZ-IVA for patients with CF aged 2 to 5 years would be congruent with the secondary prevention paradigm of CF care and would decrease the long-term burden of the disease.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the review of ELX-TEZ-IVA, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with CF, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows.

Unmet Needs

There are significant unmet therapeutic needs for patients living with CF. There are no treatments currently available that can effectively achieve the most important goals of therapy: prolong survival, prevent the need for lung transplant, slowing the decline in lung function over time, and reverse the course of the disease. In addition, the current standard treatments are burdensome for patients and their caregivers. Patients may not respond or may stop responding over time to the currently available treatments.

Place in Therapy

ELX-TEZ-IVA is a CFTR modulator that functions by increasing the amount of CFTR protein at the cell surface (ELX and TEZ) and by improving the transport of chloride through the CFTR protein (IVA). The mechanism of action for ELX-TEZ-IVA is attractive because it acts directly on the CFTR protein to address the defects that are responsible for the CF phenotype. ELX-TEZ-IVA would be added to existing treatments such as physiotherapy, mucolytics, anti-infectives, and anti-inflammatory treatments (such as azithromycin). The clinical experts noted that ELX-TEZ-IVA would replace earlier CFTR modulators that are significantly less effective (e.g., Orkambi or Kalydeco) and patients currently receiving those drugs would likely be switched to ELX-TEZ-IVA if they meet eligibility and age criteria.

It is anticipated that ELX-TEZ-IVA would be used as a preventive therapy, with the goal of initiating treatment before the patient develops significant lung disease. The current treatment paradigm would be significantly altered if ELX-TEZ-IVA can successfully prevent or delay progression to end organ disease (e.g., lung transplant). The clinical experts consulted by CADTH and those who responded to the call for clinician input noted that children aged between 2 and 5 years will often have structural lung disease (e.g., bronchial wall thickening, mucus plugging, or bronchiectasis) but that detection is challenging using the tools available to evaluate lung function in clinical practice (i.e., spirometry) or as part of a research protocol (e.g., LCI). These early stages of lung abnormalities can be visualized using CT; therefore, although younger patients with CF may demonstrate normal lung function, they have been shown through CT to often have underlying lung abnormalities, which will continue to progress.

All the clinicians who provided input into this review recommended initiating treatment with ELX-TEZ-IVA as soon as possible. This recommendation is aligned with the previously published Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients With Cystic Fibrosis, which also recommends that CFTR modulators be initiated at the youngest age possible, with the goal of attenuating disease progression and improving clinical status. All stakeholders agreed that there are no data to support withholding the initiation of CFTR modulator treatment until clinical symptoms of CF have developed.

Patient Population

The diagnosis of CF is not challenging in routine clinical practice. All provinces and territories have instituted newborn screening for CF, so most people with CF are now identified via newborn screening and have a confirmed diagnosis by 1 month of age (on average). SwCl testing is available and reliably used to confirm the screening test. The provinces and territories have slightly different testing algorithms and CFTR mutation screening panels; however, all provinces and territories have effective processes. Almost 100% of newly diagnosed infants would have both CFTR mutations identified. Infants who are not identified via newborn screening (i.e., false negatives) are usually diagnosed before 1 year of age, after the development of clinical symptoms of CF. There are clear diagnostic guidelines and very little variability in expert opinion. Misdiagnosis and underdiagnosis of CF is exceedingly rare in Canadian clinical practice.

ELX-TEZ-IVA could be used in every patient who meets the Health Canada–approved indication, regardless of their current or past treatment regimens. From a medical perspective, there is no rationale for a patient having to demonstrate an inadequate response or loss of response to prior therapies before initiating treatment with ELX-TEZ-IVA. It would be reasonable to require patients to complete important standard CF therapies at the same time as receiving treatment with ELX-TEZ-IVA. In clinical practice, eligible patients would be identified based on their CFTR genotype, and all patients would be expected to respond to the treatment.

For the expanded indication (i.e., patients aged 2 to 5 years), the clinical experts consulted by CADTH noted that nearly all patients would begin therapy with ELX-TEZ-IVA as soon as possible, provided it was safe to start treatment. The clinical experts emphasized that ELX-TEZ-IVA has been a transformative and disease-modifying therapy for CF and that it would not be appropriate to wait until the patient shows worsening symptoms, more frequent exacerbations, or a decline in lung function to initiate treatment with ELX-TEZ-IVA.

Applicability of Existing Reimbursement Criteria to Pediatric Patients

In discussions with CADTH, the sponsor noted that nearly all patients aged 12 years and older living in Canada who are eligible for treatment have begun therapy with ELX-TEZ-IVA (some may have elected to discontinue, but all who are interested have been given the opportunity to access the drug). The sponsor similarly stated that all patients aged 6 to 11 years living in Canada who wish to will have begun treatment with ELX-TEZ-IVA by the end of 2023. For those who have initiated treatment with ELX-TEZ-IVA, the sponsor noted that initial renewal criteria were met for all patients living in Canada who had started the therapy and wanted to continue (i.e., 100% of patients met the renewal criteria recommended by CADTH and/or applied by the public drug programs). The clinical experts consulted expressed general agreement with the sponsor’s position, noting that rates of initial access and renewal are very high within their individual clinics. With nearly all patients who are at least 6 years or older having met the initiation and renewal criteria, newly issued CADTH reimbursement criteria focusing exclusively on patients aged 2 to 5 years would effectively replace the previous criteria (i.e., although limited to patients aged 2 to 5 years, all older patients would have already qualified for initiation and renewal).

Table 7: CADTH-Recommended Reimbursement Conditions for Patients Aged 6 Years or Older

Category

Reimbursement conditions

Initiation

  • Confirmed diagnosis of CF with at least 1 F508del mutation in the CFTR gene

  • Aged 6 years and older

  • The following measurements must be completed prior to initiating treatment with ELX-TEZ-IVA:

    • Baseline spirometry measurements of FEV1 in litres and percent predicted (within the last 30 days)

    • Number of days treated with oral and/or IV antibiotics for pulmonary exacerbations in the previous 6 months, or the number of pulmonary exacerbations requiring oral and/or IV antibiotics in the previous 6 months

    • Number of CF-related hospitalizations in the previous 6 months

    • Weight, height, and BMI

    • CFQ-R respiratory domain score

  • Patients should be optimized with best supportive care for their CF at the time of initiation

  • The maximum duration of initial reimbursement is for 6 months

Renewal

  • For the first renewal, the physician must provide at least 1 of the following to demonstrate benefit after 6 months of treatment with ELX-TEZ-IVA:

    • Improvement in lung function by 5% of predicted or more, relative to baseline (baseline lung function should be measured within a 3-month period prior to beginning treatment with ELX-TEZ-IVA)

    • Decrease in the total number of days for which the patient received treatment with oral and/or IV antibiotics for pulmonary exacerbations compared with the 6-month period prior to initiating treatment, or decrease in the total number of pulmonary exacerbations requiring oral and/or IV antibiotics compared with the 6-month period prior to initiating treatment

    • Decrease in the number of CF-related hospitalizations at 6 months compared with the 6-month period prior to initiating ELX-TEZ-IVA treatment

    • No decline in BMI (BMI z score in children) at 6 months compared with the baseline BMI assessment

    • Improvement by 4 points or more in the CFQ-R respiratory domain score

  • The physician must provide evidence of continuing benefit from treatment with ELX-TEZ-IVA for subsequent renewal of reimbursement; subsequent renewals should be assessed annually

Discontinuation

Patient has undergone lung transplant

Prescribing

  • Prescribing of ELX-TEZ-IVA and monitoring of treatment response should be limited to CF specialists

  • ELX-TEZ-IVA should not be reimbursed in combination with other CFTR modulators

Feasibility of adoption

The feasibility of adoption of ELX-TEZ-IVA must be addressed

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; FEV1 = forced expiratory volume in the first second.

Baseline Measurements

Regarding the baseline measurements that must be completed prior to initiating treatment with ELX-TEZ-IVA, the clinical experts consulted by CADTH noted that the following baseline measurements currently recommended by CADTH would be problematic to implement, uninformative, and/or not relevant for patients aged 2 to 5 years:

Assessing Response to Treatment

Each of the end points are discussed below, with reflection on the applicability of the existing CADTH criteria to the expanded patient population (i.e., patients aged 2 to 5 years).

BMI and BMI Z Scores

The CADTH recommendation for patients aged 6 years and older included the following as one of the potential renewal criteria for ELX-TEZ-IVA: no decline in BMI (BMI z score in children) at 6 months compared with the baseline BMI assessment.

As with the previous review of ELX-TEZ-IVA, the clinical experts noted that 6 months would not be sufficient to accurately assess the response to treatment and that an assessment of BMI at 12 months would be more appropriate. The longer time was suggested to account for events that could temporarily reduce BMI (e.g., increased physical activity in summer months and growth spurts). It was strongly noted that discontinuation of ELX-TEZ-IVA in children with temporarily reduced BMI would not be clinically appropriate.

Pulmonary Exacerbations

The CADTH recommendation for patients aged 6 years and older included the following as one of the potential renewal criteria for ELX-TEZ-IVA: A decrease in the total number of days for which the patient received treatment with oral and/or IV antibiotics for pulmonary exacerbations compared with the 6-month period prior to initiating treatment, or a decrease in the total number of pulmonary exacerbations requiring oral and/or IV antibiotics compared with the 6-month period prior to initiating treatment.

Pulmonary exacerbations are less frequent in patients aged 2 to 5 years than in adults and adolescents. The clinical experts consulted by CADTH indicated that this is reflective of clinical practice, where these events are less common in children with relatively normal lung function. The clinical experts suggested that the above-noted renewal criterion would be problematic for the use of ELX-TEZ-IVA in patients aged 2 to 5 years. However, it was emphasized that patients who have not experienced a pulmonary exacerbation or those with a very low annual rate of pulmonary exacerbations would still benefit from the treatment. As with the criterion for BMI, it was noted that 12 months would be a more appropriate time frame for evaluating changes in pulmonary exacerbations.

CF-Related Hospitalizations

The CADTH recommendation for patients aged 6 years and older included the following as one of the potential renewal criteria for ELX-TEZ-IVA: Decreased number of CF-related hospitalizations at 6 months compared with the 6-month period prior to initiating ELX-TEZ-IVA treatment.

The clinical experts consulted by CADTH noted that CF-related hospitalization is infrequent and highly variable in patients aged 2 to 5 years. As such, this criterion would be very challenging to implement to evaluate response to ELX-TEZ-IVA for the purposes of reimbursement.

Sweat Chloride

The previous CADTH recommendation did not include SwCl testing as one of the initiation or renewal conditions for ELX-TEZ-IVA. The sponsor has requested that “reduction in sweat chloride” be included as a reimbursement condition for ELX-TEZ-IVA in the current review. In its comments on the draft report, the sponsor reported that a pooled analysis of phase III and open-label studies suggests that a reduction in SwCl is correlated with improvements in lung function, respiratory symptoms, BMI, and pulmonary exacerbations. However, the pediatric clinical experts agreed with the prior input from the reviews of ELX-TEZ-IVA in patients aged 6 to 11 years and 12 years and older, noting that SwCl testing should be not used to evaluate the response to ELX-TEZ-IVA for the purposes of drug reimbursement because it is not clearly predictive of clinically important outcomes and only reflects the mechanism of action of CFTR modulators like ELX-TEZ-IVA. It was noted that poor adherence with the treatment over a short period of time could increase SwCl (or, conversely, that a patient could only be adherent for a short period of time and still demonstrate considerable reductions in SwCl). The clinical experts also noted that access to SwCl testing can be challenging in some jurisdictions and that the time taken to receive the test results can fluctuate.

The clinical experts consulted by CADTH considered the SwCl renewal criterion proposed by the sponsor (i.e., a reduction in SwCl as defined by a SwCl concentration less than 60 mmol/L or by a reduction in SwCl of at least 30% from baseline) and did not believe this to be a clinically relevant measure for evaluating a patient’s response to treatment. However, they stated that the criterion could be acceptable if some form of objective criteria were also required for patients aged to 2 to 5 years.

CADTH noted that the previously published Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients With Cystic Fibrosis recommended a decrease in SwCl by 20% or 20 mmol/L from baseline at a follow-up visit 3 months after treatment initiation as a renewal criterion.

Discontinuing Treatment

The CADTH recommendation for patients aged 6 years and older stated that reimbursement should be discontinued in patients who have undergone lung transplant. ELX-TEZ-IVA is generally a well-tolerated treatment, and patients who began treatment before age 6 would be expected to remain on the therapy for many years if they continued to benefit. Some of these patients may eventually require a lung transplant; therefore, the discontinuation criterion remains relevant for a recommendation issued for the younger patient population. As was noted in previous reviews, given the expected benefit of ELX-TEZ-IVA on nutrition and growth end points, it is anticipated that clinicians would consider ELX-TEZ-IVA (balancing patient need with risk of possible drug interactions) in patients post–lung transplant. The sponsor expressed that ELX-TEZ-IVA has been shown to be beneficial in patients who have received a lung transplant through improvements in extrapulmonary manifestations of CF.

Prescribing Conditions

As with the previous review of ELX-TEZ-IVA, the only appropriate setting for initiation and monitoring of treatment with ELX-TEZ-IVA remains an adult or pediatric CF clinic. This treatment will typically be initiated and monitored in the outpatient clinic setting by a CF physician and the associated multidisciplinary team (e.g., specialists in respirology, infectious diseases, and gastroenterology). The experts noted that the drug may also be initiated in hospital. It would not be appropriate that a nonspecialty setting or physician would prescribe and monitor treatment with ELX-TEZ-IVA.

Continuation and Subsequent Renewals

The clinical experts emphasized that ELX-TEZ-IVA has the potential to modify the course of disease for patients with CF. When used in older patients, nearly all patients demonstrated sufficient clinical benefit to have reimbursement renewed by the public drug programs. The clinical experts noted that, although objective measures are challenging to implement in clinical practice for patients aged 2 to 5 years, these patients would likely benefit from initiating treatment. The clinical experts noted that subsequent renewals for ELX-TEZ-IVA can be achieved through communication that the patient is continuing to benefit from the treatment and that such an approach could be applied for younger patients, where obtaining meaningful baseline and follow-up measurements of objective criteria would be challenging.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group inputs received by CADTH have been included in the Stakeholder section of this report.

Three groups of clinicians responded to CADTH’s call for input: CF CanACT, the CF Canada Healthcare Advisory Council, and the Canadian Cystic Fibrosis Clinician groups. CF CanACT and the CF Canada Healthcare Advisory Council. CF CanACT operates under the auspices of CF Canada with the purpose of conducting clinical trials in CF and attracting research for new therapies to Canada. CF Canada is a national not-for-profit corporation committed to improving and lengthening the lives of people living with CF through treatments, research, information, and support. Information for this input was gathered from the Canadian Cystic Fibrosis Registry, outcomes of patients who have participated in clinical trials, scientific publications, and experience from treating individuals with CF who received CFTR modulators. In addition, CF Canada used information from the Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients With Cystic Fibrosis.

The input from the clinician groups identified the same unmet medical needs for patients with CF and potential place in therapy for the drug under review as the clinical experts consulted by CADTH.

According to clinician groups’ input, the treatment paradigm for CF in children aged 2 to 5 years is lifelong. It consists of nonmodulator treatments, which include high-calorie, high-fat, high-protein diets; digestive medications; and airway clearance treatments. Consequently, many of these treatments start at the time of diagnosis (including in infancy) and continue every day throughout life. Medications commonly used in CF include antibiotics, mucolytics, bronchodilators, pancreatic enzymes, fat-soluble vitamins, insulin for people with CF-related diabetes, ursodiol for liver disease, and chest physiotherapy. There are also CFTR modulator therapies, which are the first commercially available therapies targeted at correcting the basic defect in CF by improving the production and function of the abnormal CFTR protein. The first-generation (IVA) and second-generation (LUM-IVA and IVA-TEZ-IVA) modulators had a modest but important clinical effect, but the response to the third-generation modulator (ELX-TEZ-IVA) is substantially greater.

Clinician groups noted that there are significant unmet therapeutic needs for patients living with CF. Available treatments address the symptoms and complications of CF and attempt to slow down the eventual fatal progression of the disease without effectively addressing the root cause or reversing the course of the disease. The treatments also have significant side effects and numerous drug interactions. In addition, the current standard treatments are burdensome for patients and their caregivers, which affects medication adherence and the mental health and quality of life of patients and caregivers.

The clinician groups noted that ELX-TEZ-IVA is an improvement on the existing CFTR modulators and the most effective. It addresses the underlying disease process and is complementary to the existing standard of care for CF, which would potentially delay disease progression and thus delay the need for other therapies, including lung transplant. According to the clinician groups, any patient with CF who has at least 1 copy of the F508del mutation could potentially benefit from ELX-TEZ-IVA.

The 2 clinician groups indicated that the outcomes of interest are those that can be assessed during routine visits, which include BMI, frequency of pulmonary exacerbations, number of courses of antibiotics, SwCl levels, and sinopulmonary symptoms. CF Canada added laboratory tests to follow parameters associated with potential side effects (liver enzymes, creatine kinase), sputum microbiology, quality of life questionnaires and mental health screening, fecal elastase testing, and ophthalmological examination.

The clinician groups noted that discontinuation of therapy should be considered in patients with severe side effects, allergies, or the development of signs of worsening liver disease. CF Canada suggested the treatment should also be discontinued for patients aged 2 to 5 years if the patient is not responding to medication. The clinician groups stated that the treatment of patients with CF with ELX-TEZ-IVA should be limited to CF specialists practising at CF clinics.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 8.

Table 8: Summary of Drug Plan Input and Clinical Expert Response

Drug program implementation questions

Clinical expert response

Relevant comparators

Are there any physiological reasons that would caution the extrapolation of data from patients with CF aged 6 years and older treated with ELX-TEZ-IVA to patients aged 2 to 5 years?

The clinical experts consulted by CADTH and those who provided input to CADTH through the call for clinician input all support starting ELX-TEZ-IVA as soon as possible. The clinical experts supported the extrapolation of efficacy data and noted that the data in patients aged 2 to 5 years did not raise additional concerns regarding the safety of ELX-TEZ-IVA.

Can patients being treated with LUM-IVA (Orkambi) be switched to ELX-TEZ-IVA? If so, are there any special considerations (e.g., additional monitoring)?

The clinical experts consulted by CADTH noted that ELX-TEZ-IVA would replace earlier CFTR modulators that are significantly less effective (e.g., Orkambi) and that patients currently receiving those drugs would likely be switched to ELX-TEZ-IVA if they met eligibility and age criteria.

The clinical experts noted that patients with CF are monitored in specialized clinics and that switching from LUM-IVA to ELX-TEZ-IVA would not be anticipated to pose challenges for patients or health care providers.

Are there specific patient populations in which switching to ELX-TEZ-IVA would be inappropriate?

The clinical experts consulted by CADTH noted that switching would be appropriate for all patients receiving alternative CFTR modulators, provided they met the eligibility and age criteria.

Considerations for initiation of therapy

Can the clinical experts confirm that multiple breath washout tests (e.g., LCI2.5) are only available at specialty clinics at children’s hospitals and not available at all pulmonary function testing clinics?

This measurement is not currently used in routine Canadian clinical practice and would not be practical for the purposes of determining eligibility for ELX-TEZ-IVA reimbursement.

If children aged 2 to 5 years cannot complete an accurate spirometry (to obtain ppFEV1), and the CFQ-R is not validated in this age group, are there other parameters or biomarkers that could be measured at the time of treatment initiation for the purposes of evaluating response to treatment?

The clinical experts noted that clinically meaningful objective measures of response to ELX-TEZ-IVA are challenging to implement in clinical practice, as patients aged 2 to 5 years often do not show CF symptoms that can be objectively measured in practice using the tools and instruments recommended for those aged 6 years and older. In addition, they are too young for spirometry measurements to be taken, and obtaining baseline measurements of pulmonary exacerbation or CF-related hospitalization is problematic due to low frequency and interpatient variability.

Among the criteria currently recommended by CADTH, the BMI z score is the only baseline measurement that would be captured as part of routine practice for patients aged 2 to 5 years.

With respect to biomarkers, the clinical experts emphasized the following important considerations regarding sweat chloride:

  • Sweat chloride testing is not considered to be a clinically relevant measurement for determining if a patient is benefiting from a treatment.

  • If a requirement for reimbursement involves mandatory repeated sweat chloride testing as an objective validation measure for renewal, the existing capacity for sweat chloride testing would likely be quickly overwhelmed in all provinces. There is insufficient infrastructure in place to perform repeated sweat chloride testing in all patients with CF with at least 1 F508del mutation.

Considerations for continuation or renewal of therapy

Are there any clinical benefits that have not been described in the sponsor’s renewal criteria or in the previous CDEC-recommended renewal criteria that should be considered for use as renewal criteria?

The clinical experts emphasized that ELX-TEZ-IVA has the potential to modify the course of disease for patients with CF. When used in older patients, nearly all patients demonstrated sufficient clinical benefit to have reimbursement renewed by the public drug programs. The clinical experts noted that, although objective measures are challenging to implement in clinical practice for patients aged 2 to 5 years, these patients would likely benefit from initiating treatment.

The clinical experts noted that subsequent renewals for ELX-TEZ-IVA can be achieved through communication that the patient is continuing to benefit from the treatment and that such an approach could be applied for younger patients, where obtaining meaningful baseline and follow-up measurements of objective criteria would be challenging.

Can the renewal criteria for patients aged 6 years and older be used for patients aged 2 to 5 years (except for FEV1 and/or CFQ-R)?

The clinical experts consulted by CADTH noted the following regarding the application of the existing reimbursement criteria to patients aged 2 to 5 years:

  • BMI and BMI z scores: 6 months would not be sufficient to accurately assess the response to treatment, and an assessment of BMI at 12 months would be more appropriate. The longer time was suggested to account for events that could temporarily reduce BMI (e.g., increased physical activity in summer months and growth spurts). It was strongly noted that discontinuation of ELX-TEZ-IVA in children with temporarily reduced BMI would not be clinically appropriate. In these younger patients, who are not necessarily showing a reduction in age-standardized growth, clinicians are focused on maintaining stability and would not anticipate improvements from baseline measures.

  • Pulmonary exacerbations: Pulmonary exacerbations are less frequent in patients aged 2 to 5 years than in adults and adolescents. The clinical experts indicated that this is reflective of clinical practice, where these events are less common in children with relatively normal lung function. The clinical experts suggested that previously recommended renewal criterion would be problematic for the use of ELX-TEZ-IVA in patients aged 2 to 5 years. However, it was emphasized that patients who have not experienced a pulmonary exacerbation or those with a very low annual rate of pulmonary exacerbations would still benefit from the treatment. As with the criterion for BMI, it was noted that 12 months would be a more appropriate time frame for evaluating changes in pulmonary exacerbations.

  • CF-related hospitalizations: The clinical experts consulted by CADTH noted that CF-related hospitalization is infrequent and highly variable in patients within the 2 to 5-year age range. As such, this criterion would be very challenging to implement to evaluate response to ELX-TEZ-IVA for the purposes of reimbursement.

If a patient starts ELX-TEZ-IVA between the ages of 2 and 5 years, when they turn 6 years, can they just follow renewal criteria for the 6 years and older population?

The clinical experts consulted by CADTH noted that the application of the criteria for older patients may be challenging as those aged 2 to 5 years.

Considerations for discontinuation of therapy

The previous CDEC recommendation for ELX-TEZ-IVA included a criterion that reimbursement should be discontinued in patients who have undergone lung transplant. Is this discontinuation criterion appropriate for patients aged 2 to 5 years?

ELX-TEZ-IVA is generally a well-tolerated treatment, and patients who began treatment before age 6 years would be expected to remain on the therapy for many years if they continued to benefit. Some of these patients may eventually require a lung transplant; therefore, the discontinuation criterion remains relevant for a recommendation issued for the younger patient population.

Are there other discontinuation criteria that public drug plans should consider?

The clinical experts consulted by CADTH did not identify additional objective discontinuation criteria for ELX-TEZ-IVA reimbursement.

Considerations for prescribing of therapy

Currently, there are CDEC-recommended prescribing criteria for the treatment of CF in patients aged 6 years and older who have at least 1 F508del mutation in the CFTR gene:

  • Prescribing of ELX-TEZ-IVA and monitoring of treatment response should be limited to CF specialists.

  • ELX-TEZ-IVA should not be reimbursed in combination with other CFTR modulators.

Are the above prescribing criteria appropriate for patients aged 2 to 5 years?

The only appropriate setting for initiation and monitoring of treatment with ELX-TEZ-IVA remains an adult or pediatric CF clinic. This treatment will typically be initiated and monitored in the outpatient clinic setting by a CF physician and the associated multidisciplinary team (e.g., specialists in respirology, infectious diseases, and gastroenterology). The experts noted that the drug may also be initiated in hospital. It would not be appropriate that a nonspecialty setting or physician would prescribe and monitor treatment with ELX-TEZ-IVA.

ELX-TEZ-IVA would not be prescribed in combination with another CFTR modulator.

Generalizability

Is there a clinical desire to use ELX-TEZ-IVA in patients younger than 2 years?

The clinical experts consulted by CADTH and those who provided input to CADTH through the call for clinician input all supported starting ELX-TEZ-IVA as soon as possible.

Care provision issues

No questions.

System and economic issues

No questions.

BMI = body mass index; CDEC = CADTH Canadian Drug Expert Committee; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; FEV1 = forced expiratory volume in the first second; LCI2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of ELX-TEZ-IVA in the treatment of CF in patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene. The focus will be placed on comparing ELX-TEZ-IVA to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of ELX-TEZ-IVA is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. The second section includes sponsor-submitted long-term extension studies (not submitted). The third section includes indirect evidence from the sponsor (derived from a previous submission for ELX-TEZ-IVA). The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence (not submitted).

Included Studies

Clinical evidence from the following are included in the CADTH review and appraised in this document:

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Description of Study

Characteristics of the included study are summarized in Table 9.

Table 9: Details of the Study Included in the Systematic Review

Study characteristic

Study 111 (NCT04537793)

Design and population

Study design

Phase III, 2-part (Parts A and B), open-label, multicentre trial

Locations

Part A: 7 sites: US

Part B: 22 sites: US, Australia, Canada, Germany, UK

Patient enrolment dates

Start date: November 2020 (Part A ended March 2021; Part B began July 2021)

End date: June 2022

Randomized

All patients received ELX-TEZ-IVA

Part A: N = 18

Part B: N = 75

Inclusion criteria

Part A: Male and female patients with CF aged 2 to 5 years (inclusive) with F/MF or F/F genotypes.

Patients must have weighed ≥ 14 kg on day 1.

Part B: Male and female patients with CF aged 2 to 5 years (inclusive) who have at least 1 F508del mutation in the CFTR gene or another ELX-TEZ-IVA–responsive CFTR mutation.

Patients must have weighed ≥ 10 kg at the screening visit.

Exclusion criteria

Patients with clinically significant cirrhosis or portal hypertension

Patients with lung infections caused by organisms associated with a rapid decline in pulmonary status

Patients who have undergone solid organ or hematological transplant

Drugs

Intervention

Part A: ≥ 14 kg: ELX 100 mg q.d., TEZ 50 mg q.d., IVA 75 mg q.12.h.

Part B:

  • ≥ 14 kg: ELX 100 mg q.d., TEZ 50 mg q.d., IVA 75 mg q.12.h.

  • ≥ 10 kg to < 14 kg: ELX 80 mg q.d., TEZ 40 mg q.d., IVA 60 mg in the morning and 59.5 mg in the evening

Comparator(s)

None

Study duration

Screening phase

Part A: 28 days

Part B: 28 days

Treatment phase

Part A: 15 days

Part B: 24 weeks

Follow-up phase

Part A: 28 days

Part B: 28 days

Outcomes

Primary end point

Part A:

  • PK parameters of ELX, TEZ, IVA, and relevant metabolites

  • Safety and tolerability assessments as determined by AEs, clinical laboratory values, standard 12‑lead electrocardiograms, vital signs, and pulse oximetry

Part B: Safety and tolerability assessments as determined by AEs, clinical laboratory values, standard 12-lead electrocardiograms, vital signs, and pulse oximetry

Secondary and exploratory end points

Secondary

Part B:

  • PK parameters of ELX, TEZ, IVA, and relevant metabolites

  • Absolute change in sweat chloride from baseline through 24 weeks

  • Absolute change in LCI2.5 from baseline through 24 weeks

Exploratory

Part B:

  • Number of pulmonary exacerbations and CF‑related hospitalizations through 24 weeks

  • Absolute change in weight and weight‑for‑age z score from baseline at 24 weeks

  • Absolute change in height and height‑for‑age z score from baseline at 24 weeks

  • Absolute change in BMI and BMI‑for‑age z score from baseline at 24 weeks

Publication status

Publications

Goralski et al. (2023)40

Clinicaltrials.gov (NCT04537793)41

AE = adverse event; BMI = body mass index; CF = cystic fibrosis; ELX = elexacaftor; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; IVA = ivacaftor; LCI2.5 = lung clearance index; PK = pharmacokinetic; q.d. = every day; q.12.h = every 12 hours; TEZ = tezacaftor.

Source: Sponsor’s Summary of Clinical Evidence.

Study Design

The clinical development program for ELX-TEZ-IVA in patients aged 2 to 5 years was designed to demonstrate similar pharmacokinetic exposures and safety as for older patients, with the efficacy demonstrated in patients aged 6 years and older extrapolated to that in patients aged 2 to 5 years. Study 111 (NCT04537793) was an interventional, phase III, nonrandomized, 2-part (A and B), open-label study. In total, 18 patients in Part A and 75 patients in Part B were treated with ELX-TEZ-IVA.40

Part A

The primary objectives of Part A were to evaluate the pharmacokinetics of ELX, TEZ, and IVA when dosed in triple combination and to evaluate the safety and tolerability of ELX-TEZ-IVA.40 This part of Study 111 was initiated on November 19, 2020 (when the first patient gave informed consent) and concluded on March 5, 2021 (when the last patient completed their final visit). This part of the study involved a 4-week (28-day) screening period to assess patients for study eligibility and characteristics at baseline, a 15-day treatment period, and a 4-week (28-day) posttreatment follow-up visit to assess safety and tolerability (Figure 1).40 Part A was conducted at 7 study sites in the US.

Figure 1: Design of Part A of Study 111

Part A of Study 111 includes a 28-day screening period then a 15-day treatment period with ELX-TEZ-IVA followed by a safety follow-up visit 28 days after last dose.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor.

Source: Clinical Study Report.42

Part B

The primary objective of Part B was to assess safety and tolerability in 75 patients treated with ELX-TEZ-IVA. Secondary objectives included assessing pharmacokinetics, pharmacodynamics, and efficacy.40 The study design of Part B involved a 4-week (28-day) screening period to assess patients for study eligibility and characteristics at baseline, a 24-week treatment period, and a 4-week (28-day) posttreatment follow-up visit to assess safety and tolerability (provided patients had not enrolled in the associated open-label extension study, NCT0515331743) (Figure 2).40 A total of 22 sites were used to conduct Part B, 2 of which were in Canada (The Hospital for Sick Children, Toronto, and British Columbia Children’s Hospital, Vancouver).

Figure 2: Design of Part B of Study 111

Figure shows the design of Part B of Study 111, including the screening period, treatment period, and safety follow-up visit. Patients could enter an open-label extension phase at week 24.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor.

a The safety follow-up visit was not required for patients who enrolled in the optional open-label extension safety study within 28 days of the last scheduled visit in the treatment period.

Source: Clinical Study Report.42

Populations

Inclusion and Exclusion Criteria

Patients were eligible to be included in Study 111 if they had received a diagnosis of CF and were aged 2 to 5 years (inclusive). In Part A, eligible patients were required to have a F508del-CFTR mutation that was either F/F or F/MF. In Part B, patients were eligible if they had an F508del-CFTR mutation or another ELX-TEZ-IVA–responsive CFTR mutation. Patients were required to be at least 14 kg in Part A and at least 10 kg in Part B. Patients were excluded from the study if they had any comorbidities that could impact treatment outcomes or if they had received a prior hematological or solid organ transplant.

Interventions

Study 111 was a single-arm, sequential assignment trial. Patients in Part A and Part B received ELX-TEZ-IVA for 15 days and 24 weeks, respectively, with a safety follow-up visit conducted 4 weeks after treatment cessation, provided patients had not enrolled in the associated open-label extension study (NCT05153317) within 28 days of their final visit during the treatment period of Part B.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 10; the table is followed by descriptions of the outcome measures. The summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as on any outcomes identified as important to this review according to the clinical experts consulted by CADTH and on stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected the end points considered most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Sweat Chloride

SwCl samples were obtained from patients using an approved collection device. At each time point, 2 samples were collected, 1 from each of the patient’s arms, and sent to a central laboratory for analysis.42 All the included studies evaluated absolute change from baseline in SwCl. Absolute change from baseline in SwCl through 24 weeks was a secondary end point in Study 111.42

Lung Clearance Index

The LCI is a multiple breath washout test that estimates the number of lung volume turnovers required to clear the lung of an inert gas.44 The test is sensitive to changes in the small airways and may be able to detect pulmonary disease in patients with normal FEV1.8,45 LCI2.5 represents the number of lung turnovers required to reduce the end tidal nitrogen concentration to 2.5% of the starting value. The LCI assessments were derived from multiple breath washout testing using nitrogen. Absolute change from baseline in LCI2.5 was a secondary end point of Study 111.42

Pulmonary Exacerbations

Pulmonary exacerbations were evaluated as an exploratory end point in Study 111.42 Pulmonary exacerbations were defined as newly initiated or changed treatment with oral, inhaled, or IV antibiotics and fulfillment of 1 criterion from List A or of 2 criteria from List B (Table 11), within the period from 3 days before the antibiotic start date through to the antibiotic stop date.42

Table 10: Outcomes Summarized From Study 111

Outcome measure

Time point

Type of outcome

Statistical model

Adjustment factors

Handling of missing data

Sensitivity analyses

Safety and tolerability

28 weeksa

Primary

Descriptive statistics

Not applicable

Not applicable

Not applicable

Sweat chloride, LCI2.5

24 weeks

Secondary

MMRM

  • Baseline value

  • CFTR genotype (F/F or F/MF)

  • Assumed missing at random

  • No imputation of missing data

No sensitivity analyses

Pulmonary exacerbations

24 weeks

Exploratory

Descriptive statistics (annualized event rate)

Not applicable

Not applicable

Not applicable

CF-related hospitalizations

24 weeks

Exploratory

Weight

24 weeks

Exploratory

MMRM

  • Baseline value

  • CFTR genotype (F/F or F/MF)

  • Assumed missing at random

  • No imputation of missing data

No sensitivity analyses

Weight z score

Height

Height z score

BMI

BMI z score

BMI = body mass index; CF = cystic fibrosis; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI2.5 = lung clearance index; MMRM = mixed-effects model for repeated measures.

aSafety was assessed at a separate visit occurring 4 weeks after the end of the treatment period.

Source: Clinical Study Report.42

Table 11: Pulmonary Exacerbation Criteria

List

Number of criteria

Criteria

List A

Must meet 1 of these criteria

  • Decrease in FEV1 ≥ 10% from highest value in the 6 months before the first dose; unresponsive to albuterol (if applicable)

  • Oxygen saturation < 90% on room air or ≥ 5% decrease from baseline

  • New lobar infiltrate(s) or atelectasis on chest X-ray

  • Hemoptysis (more than streaks on more than 1 occasion in past week)

List B

Must meet 2 of these criteria

  • Increased work of breathing or respiratory rate (duration ≥ 3 days)

  • New or increased adventitial sounds on lung examination (duration ≥ 3 days)

  • Weight loss ≥ 5% from highest value or decrease across 1 major percentile for age in past 6 months

  • Increased cough (duration ≥ 3 days)

  • Worked harder to breathe during physical activity (duration ≥ 3 days)

  • Increased chest congestion or change in sputum (duration ≥ 3 days)

FEV1 = forced expiratory volume in the first second.

Source: Clinical Study Report.42

CF-Related Hospitalizations

Complications related to CF that led to hospitalization were recorded in Study 111, in terms of both the number of patients with a hospitalization event and the total number of events. The yearly event rate was also calculated.

Growth Parameters (BMI, Weight, Height, Z Scores)

Absolute change from baseline in BMI, BMI z score, weight, weight z score, height, and height z score at 24 weeks were exploratory end points in Study 111.

Adverse Events

AEs were defined as any untoward medical occurrence in a patient during the study, including newly occurring events or worsening of pre-existing conditions (e.g., increase in severity or frequency). An AE was considered serious if it resulted in any of the following outcomes: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability, incapacity, congenital anomaly, or birth defect; or an important medical event that jeopardized the patient or required medical or surgical intervention to prevent one of the aforementioned outcomes.

Statistical Analysis

Sample Size and Power Calculation

For Part B, no formal power calculation was performed. The sample size of approximately 70 patients was deemed adequate to meet the primary outcome of safety and tolerability. Assuming a dropout rate of 10% to 20%, approximately 56 to 63 patients were expected to complete the study.

Statistical Testing

As discussed above, an MMRM approach was used to assess the mean absolute change in SwCl from baseline through week 24.46 SwCl values obtained from all available visits up to week 24 were included in the model, with visit as a fixed effect and baseline SwCl and genotype group (F/F or F/MF) as covariates.46 The model was estimated using restricted maximum likelihood.46 Denominator degrees of freedom for the F test of fixed effects were estimated using the Kenward-Roger approximation. An unstructured covariance structure was used to model the within-patient errors.46 If the model estimation did not converge, a compound symmetry covariance structure was used instead.46 Conditional on the observed data and covariates, missing data were assumed to be missing at random; consequently, no imputation of missing data was performed. The results obtained from the model were the average treatment effect through week 24, estimated using all postbaseline visits up to and including week 24.46 The estimated mean change from baseline in SwCl through week 24, along with the corresponding 2-sided 95% CI and P value, was provided.46

The same MMRM structure was then applied to assess mean absolute change in LCI2.5 from baseline through week 24 and to analyze the absolute change from baseline in weight, height, BMI, and associated z scores at week 24 (full analysis set [FAS], Part B).46 Given that efficacy was a secondary objective of Study 111, no adjustments were made for multiplicity and all P values were considered nominal.46

Descriptive analyses were performed for all other end points in Part B.46

Multiple Testing Procedure

There was no adjustment for multiplicity for any of the end points in Study 111.

Subgroup Analyses

The absolute change in SwCl and LCI2.5 from baseline through week 24 was analyzed in each genotype subgroup (i.e., F/F and F/MF). Similar MMRMs as specified in the Statistical Testing section were conducted for each subgroup, with genotype removed from the covariates.46

Analysis Populations

A summary of analysis sets defined in Study 111 is presented in Table 12.

Table 12: Analysis Populations of Study 111

Population

Definition

Application

All patients set

All patients who were enrolled or who received at least 1 dose of ELX-TEZ-IVA

Individual patient data listings and disposition summary tables

Safety set

All patients who received at least 1 dose of ELX-TEZ-IVA

All safety analyses

Full analysis set

All enrolled patients who carried the intended CFTR allele mutation and received at least 1 dose of ELX-TEZ-IVA

Baseline characteristics; all efficacy analyses (unless specified)

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

A summary of patient dispositions for Study 111, Part B, is presented in Table 13. A total of 75 patients were enrolled and received at least 1 dose of ELX-TEZ-IVA; 74 patients (98.7%) completed the study. One (1.3%) patient discontinued due to an AE.

Table 13: Summary of Patient Disposition From Study 111 Part B

Patient disposition

ELX-TEZ-IVA (N = 75)

Screened, n

NR

Reason for screening failure, n (%)

NR

Enrolled, n

75

Discontinued from study, n (%)

1 (1.3)

Rolled over into extension study, n (%)

71 (94.7)

Reason for discontinuation, n (%)

  Adverse events

1 (1.3)

  Lost to follow-up

0 (0)

  Consent withdrawal

0 (0)

FAS, N

|| || ||||

Safety, N

75

FAS = full analysis set; NR = not reported.

Source: Clinical Study Report.42

Baseline Characteristics

The baseline characteristics outlined in Table 14 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. The mean age of the patients was 4.1 years, and over half (54.7%) of patients were female. Twenty-three (30.7%) patients had an F/F genotype, and 52 (69.3%) had an F/MF genotype. The baseline values for mean SwCl and mean LCI2.5 were 100.7 mmol/L and 8.41, respectively.

Table 14: Summary of Baseline Characteristics From Study 111 Part B

Characteristic

ELX-TEZ-IVA (N = 75)

Sex, n (%)

Male

34 (45.3)

Female

41 (54.7)

Age (years)

Mean (SD)

4.1 (1.1)

Median (range)

4.0 (2.1 to 6.0)

≥ 2 to < 3 years, n (%)

11 (14.7)

≥ 3 to < 4 years, n (%)

27 (36.0)

≥ 4 to < 5 years, n (%)

22 (29.3)

≥ 5 to < 6 years, n (%)

15 (20.0)

Geographic region, n (%)

North America

|| || |||||| || ||||

Europe and Australia

| || || || ||| || ||||

CFTR genotype, n (%)

F/F

23 (30.7)

F/MF

52 (69.3)

Other

0 (0.0)

Baseline values, mean (SD)

Weight (kg)

16.5 (3.2)

Weight z score

–0.07 (0.89)

Height (cm)

101.8 (9.2)

Height z score

–0.09 (1.10)

BMI (kg/m2)

15.79 (1.06)

BMI z score

0.09 (0.85)

Sweat chloride (mmol/L)

100.7 (11.2)

LCI2.5 (mmol/L)

8.41 (1.48)

Prior CF medications, n (%)

Prior use of CFTR modulator

10 (13.3)

Prior use of dornase alfa

33 (44.0)

Prior use of azithromycin

8 (10.7)

Prior use of inhaled antibiotic

8 (10.7)

Prior use of any bronchodilator

51 (68.0)

Prior use of any inhaled bronchodilator

51 (68.0)

Prior use of any inhaled hypertonic saline

37 (49.3)

Pseudomonas aeruginosa infection, n (%)

Infection in 2 years prior to screening

14 (18.7)

BMI = body mass index; CF = cystic fibrosis; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI2.5= lung clearance index; SD = standard deviation.

Source: Clinical Study Report.42

Exposure to Study Treatments

Table 15 summarizes the exposure to ELX-TEZ-IVA in Study 111.

Table 15: Summary of Patient Exposure From Study 111 Part B

Exposure

ELX-TEZ-IVA (N = 75)

Total (patient-weeks)

|| || ||||

Duration, mean (SD)

| || || || || || |

Duration, median (range)

| || || || || || || | |

Adherence (%)

| || |

SD = standard deviation.

Source: Clinical Study Report.42

Concomitant Medications and Co-Interventions

A summary of concomitant medications used among patients in Part B of Study 111 is presented in Table 16. The most common concomitant medications were typically used for the management of CF. Pancreatin, sodium chloride, and salbutamol were the most commonly used concomitant medications in Part B.

Table 16: Summary of Concomitant Medications Used in Study 111 Part B

Concomitant medication, n (%)

ELX-TEZ-IVA (N = 75)

| || || || || || || || || || || || |

|| || |||| || ||

|| || || || || || || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || |||| || |||| || |||| || |||| || |||| || ||||

|| || |||| || ||

|| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || |||| || ||

|| || |||| || ||

|| || |||| || ||

|| || |||| || ||

Source: Clinical Study Report.42

Efficacy

Key efficacy outcomes assessed in Study 111 included SwCl concentration, LCI2.5, number of pulmonary exacerbations, number of CF-related hospitalizations, as well as body weight, height, BMI, and their respective z scores (Table 17). Specific outcomes are discussed in further detail in the following subsections.

Table 17: Summary of Key Efficacy Results From Study 111 Part B

End point

ELX-TEZ-IVA (N = 75)

Sweat chloride

Patients contributing to the analysis, n

69

Baseline (mmol/L), mean (SD)

100.7 (11.2)

Change from baseline (mmol/L), mean (95% CI)

–57.9 (–61.3 to –54.6)

Treatment group difference versus control (95% CI)

NR

P value

< 0.0001

LCI2.5

Patients contributing to the analysis, n

50

Baseline, mean (SD)

8.41 (1.48)

Change from baseline, mean (95% CI)

–0.83 (–1.01 to –0.66)

Treatment group difference versus control (95% CI)

NR

P value

< 0.0001

Pulmonary exacerbations

Patients contributing to the analysis, n

75

Patients with events, n (%)

12 (16.0)

Number of events

12

Observed event rate per year

0.32

P value

NR

CF-related hospitalizations

Patients contributing to the analysis, n

|| || ||||

Patients with events, n (%)

|| || ||||

Number of events

|| || ||||

Observed event rate per year

|| || ||||

P value

|| || ||||

Body weight

Patients contributing to the analysis, n

|| || ||||

Baseline (kg), mean (SD)

|| || ||||

Change from baseline (kg), mean (95% CI)

|| || ||||

Treatment group difference versus control (95% CI)

|| || ||||

P value

|| || ||||

Body weight z score

Patients contributing to the analysis, n

|| || ||||

Baseline, mean (SD)

|| || ||||

Change from baseline, mean (95% CI)

|| || ||||

Treatment group difference versus control (95% CI)

|| || ||||

P value

|| || ||||

Height

Patients contributing to the analysis, n

|| || ||||

Baseline (cm), mean (SD)

|| || ||||

Change from baseline (cm), mean (95% CI)

|| || ||||

Treatment group difference versus control (95% CI)

|| || ||||

P value

|| || ||||

Height z score

Patients contributing to the analysis, n

75

Baseline, mean (SD)

|| || ||||

Change from baseline, mean (95% CI)

–0.06 (–0.11 to 0.00)

Treatment group difference versus control (95% CI)

NR

P value

NR

BMI

Patients contributing to the analysis, n

75

Baseline (kg/m2), mean (SD)

15.79 (1.06)

Change from baseline (kg/m2), mean (95% CI)

0.03 (–0.10 to 0.17)

Treatment group difference versus control (95% CI)

NR

P value

NR

BMI z score

Patients contributing to the analysis, n

75

Baseline, mean (SD)

0.09 (0.85)

Change from baseline, mean (95% CI)

0.10 (0.00 to 0.20)

Treatment group difference versus control (95% CI)

NR

P value

NR

BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; LCI2.5 = lung clearance index; NR = not reported; SD = standard deviation.

Source: Sponsor’s Summary of Clinical Evidence.

Sweat Chloride Concentration

In Study 111, SwCl concentration was reported for the FAS as well as for the F/F and F/MF subgroups. The mean baseline concentration was calculated across 71 patients in the FAS (n = 75) and was applied to the F/F (n = 23) and F/MF (n = 52) subgroups (100.7 mmol/L; standard deviation [SD] = 11.2). In the FAS, treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in SwCl by week 4 that was sustained throughout the treatment period (Figure 3). The within-group LS mean absolute change from baseline through week 24 was –57.9 mmol/L (95% CI, –61.3 to –54.6; nominal P < 0.0001). A numerically larger reduction in SwCl was observed in the F/F group (–70.0 mmol/L; 95% CI, –75.4 to –64.5) than in the F/MF group (–52.6 mmol/L; 95% CI, –56.9 to –48.4) (Table 18).

Table 18: Summary of Sweat Chloride Concentration in Study 111 Part B

SwCl analysis

ELX-TEZ-IVA

All patients

N = 75

Patients with F/F

n = 23

Patients with F/MF

n = 52

Patients contributing to the analysis, n

69

22

47

Baseline (mmol/L), mean (SD)

100.7 (11.2)a

100.7 (11.2)a

100.7 (11.2)a

End of treatment time point, mean

24 weeks

24 weeks

24 weeks

Change from baseline (mmol/L), mean (95% CI)

–57.9 (–61.3 to –54.6)

–70.0 (–75.4 to –64.5)

–52.6 (–56.9 to –48.4)

P value

< 0.0001

NR

NR

CI = confidence interval; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; NR = not reported; SD = standard deviation; SwCl = sweat chloride.

aBaseline was taken across 71 patients.

Source: Clinical Study Report.42

Table 19: Summary of Lung Clearance Index in Study 111 Part B

LCI2.5 analysis

ELX-TEZ-IVA

All patients

N = 63

Patients with F/F

n = 23

Patients with F/MF

n = 52

Patients contributing to the analysis, n

50

17

33

Baseline LCI2.5, mean (SD)

8.41 (1.48)a

8.41 (1.48)a

8.41 (1.48)a

End of treatment time point, mean

24 weeks

24 weeks

24 weeks

Change in LCI2.5 from baseline, mean (95% CI)

–0.83 (–1.01 to –0.66)

–0.89 (–1.15 to –0.63)

–0.82 (–1.06 to –0.57)

P value

< 0.0001

NR

NR

CI = confidence interval; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI2.5 = lung clearance index; NR = not reported; SD = standard deviation.

aBaseline was taken across 51 patients.

Source: Clinical Study Report.42

Figure 3: Absolute Change in Sweat Chloride by Visit in Study 111 Part B

Figure shows the absolute change from baseline in sweat chloride at weeks 4, 12, and 24. Treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in SwCl by week 4 that was sustained throughout the treatment period.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; LS = least squares; SE = standard error.

Source: Clinical Study Report.42

Lung Clearance Index

Results for within-group change from baseline in LCI2.5 are summarized in Table 19. LCI2.5 was only evaluated in patients aged 3 years or older at the time of screening (n = 50). Among those patients, treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in LCI2.5 by 24 weeks: the within-group LS mean absolute change from baseline was –0.83 (95% CI, –1.01 to –0.66; nominal P < 0.0001). As shown in Figure 4, the reduction from baseline was observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). The results were similar in the F/F and F/MF genotype subgroups: LS mean change of –0.89 (95% CI, –1.15 to –0.63) and LS mean change of –0.82 (95% CI, –1.06 to –0.57), respectively.

Pulmonary Exacerbations

In Study 111, 16.0% of patients experienced a pulmonary exacerbation event through week 24 (1 event each). This corresponded to a yearly pulmonary exacerbation event rate of 0.32 (Table 20).

Table 20: Summary of Pulmonary Exacerbations in Study 111 Part B

Analysis

ELX-TEZ-IVA (N = 75)

PEx

Patients contributing to the analysis, n

75

End of treatment time point, mean

24 weeks

Patients with events, n (%)

12 (16.0)

Number of events

12

Observed event rate per year

0.32a

P value

NR

PEx requiring hospitalization

Patients with events, n (%)

|| || ||||

Number of events

|| || ||||

Observed event rate per year

|| || ||||

PEx requiring IV antibiotic therapy

Patients with events, n (%)

|| || ||||

Number of events

|| || ||||

Observed event rate per year

|| || ||||

PEx requiring hospitalization or IV antibiotic therapy

Patients with events, n (%)

|| || ||||

Number of events

|| || ||||

Observed event rate per year

|| || ||||

NR = not reported; PEx = pulmonary exacerbation.

aOne year was counted as 48 weeks (336 days).

Source: Clinical Study Report.42

Body Weight

In Study 111, the mean baseline weight in the FAS was || || |||||| || ||||. The absolute increase in body weight at week 24 was || || |||||| || |||||| || ||||. The mean baseline body weight z score was || || |||||| || ||||. The absolute increase in body weight z score at week 24 was || || |||||| || |||||| || ||||.

Height

In Study 111, the mean baseline height among all 75 patients in the FAS was || || |||||| || ||||. The absolute increase in height at week 24 was || || |||||| || |||||| || ||||. At baseline, the mean height z score was || || |||| || || ||||. The absolute decrease in height z score at week 24 was –0.06 (95% CI, –0.11 to 0.00).

Body Mass Index

In Study 111, the mean baseline BMI for the FAS was 15.79 kg/m2 (SD = 1.06 kg/m2). The absolute increase in BMI at week 24 was || || |||||| || |||||| || |||||| || ||||. The mean baseline BMI z score was 0.09 (SD = 0.85). The absolute increase in BMI z score at 24 weeks was 0.10 (95% CI, 0.00 to 0.20).

Figure 4: Absolute Change in Lung Clearing Index by Visit in Study 111 Part B

Figure shows the absolute change from baseline in LCI2.5 at weeks 4, 12, and 24 in Study 111 Part B.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; LCI2.5 = lung clearance index; LS = least squares; SE = standard error.

Source: Clinical Study Report.42

CF-Related Hospitalizations

There were no CF-related hospitalizations in Study 111.

Harms

Refer to Table 21 for harms data. Safety and tolerability were evaluated as the primary outcomes in Part B. The overall safety profile of ELX-TEZ-IVA was assessed based on the following safety and tolerability end points: treatment-emergent AEs, clinical laboratory values, standard 12-lead electrocardiograms, vital signs, and pulse oximetry. Rash and elevated transaminase levels were investigated as AEs of special interest.

Adverse Events

In total, 98.7% of patients experienced 1 or more AEs, all of which were either mild (62.7%) or moderate (36.0%) in severity. Overall, common AEs (i.e., in ≥ 10% of patients) were generally consistent with common manifestations and complications of CF in patients aged 2 through 5 years, as well as with the established safety profile of ELX-TEZ-IVA. The AEs most commonly reported among the patients were cough (61.3%), pyrexia (34.7%), and rhinorrhea (33.3%).

Serious Adverse Events

Two patients (2.7%) experienced SAEs. One patient had concurrent SAEs of anal incontinence (mild in severity), urinary incontinence (moderate in severity), and abnormal behaviour (moderate in severity). The other patient had an SAE of infective pulmonary exacerbation of CF (moderate in severity) that was not related to the treatment.

Withdrawals Due to Adverse Events

One patient (1.3%) discontinued treatment due to an SAE of abnormal behaviour. Five patients (6.7%) experienced AEs leading to treatment interruption. Of these 5 patients, 2 experienced rash leading to treatment interruption, 1 experienced anal and urinary incontinence, 1 experienced aggression, and 1 experienced increased levels of ALT, AST, and gamma-glutamyl transferase.

Adverse Events of Special Interest

Eight patients (10.7%) experienced elevated transaminase events and 15 (20.0%) experienced rash events. All events were deemed mild or moderate in severity, and none were serious. Two of the patients experienced rash events leading to treatment interruption. There were no study discontinuations due to rash events or elevated transaminase events.

Table 21: Summary of Harms Results From Study 111 Part B

Adverse events

ELX-TEZ-IVA (N = 75)

Most common adverse events, n (%)a

≥ 1 adverse event

74 (98.7)

Cough

46 (61.3)

ALT increased

8 (10.7)

Rhinorrhea

25 (33.3)

AST increased

4 (5.3)

Rash

12 (16.0)

Pyrexia

26 (34.7)

Vomiting

21 (28.0)

COVID-19

14 (18.7)

Nasal congestion

13 (17.3)

Upper respiratory tract infection

11 (14.7)

Decreased appetite

9 (12.0)

Infective pulmonary exacerbation of CF

8 (10.7)

Headache

|| || ||||

SARS-CoV-2 test positive

|| || ||||

Constipation

|| || ||||

Nasopharyngitis

|| || ||||

Abdominal discomfort

|| || ||||

Diarrhea

|| || ||||

Abdominal pain

|| || ||||

GGT increased

|| || ||||

Irritability

|| || ||||

Serious adverse events, n (%)

Patients with ≥ 1 serious adverse event

2 (2.7)

Patients who stopped treatment due to adverse events, n (%)

Patients who had adverse events leading to treatment discontinuation

1 (1.3)

Patients who had adverse events leading to interruption of treatment

5 (6.7)

Deaths, n (%)

Patients who died

0 (0)

Adverse events of special interest, n (%)

Elevated transaminase levels

8 (10.7)

Rash

15 (20.0)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CF = cystic fibrosis; GGT = gamma-glutamyl transferase.

aAdverse events occurring in at least 5% of patients by preferred term.

Source: Sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study 111 was conducted in a manner similar to all other pivotal studies for the use of CFTR modulators in patients aged between 2 and 5 years (i.e., expansion of approval indications for Orkambi4,5 and Kalydeco6,7). Each of these studies was conducted in 2 parts, with Part A involving a small number of patients (n = 18 for Study 111), with a primary objective of evaluating pharmacokinetics, and Part B enrolling more patients (n = 75 for Study 111), with the primary objective of evaluating safety and tolerability.

As with the previously reviewed trials in adults, adolescents, and children aged 6 to 11 years, few patients were discontinued from Study 111 (100% completion for Part A and 98.7% completion for Part B). Adherence to the study treatments was evaluated by counting the number of study drugs at each visit and was reported to be || || |||| for Part A and || || |||| for Part B. In accordance with the study protocols, the use of concomitant medications remained stable throughout the treatment period for all treatment groups.

As with the other trials for CFTR modulators in patients aged 2 to 5 years, ELX-TEZ-IVA was administered in an open-label manner in Study 111, and there was no comparator group for either Part A or Part B. The limited number of secondary efficacy end points evaluated in the study were objective and unlikely to be influenced by the open-label administration of a CFTR modulator (i.e., change from baseline in SwCl concentration and change from baseline in LCI2.5).

There are no globally accepted definitions of pulmonary exacerbations in patients with CF. The definitions used in Study 111 were considered appropriate by regulatory authorities and the clinical experts consulted by CADTH. There was no independent adjudication of pulmonary exacerbation events. Pulmonary exacerbations were only evaluated with descriptive statistics, and there were no prebaseline or postbaseline comparisons of event rates. In response to an inquiry from CADTH regarding why pulmonary exacerbations were not included as an efficacy end point, the sponsor reported that, as had been noted in relation to the pediatric trial for patients aged 6 to 11 years, exacerbations occur less frequently in younger patients than in older patients. As Study 111 was a single-arm trial without a defined pretreatment evaluation period, and due to the low pulmonary exacerbation rates in the study population, comparison to a pretreatment event rate was not possible.

Statistical power calculations were performed for Part A of Study 111 (pharmacokinetic assessment) but were not performed for Part B, as the primary objective was the evaluation of safety and tolerability. The sponsor planned for a sample size of approximately 70 patients; the assumed dropout rate of 10% to 20% was far greater than the 1 patient (1.3%) who did drop out. Enough patients were enrolled and completed both parts of the study for the sponsor to evaluate the primary objectives. The MMRM analyses for the primary evaluations assumed data were missing at random, which may not be a valid assumption. However, the amount of missing data in the trials was low.

The secondary end points were analyzed without statistical testing procedures to control the type I error rate (the sponsor noted that all P values were considered nominal); therefore, the results should be interpreted with caution due to the risk of inflated type I error.

External Validity

The eligibility and diagnostic criteria used to screen patients for Study 111 were similar to those used in the other phases of the ELX-TEZ-IVA clinical development program (i.e., Studies 106 and 116 for patients aged 6 to 11 years and Studies 102, 103, 104, and 109 for patients aged 12 years and older). As noted in the previous CADTH review of ELX-TEZ-IVA, these criteria are generally consistent with Canadian clinical practice for diagnosing patients with CF. As all Canadian provinces and territories have instituted newborn screening, diagnosis of CF and confirmation of genotyping would typically occur early in the child’s life (an average of 1 month after birth). As such, no changes would be needed in diagnostic testing requirements to establish patient eligibility based on CF diagnosis and genotype for the revised age range for ELX-TEZ-IVA.

The clinical experts consulted by CADTH noted that the baseline growth parameters for the patients in Study 111 were a reasonable reflection of the typical patient in Canadian practice.

Changes from baseline in lung function were evaluated as a secondary efficacy end point in Study 111 using LCI2.5. This is reflective of regulatory guidance, which has noted that spirometry may not be sensitive enough to detect treatment differences in children with CF. In addition, spirometry is not typically performed in patients younger than 6 years in Canada, and FEV1 has not been used as a clinical trial end point in any CFTR modulator studies for patients younger than 6 years. LCI is used in CF clinical trials as it may be more sensitive in identifying early underlying structural deficiencies within the lungs of patients with CF that cannot be detected using spirometry.8,9 Similar to spirometry assessments, the LCI test can be challenging to accurately perform with young children. In Study 111, the sponsor noted that the LCI test was only performed on patients aged 3 years or older at the time of screening. Although LCI is used as an end point in clinical studies, it is not routinely used in Canadian clinical practice, and the clinical relevance of differences in this end point have not been characterized.9,10 The clinical experts consulted by CADTH indicated that LCI is not reliably correlated with FEV1. A literature review conducted by CADTH found that variable correlation was observed between FEV1 and LCI in children.

As with all other CFTR modulator phase III trials, Study 111 excluded patients with a history of colonization with B. cenocepacia, B. dolosa, and/or M. abscessus. CF Canada reports that a small minority of patients in Canada have colonization with Burkholderia species (3.2% in 2020), with only 12.9% of those cases reported in children.47 As with previous CADTH reviews of ELX-TEZ-IVA, the clinical experts consulted by CADTH noted that the exclusion of such patients does not reduce the generalizability of the study results.

The proportion of patients in Study 111 who were positive for P. aeruginosa was 18.7%, which is close to the rate reported for children aged 2 to 5 years in the 2019 CF Canada data registry (approximately 14%). The clinical experts consulted by CADTH noted that the rate of P. aeruginosa infection in Study 111 is similar to what would be anticipated in routine Canadian clinical practice.

Similar to other phase III studies for CFTR modulators, including those for ELX-TEZ-IVA for patients aged 6 to 11 years and 12 years and older, Study 111 excluded patients who had a respiratory infection, pulmonary exacerbation, or changes in their therapy for pulmonary disease in the 4 weeks prior to the first dose of the study drug. As in the previous CADTH reviews of ELX-TEZ-IVA,48,49 the clinical experts consulted by CADTH noted that the exclusion of these patients is unlikely to limit the generalizability of the results to the broader patient population with CF.

ELX-TEZ-IVA was added to the existing therapeutic regimens used by the patients, which is reflective of how ELX-TEZ-IVA would be administered in clinical practice. The clinical experts consulted by CADTH indicated that the background therapies used in Study 111 were similar to what would be anticipated in Canadian clinical practice, with the following exceptions: all patients in Canadian practice would be supplementing with vitamins, and the use of mucolytics (i.e., dornase alfa and inhaled hypertonic saline) could be slightly lower for patients aged 2 to 5 years in Canada.

The 24-week study treatment periods were sufficient for observing change from baseline in SwCl and LCI2.5 in Study 111; however, the clinical experts consulted by CADTH suggested that 24 weeks is unlikely to be enough time to observe meaningful changes in BMI for a younger patient population that is relatively healthy. In addition, the absence of a control group in Study 111 limits the ability to interpret the results of change from baseline in the growth parameters.

Patients and caregivers in Study 111 received extensive contact with health professionals over the study period (i.e., 8 clinic visits and 2 phone contacts). This level of contact is not reflective of routine care for patients with CF with relatively stable disease.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Patients who completed Study 111 were eligible to enrol in an open-label extension study. However, the sponsor reported that the interim results of the extension study were not available at the time of filing the application with CADTH.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

Feasibility of ITC in patients aged 2 to 5 years: The sponsor conducted an ITC to compare the clinical efficacy of ELX-TEZ-IVA in Study 111 with other CFTR modulators in patients with F/F and F/MF mutations to generate the inputs needed for the cost-effectiveness analysis. A meta-analysis approach via MMRM was used with individual patient-level data from relevant trials; data from all comparators were included in 1 model for each genotype. The sponsor concluded that the ITC was not feasible due to the small number of patients in this age group, which reduced the power to detect differences between ELX-TEZ-IVA, LUM-IVA, and/or placebo. As such, the sponsor did not include the ITC in its submission to CADTH and used estimates from the previous CADTH submission for patients aged 6 to 11 years as assumptions within its economic model.

ITCs in patients aged 6 to 11 years and 12 years and older: To inform the pharmacoeconomic model, the sponsor submitted estimates of clinical efficacy of ELX-TEZ-IVA compared to placebo derived from ITCs previously conducted for patients aged 6 to 11 years and 12 years and older using individual patient-level data from relevant phase III randomized controlled clinical trials.

Table 22: Summary of Methods Used to Inform Acute ppFEV1 Increase in the Cost-Effectiveness Model

Model input

F/F

F/G

F/RF

F/MF

Acute ppFEV1 increase when simulated patients aged 2 to 5 years turn age 6 years in the cost-effectiveness model.

ITC conducted for patients aged 6 to 11 years was used to inform efficacy for ELX-TEZ-IVA vs. placebo and LUM-IVA vs. placebo.

ITC conducted for patients aged 12 years and older was used to inform efficacy for ELX-TEZ-IVA vs. placebo and relative efficacy observed between patient populations aged 6 to 11 years and 12 years and older.

ITC conducted for patients aged 12 and older was used to inform efficacy for ELX-TEZ-IVA vs. placebo and relative efficacy observed between patient populations aged 6 to 11 years and 12 years and older.

Separate ITC was not conducted. Placebo-adjusted data from Study 116 in patients aged 6 to 11 years were used to inform efficacy.

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; vs. = versus.

Description of Indirect Comparison

As shown in Table 23, for patients aged 6 to 11 years, the sponsor conducted an indirect comparison investigating the comparative efficacy of ELX-TEZ-IVA versus other CFTR modulators and placebo for patients with an F/F genotype.50

Table 23: Study Selection Criteria and Methods for Indirect Treatment Comparison

Characteristic

ITC study selection criteria and methods

Population

Patients with CF aged 6 to 11 years with F/F genotype

Intervention

ELX 200 mg–TEZ 100 mg–IVA 150 mg (every morning) + IVA 150 (every evening)

Comparator

  • Placebo

  • LUM-IVA

  • TEZ-IVA

Outcome

ppFEV1

Study design

  • Phase III studies

  • Study duration ≥ 24 weeks

Publication characteristics

Not reported

Exclusion criteria

Not reported

Databases searched

Not reported

Selection process

Not reported

Data extraction process

Not reported

Quality assessment

Not reported

CF = cystic fibrosis; ELX = elexacaftor; F/F = homozygous for F508del mutation in the CFTR gene; IVA = ivacaftor; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ = tezacaftor; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.50,51

ITC for Patients Aged 6 to 11 Years With F/F Genotype

Study Selection Methods

The criteria used by the sponsor to select studies for inclusion in the ITC for patients aged 6 to 11 years with F/F genotype were as follows:

A systematic literature search and review was not undertaken by the sponsor to identify studies for inclusion. The sponsor reported that since Vertex Pharmaceuticals is the only manufacturer with relevant CFTR modulators and conducted all the relevant phase III trials, a systematic literature review was unlikely to retrieve any additional relevant evidence.50 CADTH did not identify any additional studies that would have met the inclusion criteria but were not included in the ITC.

ITC Analysis Methods

The ITC analyses for ELX-TEZ-IVA versus LUM-IVA, TEZ-IVA, and placebo, as well as for LUM-IVA and TEZ-IVA versus placebo, were conducted using an MMRM meta-analysis approach and individual patient-level data from patients with an F/F genotype in the relevant treatment groups from each of the included trials. The sponsor reported that an MMRM meta-analysis approach was the most appropriate methodology for the following reasons:

The relevant comparisons for the CADTH review are ELX-TEZ-IVA versus LUM-IVA or IVA (as TEZ-IVA is not approved for use in patients aged 6 to 11 years in Canada). For these comparisons, the sponsor calculated the estimated treatment difference for ppFEV1 (defined as the average of weeks 4, 8, 16, and 24). The MMRMs included treatment group, visit, and treatment-by-visit interaction as fixed effects. The covariates for adjustment were sex and the corresponding baseline variable. A 2-sided 95% CI and a 2-sided P value for the estimated indirect treatment difference were calculated based on normal approximation. The sponsor conducted additional analyses for ELX-TEZ versus TEZ-IVA using 8-week end points, as 24-week data were unavailable. These analyses are reported in this section of the report but are not appraised in detail as TEZ-IVA is not approved for use in patients aged 6 to 11 years in Canada.50

Table 24: Indirect Comparisons for Patients Aged 6 to 11 Years With F/F Genotype

Within-group estimates (study)

End point

  • ELX-TEZ-IVA (Study 106B)

  • Placebo (Study 809-109)

  • LUM-IVA (Studies 809-109 and 809-011B)

  • TEZ-IVA (Study 661-113B)

Absolute change in ppFEV1 (through 24 weeks)a

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

aAnalyses for TEZ-IVA were conducted at 8 weeks.

Source: Sponsor’s indirect treatment comparison.50

Results for ITC Analysis
Included Studies

The evidence network for the studies with patients aged 6 to 11 years who have an F/F genotype is shown in Figure 5. Indirect comparisons were performed for ELX-TEZ-IVA versus placebo, ELX-TEZ-IVA versus LUM-IVA, and ELX-TEZ-IVA versus TEZ-IVA.50

Study Characteristics

Table 25 provides a summary of the characteristics of the studies that were included in the indirect comparison for patients aged 6 to 11 years with an F/F genotype. There were 4 studies included in the primary analysis (Studies 106B, 809-109, 809-011B, and 661-113B), and an additional study involving TEZ-IVA was used in sensitivity analyses (Study 661-115). The single-arm Study 109B provided the estimated treatment effect for ELX-TEZ-IVA. Pooled data from Study 809-109 (a double-blind, placebo-controlled RCT) and the single-arm Study 809-011B provided the estimated treatment effect for LUM-IVA. The estimated effect for the placebo was also derived from Study 809-109. The estimated treatment effects for TEZ-IVA were from the single-arm Study 661-113B in the primary analyses and from Study 661-115 for sensitivity analyses.50

The inclusion criteria were generally similar across the studies. The key exceptions were the inclusion of patients with genotypes other than F/F in Study 106B (patients with an F/MF genotype were also enrolled) and Studies 661-113B and 661-115 (patients with an F/RF genotype were also enrolled) and the lower threshold for ppFEV1 in the inclusion criteria (≥ 40% in Studies 106B, 809-011B, and 661-113B versus ≥ 70% in Studies 809-109 and 661-115). Despite this difference, the baseline ppFEV1 was similar across the studies (summarized in Table 26). All the studies enrolled patients aged between 6 and 11 years. The ppFEV1 was calculated using the Global Lung Function Initiative approach in the trials for ELX-TEZ-IVA (Study 106B) and TEZ-IVA (Studies 661-113B and 661-115) and using the Wang-Hankinson reference equations in the studies for LUM-IVA (Studies 809-109 and 809-011B). The sponsor recalculated the ppFEV1 values from the LUM-IVA studies using the Global Lung Function Initiative normalization approach to align with the approach used in the ELX-TEZ-IVA and TEZ-IVA trials. The end points were generally similar across the studies; however, only Studies 809-109 and 661-115 included a prespecified primary efficacy end point.50

Figure 5: Indirect Comparison Network for Patients Aged 6 to 11 Years With F/F Genotype

Figure shows the indirect comparison evidence network for patients aged 6 to 11 years who are homozygous for the F508del mutation in the CFTR gene.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; LUM/IVA = lumacaftor-ivacaftor; TEZ/IVA = tezacaftor-ivacaftor and ivacaftor; vs = versus.

Source: Sponsor’s indirect treatment comparison.50

Table 25: Study Characteristics in Patients Aged 6 to 11 Years With F/F Genotype

Characteristic

ELX-TEZ-IVA

LUM-IVA

TEZ-IVA

Study 106B

Study 809-109

Study 809-011B

Study 661-113B

Study 661-115a

Study design

Single arm, OL

DB RCT

Single arm, OL

Single arm, OL

DB RCT

Study population

  • F/F or F/MF

  • 6 to 11 years

  • F/F

  • 6 to 11 years

  • F/F

  • 6 to 11 years

  • F/F or F/RF

  • 6 to 11 years

  • F/F or F/RF

  • 6 to 11 years

Treatment groups

ELX-TEZ-IVA

  • LUM-IVA

  • Placebo

LUM-IVA

TEZ-IVA

  • TEZ-IVA

  • Placebo

  • IVA (F/RF; not used in ITC)

CFTR modulator washout requirements

≥ 28 days prior to day 1 visit

≥ 30 days prior to screening visit

≥ 30 days prior to screening visit

≥ 30 days prior to day 1 visit (≥ 28 days for LUM-IVA)

≥ 28 days prior to day 1 visit

Treatment duration

24 weeks

24 weeks

24 weeks

24 weeks

8 weeks

Baseline ppFEV1 inclusion criteria

≥ 40% (GLI)

≥ 70% (Wang equation)

≥ 40% (Wang equation)

≥ 40% (GLI)

≥ 70% (GLI)

Sample size

ELX-TEZ-IVA: 66

  • LUM-IVA: 103

  • Placebo: 101

LUM-IVA: 58

TEZ-IVA: 70

  • TEZ-IVA: 54

  • Placebo: 10

  • IVA: 3

Primary efficacy end point

NA

Absolute change from baseline in LCI2.5 through week 24

NA

NA

Absolute change from baseline in LCI2.5 through week 8

DB = double blind; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; GLI = Global Lung Function Initiative; ITC = indirect treatment comparison; IVA = ivacaftor; LCI2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; NA = not applicable; OL = open label; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

aSensitivity analysis only.

Source: Sponsor’s indirect treatment comparison.50

Baseline Characteristics

As shown in Table 26, the baseline and demographic characteristics were generally similar across the studies included in the indirect comparisons for patients aged 6 to 11 years with an F/F genotype. For the comparisons of interest for this review (i.e., ELX-TEZ-IVA versus LUM-IVA or placebo), the baseline ppFEV1, LCI2.5, weight-for-age z score, and BMI-for-age z score were similar across the treatment groups, with the exception of the BMI-for-age z score, which was greater in Study 661-113B (TEZ-IVA), at 0.39 (SD = 0.90) than in the other trials (range, –0.09 [0.86] in the pooled LUM-IVA studies to 0.09 [0.96] in the pooled TEZ-IVA studies). The baseline CFQ-R respiratory domain scores were lower for the placebo (77.1) and LUM-IVA groups (78.5) than for the ELX-TEZ-IVA and TEZ-IVA groups (81.8 and 83.2, respectively).

Table 26: Baseline Characteristics in Patients Aged 6 to 11 Years With F/F Genotype

Characteristic

ELX-TEZ-IVA

Study 106B

(N = 29)

Placebo

Study 809-109

(N = 101)

LUM-IVA

Studies 809-109 and 809-011, Part B, pooled

(N = 160)

TEZ-IVA

Study 661-113, Part B

(N = 61)

Study 661-115

(N = 42)

Studies 661-113, Part B, and 661-115, pooled

(N = 103)

Sex, n (%)

  Male

12 (41.4)

43 (42.6)

66 (41.3)

31 (50.8)

20 (47.6)

51 (49.5)

  Female

17 (58.6)

58 (57.4)

94 (58.8)

30 (49.2)

22 (52.4)

52 (50.5)

Age at screening (years)

  Mean (SD)

8.3 (1.9)

8.9 (1.6)

8.8 (1.6)

8.0 (1.8)

8.5 (1.6)

8.2 (1.7)

  Median

8.0

9.0

9.0

8.0

9.0

8.0

ppFEV1 (%), mean (SD)

87.3 (18.3)

88.6 (11.1)

87.5 (13.6)

91.2 (12.4)

NA

88.7 (12.9)

LCI2.5 (lung turnovers), mean (SD)

10.26 (3.36)

10.26 (2.24)

10.25 (2.42)

NA

9.84 (2.17)

NA

Weight z score, mean (SD)

–0.23 (0.59)

–0.21 (0.76)

–0.14 (0.90)

0.18 (0.94)

NA

–0.04 (0.90)

BMI z score, mean (SD)

–0.10 (0.61)

–0.14 (0.88)

–0.09 (0.86)

0.39 (0.90)

NA

0.09 (0.96)

CFQ-R respiratory domain, mean (SD)

81.8 (12.0)

77.1 (15.5)

78.5 (14.4)

81.7 (13.9)

NA

83.2 (12.5)

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; LCI2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; NA = not applicable; ppFEV1 = percent predicted forced expiratory volume in the first second; SD = standard deviation; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.50

Indirect Comparison Results

Table 27 provides a summary of the results of the indirect comparisons for studies conducted in patients aged 6 to 11 years with an F/F genotype. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with LUM-IVA: || || |||||| || |||||| || |||||| || |||||| || |||||| || |||| for absolute change in ppFEV1 from baseline through 24 weeks.50

Table 27: Results of Indirect Comparison for Patients Aged 6 to 11 Years With F/F Genotype

Absolute change in ppFEV1 from baseline through 24 weeks

ELX-TEZ-IVA

Study 445-106B

(N = 29)

LUM-IVA

Studies 809-109 and 809-011B

(N = 160)

TEZ-IVA

Study 661-113B

(N = 61)

Placebo

Study 809-109

(N = 101)

LS mean within-group (95% CI)

P value

|| || |||||| || |||||| |

|| || |||||| || |||||| |

|| || |||||| || |||||| |

|| || |||||| || |||||| |

LS mean between-group difference (95% CI) (ELX-TEZ-IVA versus comparator)

P value

|| || |||||| || |||||| |

|| || |||||| || |||||| |

|| || |||||| || |||||| |

|| || |||||| || |||||| |

CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; LS = least squares; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.50

Critical Appraisal

The screening phase (4 weeks), treatment phase (24 weeks), and follow-up phase were similar across the studies. The key baseline characteristics were generally similar across the studies, with the exception that the baseline CFQ-R respiratory domain scores were lower for the placebo (77.1) and LUM-IVA groups (78.5) than for the ELX-TEZ-IVA and TEZ-IVA groups (81.8 and 83.2, respectively).

Table 28: CADTH Assessment of Homogeneity for the ITC for Patients Aged 6 to 11 Years With F/F Genotype

Characteristic

Description and handling of potential effect modifiers

Disease severity

  • Lung function: For the comparisons of interest for this review (i.e., ELX-TEZ-IVA versus LUM-IVA or placebo), baseline ppFEV1 and LCI2.5 values were similar across the treatment groups.

  • CFQ-R: Baseline CFQ-R respiratory domain scores were lower for the placebo (77.1) and LUM-IVA groups (78.5) than for the ELX-TEZ-IVA and TEZ-IVA groups (81.8 and 83.2, respectively). The sponsor noted that MMRM analyses were adjusted for baseline values.

  • BMI: The baseline BMI z score was greater in Study 661-113B (TEZ-IVA), at 0.39 (SD = 0.90) than in the other trials (range, –0.09 [0.86] in the pooled LUM-IVA studies to 0.09 [0.96] in the pooled TEZ-IVA studies). The sponsor noted that MMRM analyses were adjusted for baseline values.

  • SwCl: Baseline SwCl levels were not reported for the indirect comparison.

Treatment history

All the trials required patients with prior exposure to a CFTR modulator to undergo a washout period of at least 4 weeks.

Clinical trial eligibility criteria

Eligibility criteria were generally similar across the included trials, with the following exceptions:

  • Patients were required to have ppFEV1 ≥ 40% in Studies 106B, 809-011B, and 661-113B and ≥ 70% in Studies 809-109 and 661-115; however, as noted in Table 26, baseline ppFEV1 levels were similar across the included studies.

  • In addition to patients with an F/F genotype, Study 106B enrolled patients with an F/MF genotype, and the TEZ-IVA studies (661-113B and 661-115) also enrolled patients with an F/RF genotype. Only patients with an F/F genotype were included in the indirect comparison.

Dosing of comparators

All the study drugs were used in accordance with the recommendations in the Canadian product monographs.29,37,39

Definitions of end points

The end points included in the ITC were similarly defined and evaluated for each of the included studies.

Timing of end point evaluation or trial duration

All the end points were calculated using the same approach for the MMRM (e.g., through 24 weeks for ppFEV1).

Withdrawal frequency

There were few withdrawals from any of the trials included in the ITC.

Clinical trial setting

All of the studies included in the ITC were phase III studies conducted at specialized CF clinics.

Study design

The screening phase (4 weeks), the treatment phase (24 weeks), and the follow-up phase were similar across the included studies. Studies 106B, 809-011B, and 661-113B were single-arm, open-label trials. Studies 809-109 and 661-115 were double-blind, placebo-controlled trials.

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; LCI2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; MMRM = mixed-effects model for repeated measures; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; SwCl = sweat chloride; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

ITC for Patients Aged 12 Years and Older With F/G Genotype

Study Selection Methods

The criteria used by the sponsor to select studies for inclusion in the ITC for patients aged 12 years and older with an F/G genotype were as follows:

It was not reported if a systematic literature search and review was undertaken by the sponsor to identify studies for inclusion; however, CADTH did not identify any additional studies that would have met the inclusion criteria but were not included in the ITC.

ITC Analysis Methods

The indirect comparison for ELX-TEZ-IVA versus placebo in patients aged 12 years and older with an F/G genotype was estimated using the Bucher method for continuous end points, with IVA as the common comparator. The sponsor stated that the Bucher method was considered the most appropriate approach for this indirect comparison because of the 4-week IVA run-in period included in Study 104 (but not in the STRIVE, KONNECTION, or KONDUCT trials). As all the patients in the STRIVE, KONNECTION, and KONDUCT trials were naive to CFTR modulator treatment at baseline, the baselines were not considered to be sufficiently comparable to conduct an individual patient-level data meta-analysis.

The sponsor used MMRMs to estimate the direct treatment effects from each of the studies, which were subsequently used in the Bucher indirect comparison. For ppFEV1, CFQ-R domain scores, and SwCl, the sponsor calculated the estimated treatment difference through 8 weeks. This was calculated using the average of weeks 4 and 8 for Study 104, KONNECTION, and KONDUCT, but only the week 8 measurement for STRIVE (as the trial did not include a week 4 assessment). The sponsor conducted an additional supportive analysis, in which the week 8 assessments were used for all the studies. For BMI-for-age z score and weight-for-age z score, the sponsor calculated the estimated treatment difference at week 8.

Each MMRM included treatment group, visit, and treatment-by-visit interaction as fixed effects and patient as the random effect. Additionally, the MMRM that used data from KONNECTION included treatment period as a fixed effect (as KONNECTION was a crossover trial and the others were parallel group trials). The covariates included for adjustment were based on those included in the MMRM for each of the trials used in the ITC and included age at screening (≥ 12 years to < 18 years, versus ≥ 18 years) and continuous baseline ppFEV1. Age at screening was not included as a covariate for the MMRM that used data from the KONDUCT trial, because only 1 patient was aged at least 12 years but younger than 18 years at the time of screening. Additionally, continuous baseline SwCl was included as a covariate in the MMRM used to estimate the ELX-TEZ-IVA versus IVA treatment effect, as it was included as a covariate in the MMRM of Study 104.

The direct estimates for IVA versus placebo were derived from a meta-analysis of subgroup analyses from 3 studies: STRIVE, KONNECTION, and KONDUCT. A fixed-effect, meta-analysis approach was used to combine the individual treatment effects and estimate the overall treatment effect of IVA versus placebo. The individual effects were weighted by the inverse variance of each effect-size estimate.

A 2-sided 95% CI and a 2-sided P value for each estimated indirect treatment difference were calculated based on normal approximation.

Table 29: Indirect Comparisons for Patients Aged 12 Years and Older With F/G Genotype

Indirect estimate

Direct estimates (study)

End point

ELX-TEZ-IVA versus placebo

ELX-TEZ-IVA versus TEZ-IVA (subgroup data from Study 104) + IVA versus placebo (meta-analysis of STRIVE, KONNECTION, and KONDUCT)

ppFEV1 (through 8 weeks)

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; IVA = ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.51

Results for ITC Analysis
Included Studies

The evidence network for the studies with patients aged 12 years and older who have an F/G genotype is shown in Figure 6. Indirect comparison was performed for ELX-TEZ-IVA versus placebo. The direct evidence for ELX-TEZ-IVA versus IVA was derived from a subgroup analysis of Study 104. The direct estimates for IVA versus placebo were derived from a meta-analysis of subgroup analyses from 3 studies: STRIVE, KONNECTION, and KONDUCT.

Figure 6: Indirect Comparison Network for Patients Aged 12 Years and Older With F/G Genotype

Figure shows the evidence network diagram for the indirect comparison for patients aged 12 years and older with an F/G genotype.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; IVA = ivacaftor; vs = versus.

Source: Sponsor’s indirect treatment comparison.51

Study Characteristics

Table 30 provides a summary of the characteristics of the studies included in the indirect comparison for patients aged 12 years and older with an F/G genotype. A key difference across the studies was the use of a 4-week, open-label run-in period in Study 104, in which all patients received treatment with IVA prior to randomization. The studies had different durations for the treatment periods, ranging from 8 weeks in Study 104 and KONNECTION to 48 weeks in STRIVE. The sponsor performed the indirect comparisons using the 8-week time point for all assessments.

The inclusion criteria differed across the studies with respect to age and CFTR genotypes. Patients were required to be aged 12 years or older to be eligible for Study 104 and STRIVE, but patients aged 6 years and older were eligible for KONNECTION and KONDUCT. Study 104 enrolled patients with an F/G (including F/R117H) or an F/RF genotype. In contrast, the other studies were conducted in patients who did not necessarily have an F508del mutation: STRIVE enrolled patients with at least 1 G551D gating mutation; KONNECTION enrolled patients with at least 1 non-G551D gating mutation; and KONDUCT enrolled patients with at least 1 R117H mutation. Given the heterogenous study populations, the sponsor extracted subgroup data for patients who had an F/G genotype: 95 of 258 (37%) for Study 104, 122 of 161 (76%) for STRIVE, 34 of 78 (44%) for KONNECTION, and 39 of 69 (57%) for KONDUCT.

All the studies specified that patients had to have a ppFEV1 of at least 40% at screening to be eligible. Study 104, STRIVE, and KONDUCT all specified an upper threshold for ppFEV1 of 90% at screening to determine eligibility for enrolment; KONNECTION did not specify an upper threshold for ppFEV1.

All the studies specified absolute change in ppFEV1 from baseline as the primary end point. The primary end point was assessed through 8 weeks in Study 104 and KONNECTION and through 24 weeks in STRIVE and KONDUCT. All the studies included changes in BMI, CFQ-R, SwCl, and body weight as additional end points. STRIVE, KONNECTION, and KONDUCT included pulmonary exacerbations as an efficacy end point, and Study 104 did not; therefore, no indirect comparison can be conducted for this end point.

Table 30: Study Characteristics for Patients Aged 12 Years and Older With F/G Genotype

Characteristic

Study 104

(F/G subset)

STRIVE

(F/G551D subset)

KONNECTION

(F/non-G551D subset)

KONDUCT

(F/R117H subset)

Study population

Patients with F/G (including F/R117H) or F/RF genotypes and aged ≥ 12 years

Patients with ≥ 1 G551D gating mutation and aged ≥ 12 years

Patients with ≥ 1 non-G551D gating mutation and aged ≥ 6 years

Patients with ≥ 1 R117H mutation and aged ≥ 6 years

Design

DB, active-controlled, parallel group RCT

DB, placebo-controlled parallel group RCT

DB, placebo-controlled, crossover RCT

DB, placebo-controlled, parallel group RCT

Active run-in period

4 weeks with TEZ-IVA or IVA

None

None

None

Treatment period

8 weeks

48 weeks

8 weeks

24 weeks

Treatment groups

  • ELX-TEZ-IVA

  • TEZ-IVA (F/RF)

  • IVA (F/G)

  • IVA

  • Placebo

  • IVA

  • Placebo

  • IVA

  • Placebo

ppFEV1 inclusion criteria at screening

40% to 90%

40% to 90%

≥ 40%

40% to 90% for patients aged ≥ 12 years

Schedule of assessments

Day 1, day 15, week 4, week 8

Day 1, day 15, week 8, every 4 weeks thereafter

Day 1, week 2, week 4, week 8 of each treatment period

Day 1, week 2, week 4, week 8, week 16, week 24

Sample size

  • ELX-TEZ-IVA: 132

  • TEZ-IVA: 81

  • IVA: 45

  • IVA: 83

  • Placebo: 78

  • IVA: 39

  • Placebo: 39

  • IVA: 34

  • Placebo: 35

Subset of patients included in ITC

  • ELX-TEZ-IVA: 50

  • IVA: 45

  • IVA: 64

  • Placebo: 58

  • IVA: 17

  • Placebo: 17

  • IVA: 20

  • Placebo: 19

Primary efficacy end point

Absolute change in ppFEV1 from baseline through 8 weeks

Absolute change in ppFEV1 from baseline through 24 weeks

Absolute change in ppFEV1 from baseline through 8 weeks

Absolute change in ppFEV1 from baseline through 24 weeks

Other end points

BMI, CFQ-R, SwCl, weight

BMI, CFQ-R, PEx, SwCl, weight

BMI, CFQ-R, PEx, SwCl, weight

BMI, CFQ-R, PEx, SwCl, weight

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; DB = double blind; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; patients with at least 1 non-G551D gating mutation; F/G551D = 1 F508del mutation and 1 G551D gating mutation; F/non-G551D = 1 F508del mutation and at least 1 non-G551D gating mutation; F/R117H = 1 F508del mutation and 1 R117H mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; IVA = ivacaftor; PEx = pulmonary exacerbation; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; SwCl = sweat chloride; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.51

Baseline Characteristics

Baseline and demographic characteristics for the F/G studies are summarized in Table 31. The median age of patients differed across the 4 studies, ranging from 22.0 and 25.0 years in the placebo and IVA groups, respectively, of the STRIVE trial to 43.0 and 39.5 years in the placebo and IVA groups, respectively, of the KONDUCT trial. Only 1 patient was younger than 18 years in the relevant subgroup of patients from the KONDUCT trial. The other trials included a subset of patients younger than 18 years at screening, ranging from 13.3% and 16.0% in the IVA and ELX-TEZ-IVA groups, respectively, of Study 104 to 29.4% and 35.3% in the placebo and IVA groups, respectively, of the KONNECTION trial.

Patients in KONNECTION had a higher mean ppFEV1 (79.9% and 78.8% in the placebo and IVA groups, respectively) than those in Study 104 (68.1% and 66.0% in the IVA and ELX-TEZ-IVA groups, respectively), STRIVE (63.9% and 59.6% in the placebo and IVA groups, respectively) and KONDUCT (61.3% and 68.1% in the placebo and IVA groups, respectively). The proportion of male and female patients differed across the studies, with the proportion of female patients ranging from 37.8% and 44.0% in the IVA and ELX-TEZ-IVA groups of Study 104, respectively, to 63.2% and 55.0% in the placebo and IVA groups of the KONDUCT trial, respectively. SwCl levels were substantially lower in Study 104 (47.6 mmol/L and 50.9 mmol/L in the IVA and ELX-TEZ-IVA groups, respectively) than in the other studies, where baseline SwCl ranged from 73.4 mmol/L and 66.1 mmol/L in the placebo and IVA groups of KONDUCT, respectively, to 101.0 mmol/L and 101.1 mmol/L in the placebo and IVA groups, respectively, of the STRIVE trial. Mean BMI at baseline was greater in the KONDUCT trial (24.51 kg/m2 and 27.56 kg/m2 in the placebo and IVA groups, respectively) than in the other trials. Baseline CFQ-R respiratory domain scores differed across the trials, ranging from 59.1 and 70.2 in the placebo and IVA groups, respectively, of the KONDUCT trial to 80.7 and 77.3 in the placebo and IVA groups of the KONNECTION trial, respectively.

Table 31: Baseline Characteristics for Patients Aged 12 Years and Older With F/G Genotype

Characteristic

Study 104

(F/G subset)

STRIVE

(F/G551D subset)

KONNECTION

(F/non-G551D subset)

KONDUCT

(F/R117H subset)

IVA

(N = 45)

ELX-TEZ-IVA

(N = 50)

Placebo

(N = 58)

IVA

(N = 64)

Placebo

(N = 17)

IVA

(N = 17)

Placebo

(N = 19)

IVA

(N = 20)

Sex, n (%)

   Male

28 (62.2)

28 (56.0)

28 (48.3)

30 (46.9)

9 (52.9)

9 (52.9)

7 (36.8)

9 (45.0)

   Female

17 (37.8)

22 (44.0)

30 (51.7)

34 (53.1)

8 (47.1)

8 (47.1)

12 (63.2)

11 (55.0)

Age at screening (years)

   Mean (SD)

30.7 (11.2)

33.4 (13.8)

24.0 (9.5)

26.0 (10.1)

28.8 (12.7)

28.1 (13.2)

41.2 (12.3)

37.7 (12.6)

   Median

29.0

32.7

22.0

25.0

26.0

26.0

43.0

39.5

Age group at screening (years), n (%)

   ≥ 12 to < 18

6 (13.3)

8 (16.0)

15 (25.9)

16 (25.0)

5 (29.4)

6 (35.3)

1 (5.0)

   ≥ 18

39 (86.7)

42 (84.0)

43 (74.1)

48 (75.0)

12 (70.6)

11 (64.7)

19 (100.0)

19 (95.0)

ppFEV1, mean (SD)

68.1 (16.6)

66.0 (14.8)

63.9 (14.4)

59.6 (15.3)

79.9 (15.1)

78.8 (18.9)

61.3 (14.6)

68.1 (16.8)

BMI (kg/m2), mean (SD)

22.91 (3.39)

23.71 (3.76)

22.02 (3.10)

21.40 (3.04)

23.49 (5.17)

23.12 (5.36)

24.51 (5.30)

27.56 (5.42)

Sweat chloride (mmol/L), mean (SD)

47.6 (19.1)

50.9 (23.3)

101.0 (10.3)

101.1 (9.8)

91.0 (24.0)

88.5 (22.3)

73.4 (16.0)

66.1 (22.9)

CFQ-R respiratory domain score, mean (SD)

75.8 (17.6)

76.3 (16.4)

71.9 (16.4)

70.6 (16.6)

80.7 (16.7)

77.3 (14.4)

59.1 (21.2)

70.2 (20.7)

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/G551D = 1 F508del mutation and 1 G551D gating mutation; F/non-G551D = 1 F508del mutation and at least 1 non-G551D gating mutation; F/R117H = 1 F508del mutation and 1 R117H mutation in the CFTR gene; IVA = ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; SD = standard deviation.

Source: Sponsor’s indirect treatment comparison.51

Indirect Comparison Results

Table 32 provides a summary of the results of the direct and indirect comparisons for studies conducted in patients aged 12 years and older with an F/G genotype. The indirect comparison results are shown side by side with the direct comparison results for ELX-TEZ-IVA versus IVA (derived from the subgroup analysis from Study 104) and with direct comparison results for IVA versus placebo (derived from the meta-analysis of STRIVE, KONNECTION, and KONDUCT). The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo: || || |||||| || |||||| ||| || |||||| || |||||| | for absolute change in ppFEV1 from baseline through 8 weeks; || || |||||| || |||||| ||| || |||||| || |||||| | for absolute change in SwCl from baseline through 8 weeks; || || |||||| || |||||| ||| || |||||| || |||||| | for absolute change in BMI from baseline at 8 weeks; and || || |||||| || |||||| ||| || |||||| || |||||| | for absolute change in weight-for-age z score from baseline at 8 weeks.

Indirect estimates of effect for ELX-TEZ-IVA compared with placebo are provided for each of the CFQ-R domains, with favourable effects reported for respiratory symptoms || || |||||| || |||||| ||| || |||||| || |||||| |; physical functioning || || |||||| || |||||| ||| || |||||| || |||||| |; vitality || || |||||| || |||||| ||| || |||||| || |||||| |; health perceptions || || |||||| || |||||| ||| || |||||| || |||||| |; and social functioning || || |||||| || |||||| ||| || |||||| || |||||| |.

Table 32: Results of Direct and Indirect Comparison for Patients Aged 12 Years and Older With F/G Genotype

End point

Direct estimate

ELX-TEZ-IVA vs. IVA

LSMD (95% CI), P value

Indirect estimates

Bucher mean between-group difference

(95% CI), P value

Pooled IVA vs. placebo

ELX-TEZ-IVA vs. placebo

Absolute change in ppFEV1 from baseline through 8 weeks

|| || |||||| || |||||| |

|| || |||||| || |||||| |

|| || |||||| || |||||| |

CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; IVA = ivacaftor; LSMD = least squares mean difference; ppFEV1 = percent predicted forced expiratory volume in the first second; vs. = versus.

Source: Sponsor’s indirect treatment comparison.51

Critical Appraisal

Table 33 summarizes the assessment of homogeneity for the ITC of the studies of patients aged 12 years and older with an F/G genotype. The primary difference across the studies included in the ITC was the use of an open-label, 4-week active treatment period with TEZ-IVA in Study 104. This trial was essentially investigating switching to ELX-TEZ-IVA from IVA compared with remaining on IVA for patients with an F/G genotype. This is a different design than the placebo-controlled trials included in the ITC (i.e., KONNECTION, KONDUCT, and STRIVE). The baseline ppFEV1 for patients in Study 104 was assessed after 4 weeks of treatment with a CFTR modulator (IVA). In contrast, the baseline assessments in KONNECTION, KONDUCT, and STRIVE reflected patients who were naive to CFTR modulator therapy. As both the ELX-TEZ-IVA and IVA groups of Study 104 received 4 weeks of treatment with TEZ-IVA, it is unclear if the run-in period would introduce bias into the ITC analysis. (For example, would the mean difference between IVA and ELX-TEZ-IVA be reduced because of the run-in period, or would it be relatively unchanged?)

Randomization was stratified according to F/G or F/RF genotype in Study 104;52 however, randomization was not stratified according to whether the patient had an F508del mutation in STRIVE, KONDUCT, or KONNECTION.53-55 Hence, the selection of the F508del subgroup of patients in the placebo-controlled IVA trials would not have maintained randomization.

The sponsor pooled the patient-level subgroup data from the 3 placebo-controlled IVA studies to derive a single estimate of effect for IVA versus placebo. However, the results for these individual studies demonstrated different effect sizes for ppFEV1 response to IVA. Specifically, the results in the KONDUCT trial (LS mean difference = 4.1%; 95% CI, –1.0 to 9.1) were considerably smaller than the responses in the STRIVE trial (LS mean difference = 10.4%; 95% CI, 8.0 to 12.9) and the KONNECTION trial (LS mean difference = 10.3%; 95% CI, 5.4 to 15.3). This resulted in a pooled estimate of effect for IVA versus placebo of || || |||||| || |||||| ||| ||, which may overestimate the effect of IVA in patients with a F/R117H genotype (i.e., those patients from the KONDUCT trial) and underestimate the effect in patients with an F/G genotype (i.e., those from the STRIVE and KONNECTION trials).

Table 33: CADTH Assessment of Homogeneity for the ITC for Patients Aged 12 Years and Older With F/G Genotype

Characteristic

Description and handling of potential effect modifiers

Disease severity

ppFEV1: Patients in KONNECTION had a higher mean ppFEV1 (79.9% and 78.8% in the placebo and IVA groups, respectively) than those in Study 104 (68.1% and 66.0% in the IVA and ELX-TEZ-IVA groups, respectively), STRIVE (63.9% and 59.6% in the placebo and IVA groups, respectively), and KONDUCT (61.3% and 68.1% in the placebo and IVA groups, respectively).

CFQ-R: Baseline CFQ-R respiratory domain scores differed across the trials, ranging from 59.1 and 70.2 in the placebo and IVA groups of the KONDUCT trial, respectively, to 80.7 and 77.3 in the placebo and IVA groups of the KONNECTION trial, respectively.

Age: The median age of patients ranged from 22.0 and 25.0 years in the placebo and IVA groups of the STRIVE trial, respectively, to 43.0 and 39.5 years in the placebo and IVA groups of the KONDUCT trial, respectively.

Treatment history

Patients in Study 104 underwent open-label treatment with IVA or TEZ-IVA (for those with F/G or F/RF genotypes, respectively) for 4 weeks prior to initiating treatment with the randomized study drugs (i.e., none of the patients were I to CFTR modulator therapy at the time of baseline measurements).

Clinical trial eligibility criteria

The trial eligibility criteria differed with respect to the following:

CFTR genotypes: Study 104 (F/G [including F/R117H] or F/RF); STRIVE (≥ 1 G551D gating mutation); KONNECTION (≥ 1 non-G551D gating mutation), KONDUCT (≥ 1 R117H mutation). Given the heterogenous populations, the subgroup data were used for patients with an F/G genotype.

Patient ages: ≥ 12 years in Study 104 and STRIVE; ≥ 6 years in KONNECTION and KONDUCT.

ppFEV1: All the studies specified that patients had to have a ppFEV1 of at least 40% at screening to be eligible. Study 104, STRIVE, and KONDUCT all specified an upper threshold for ppFEV1 of 90% at screening to determine eligibility for enrolment; KONNECTION did not specify an upper threshold for ppFEV1.

Dosing of comparators

The study drugs were used in accordance with recommendations in the Canadian product monographs for ELX-TEZ-IVA and IVA.

Response in the common comparator (i.e., placebo)

There were differences in the treatment effects in the placebo groups across the 3 placebo-controlled trials:

ppFEV1: The change from baseline in the placebo group was greater in the KONNECTION study (–2.3%) than in the STRIVE and KONDUCT trials (–0.5% and –0.1%, respectively).

CFQ-R: The CFQ-R scores decreased from baseline in the placebo groups of the STRIVE trial (–2.0) and the KONNECTION trial (–2.8) but increased in the placebo group of KONDUCT (5.1).

BMI: There were differences across the 3 trials with respect to BMI: 0.11 kg/m2 (STRIVE) 0.03 kg/m2 (KONNECTION), and 0.28 kg/m2 (KONDUCT).

Definitions of end points

The end points included in the ITC were similarly defined and evaluated for each of the included studies.

Timing of end point evaluation or trial duration

There were differences across the individual clinical trials (e.g., evaluation of ppFEV1 through 24 weeks in STRIVE and KONDUCT and through 8 weeks in Study 104 and KONNECTION); however, the sponsor recalculated the results using an MMRM to ensure that all analyses reflected the same approach.

Withdrawal frequency

There were few withdrawals from any of the trials included in the ITC.

Clinical trial setting

All 4 studies included in the ITC were phase III RCTs conducted at specialized CF clinics.

Study design

As shown in Table 30, there were differences in the following aspects of the studies:

Design: Study 104, STRIVE, and KONDUCT were all parallel group RCTs, and KONNECTION was a crossover RCT.

Run-in period: A key difference across the studies was the use of a 4-week, open-label run-in period in Study 104, where all patients received treatment with IVA prior to randomization.

Duration: The studies had different durations for the treatment periods, ranging from 8 weeks in Study 104 and KONNECTION to 48 weeks in STRIVE.

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/R117H = 1 F508del mutation and 1 R117H mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; IVA = ivacaftor; MMRM = mixed-effects model for repeated measures; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

ITC for Patients Aged 12 Years and Older With F/RF Genotype

Study Selection Methods

The criteria used by the sponsor to select studies for inclusion in the ITC for patients aged 12 years and older with F/RF genotype were as follows:

It was not reported if a systematic literature search and review was undertaken by the sponsor to identify studies for inclusion; however, CADTH did not identify any additional studies that would have met the inclusion criteria but were not included in the ITC.

ITC Analysis Methods

The indirect comparison for ELX-TEZ-IVA versus placebo in patients aged 12 years and older with an F/RF genotype was estimated using the Bucher method for continuous end points, with TEZ-IVA as the common comparator. The sponsor stated that the Bucher method was considered the most appropriate approach for this indirect comparison because of the 4-week TEZ-IVA run-in period included in Study 104 (but not in the EXPAND trial).

The sponsor used MMRMs to estimate the direct treatment effects from each of the studies, which were subsequently used in the Bucher indirect comparison. For ppFEV1, CFQ-R domain scores, and SwCl, the sponsor calculated the estimated treatment difference through 8 weeks (defined as the average of weeks 4 and 8). For BMI and weight-for-age z score, the sponsor calculated the estimated treatment difference at week 8. The model estimating the treatment difference between ELX-TEZ-IVA and TEZ-IVA included treatment group, visit, and treatment-by-visit interaction as fixed effects, patient as the random effect, and age group at screening (≥ 12 to < 18 years versus ≥ 18 years), continuous baseline ppFEV1, and continuous baseline SwCl as covariates. The model estimating the treatment difference between TEZ-IVA and placebo included treatment group, treatment period, visit within treatment period, and treatment-by-visit interaction as fixed effects, patient as the random effect, and age group at screening (≥ 12 to < 18 years versus ≥ 18 years) and continuous baseline ppFEV1 as covariates. A 2-sided 95% CI and 2-sided P values for the estimated indirect treatment differences were calculated based on normal approximation.

Table 34: Indirect Comparisons for Patients Aged 12 Years and Older With F/RF Genotype

Indirect estimate

Direct estimates (study)

End point

ELX-TEZ-IVA versus placebo

ELX-TEZ-IVA versus TEZ-IVA (subgroup data from Study 104) + TEZ-IVA versus placebo (EXPAND)

ppFEV1 (through 8 weeks)

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.51

Results for ITC Analysis
Included Studies

The evidence network for the studies with patients aged 12 years and older who have an F/RF genotype is shown in Figure 7. Indirect comparison was performed for ELX-TEZ-IVA versus placebo. The direct evidence for ELX-TEZ-IVA versus TEZ-IVA was derived from a subgroup analysis of Study 104. The direct estimate for TEZ-IVA versus placebo was from the EXPAND trial.

Figure 7: Indirect Comparison Network for Patients Aged 12 Years and Older With F/RF Genotype

Figure shows evidence network for indirect comparison for patients aged 12 years and older with an F/RF genotype.

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; TEZ/IVA = tezacaftor-ivacaftor and ivacaftor; vs = versus.

Source: Sponsor’s indirect treatment comparison.51

Study Characteristics

Table 35 provides a summary of the characteristics of the trials included in the indirect comparison for patients aged 12 years and older with an F/RF genotype (Study 104 and the EXPAND trial). A key difference between the 2 studies was the use of a 4-week, open-label run-in period in Study 104, in which all patients received treatment with TEZ-IVA prior to randomization. The double-blind treatment period was the same in the 2 studies (i.e., 8 weeks). Both trials enrolled patients aged 12 years or older and specified that patients had to have a ppFEV1 between 40% and 90% to be eligible. The inclusion criteria differed across the 2 studies with respect to CFTR genotypes. Study 104 enrolled patients with an F/G (including F/R117H) or an F/RF genotype. The EXPAND trial was conducted only in patients with an F/RF genotype. Given the heterogenous study population of Study 104, the sponsor extracted subgroup data for patients who had an F/RF genotype (163 of 258 [63%]) for use in the indirect comparison.

Both Study 104 and the EXPAND trial specified absolute change in ppFEV1 from baseline as the primary end point but differed in how the assessments were performed (through 8 weeks in Study 104 and using an average of weeks 4 and 8 in EXPAND). Both studies included changes from baseline in BMI, CFQ-R, SwCl, and body weight as additional end points. The EXPAND trial included pulmonary exacerbations as an efficacy end point, and Study 104 did not; therefore, no indirect comparison can be conducted for this end point.

Table 35: Study Characteristics for Patients Aged 12 Years and Older With F/RF Genotype

Characteristic

Study 104

EXPAND

Study population

Patients with F/G (including F/R117H) or F/RF genotypes and aged ≥ 12 years

Patients with F/RF genotypes and aged ≥ 12 years

Design

DB, active-controlled, parallel group RCT

DB, placebo-controlled, crossover RCT

Active run-in period

4 weeks with TEZ-IVA or IVA

None

Treatment period

8 weeks

8 weeks

Treatment groups

  • ELX-TEZ-IVA

  • TEZ-IVA (F/RF)

  • IVA (F/G)

  • TEZ-IVA

  • IVA

  • Placebo

ppFEV1 inclusion criteria at screening

40% to 90%

40% to 90%

Schedule of assessments

Day 1, day 15, week 4, week 8

Day 1, day 15, week 4, week 8, week 12 of each treatment period

Sample size

  • ELX-TEZ-IVA: 132

  • TEZ-IVA: 81

  • IVA: 45

  • TEZ-IVA: 161

  • IVA: 156

  • Placebo: 161

Subset of patients included in ITC

  • ELX-TEZ-IVA: 82

  • TEZ-IVA: 81

  • TEZ-IVA: 161

  • Placebo: 161

Primary efficacy end point

Absolute change in ppFEV1 from baseline through 8 weeks

Absolute change in ppFEV1 from baseline through average of week 4 and week 8 measurements

Other end points

BMI, CFQ-R, SwCl, body weight (Did not include PEx as an efficacy end point)

BMI, CFQ-R, PEx, SwCl, body weight

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; DB = double blind; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/R117H = 1 F508del mutation and 1 R117H mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; IVA = ivacaftor; PEx = pulmonary exacerbation; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; SwCl = sweat chloride; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.51

Baseline Characteristics

Baseline and demographic characteristics for the F/RF studies are summarized in Table 36. The median age at screening differed between Study 104 (42.0 and 40.3 years in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) and EXPAND (33.0 and 35.0 years in the placebo and TEZ-IVA groups, respectively). The percentage of male and female patients in the 2 studies was similar. The percentage of patients younger than 18 years at screening was greater in the EXPAND trial (14.9% and 13.0% in the placebo and TEZ-IVA groups, respectively) than in Study 104 (3.7% and 8.5% in the TEZ-IVA and ELX-TEZ-IVA groups, respectively). Patients in Study 104 had a higher mean ppFEV1 at baseline (68.1% and 67.8% in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than those in the EXPAND trial (62.1% and 62.0% in the placebo and TEZ-IVA groups, respectively). Mean BMI at baseline was similar in Study 104 and the EXPAND trial. Baseline SwCl levels were lower in Study 104 (61.4 mmol/L and 64.7 mmol/L in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than in the EXPAND trial (70.2 mmol/L and 67.0 mmol/L in the placebo and TEZ-IVA groups, respectively). Baseline CFQ-R respiratory domain scores were higher in Study 104 (78.1 and 76.7 in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than in the EXPAND trial (68.7 and 68.2 in the placebo and TEZ-IVA groups, respectively).

Table 36: Baseline Characteristics for Patients Aged 12 Years and Older With F/RF Genotype

Characteristic

Study 104

EXPAND

TEZ-IVA

(N = 81)

ELX-TEZ-IVA

(N = 82)

Placebo

(N = 161)

TEZ-IVA

(N = 161)

Sex, n (%)

   Male

37 (45.7)

37 (45.1)

71 (44.1)

72 (44.7)

   Female

44 (54.3)

45 (54.9)

90 (55.9)

89 (55.3)

Age at screening (years)

   Mean (SD)

41.3 (14.4)

40.1 (14.7)

34.6 (14.4)

35.6 (14.5)

   Median

42.0

40.3

33.0

35.0

Age group at screening (years), n (%)

   12 to < 18

3 (3.7)

7 (8.5)

24 (14.9)

21 (13.0)

   ≥ 18

78 (96.3)

75 (91.5)

137 (85.1)

140 (87.0)

ppFEV1, mean (SD)

68.1 (16.4)

67.8 (16.3)

62.1 (14.2)

62.0 (14.5)

BMI (kg/m2), mean (SD)

24.68 (5.22)

24.29 (5.23)

24.63 (5.41)

24.06 (4.74)

Sweat chloride (mmol/L), mean (SD)

61.4 (27.3)

64.7 (27.9)

70.2 (25.7)

67.0 (26.8)

CFQ-R respiratory domain score, mean (SD)

78.1 (14.7)

76.7 (16.9)

68.7 (18.3)

68.2 (17.5)

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ppFEV1 = percent predicted forced expiratory volume in the first second; SD = standard deviation; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.51

Indirect Comparison Results

Table 37 provides a summary of the results for the direct and indirect comparisons for studies conducted in patients aged 12 years and older with an F/RF genotype. The indirect comparison results are shown side by side with the direct comparison results for ELX-TEZ-IVA versus TEZ-IVA (derived from the subgroup analysis from Study 104) and direct comparison results for TEZ-IVA versus placebo from the EXPAND trial.

The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo: || || |||||| || |||||| ||| || ||| for absolute change in ppFEV1 from baseline through 8 weeks; –33.6 mmol/L || || |||||| || |||||| ||| || ||| for absolute change in SwCl from baseline through 8 weeks; 0.31 kg/m2 (95% CI, 0.04 to 0.57; P = 0.0219) for absolute change in BMI from baseline at 8 weeks; and || || |||||| || |||||| ||| || ||| for absolute change in weight-for-age z score from baseline at 8 weeks.

Indirect estimates of effect for ELX-TEZ-IVA compared with placebo are provided for each of the CFQ-R domains, with favourable effects reported for respiratory symptoms || || |||||| || |||||| ||| || |||; physical functioning || || |||||| || |||||| ||| || |||; vitality || || |||||| || |||||| ||| || |||; eating problems || || |||||| || |||||| ||| || |||; health perceptions || || |||||| || |||||| ||| || |||; digestive symptoms || || |||||| || |||||| ||| || |||; and social functioning || || |||||| || |||||| ||| || |||.

Table 37: Results of Direct and Indirect Comparison for Patients Aged 12 Years and Older With F/RF Genotype

End point

Direct estimate LSMD (95% CI), P value

Indirect estimates

Bucher mean between-group difference

(95% CI), P value

ELX-TEZ-IVA vs. placebo

ELX-TEZ-IVA vs. TEZ-IVA

TEZ-IVA vs. placebo

Absolute change in ppFEV1 from baseline through 8 weeks

|| || |||||| || |||||| ||| || |||

|| || |||||| || |||||| ||| || |||

|| || |||||| || |||||| ||| || |||

CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; LSMD = least squares mean difference; ppFEV1 = percent predicted forced expiratory volume in the first second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor; vs. = versus.

Source: Sponsor’s indirect treatment comparison.51

Critical Appraisal

Table 38 summarizes the assessment of homogeneity for the ITC of the studies of patients aged 12 years and older with an F/RF genotype. The primary difference between Study 104 and the EXPAND trial was the use of an open-label, 4-week active treatment period with TEZ-IVA in Study 104. This trial was essentially investigating switching to ELX-TEZ-IVA from TEZ-IVA compared with remaining on TEZ-IVA for patients with an F/RF genotype. This is a different design than the placebo-controlled EXPAND trial, in which all patients were naive to CFTR modulators at baseline. In contrast, the baseline parameters for patients in Study 104 were assessed after 4 weeks of treatment with a CFTR modulator (TEZ-IVA). As both the ELX-TEZ-IVA and TEZ-IVA groups of Study 104 received 4 weeks of treatment with TEZ-IVA, it is unclear if the run-in period would introduce bias into the ITC analysis (e.g., would the mean difference between TEZ-IVA and ELX-TEZ-IVA be reduced because of the run-in period, or would it be relatively unchanged?).

As noted in Table 38, there are important differences in the baseline and end point values between Study 104 and the EXPAND trial due to the 4 weeks of active treatment that patients in Study 104 received prior to randomization.

Table 38: CADTH Assessment of Homogeneity for the ITC for Patients Aged 12 Years and Older With F/RF Genotype

Characteristic

Description and handling of potential effect modifiers

Disease severity

Age: Median age at screening was greater in Study 104 (42.0 and 40.3 years in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than in the EXPAND trial (33.0 and 35.0 years in the placebo and TEZ-IVA groups, respectively).

ppFEV1: Study 104 had a higher mean ppFEV1 at baseline (68.1% and 67.8% in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than the EXPAND trial (62.1% and 62.0% in the placebo and TEZ-IVA groups, respectively).

SwCl: Baseline SwCl levels were lower in Study 104 (61.4 mmol/L and 64.7 mmol/L in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than in the EXPAND trial (70.2 mmol/L and 67.0 mmol/L in the placebo and TEZ-IVA groups, respectively).

CFQ-R: Baseline CFQ-R respiratory domain scores were greater in Study 104 (78.1 and 76.7 in the TEZ-IVA and ELX-TEZ-IVA groups, respectively) than in the EXPAND trial (68.7 and 68.2 in the placebo and TEZ-IVA groups, respectively).

Treatment history

Patients in Study 104 underwent open-label treatment with IVA or TEZ-IVA (for those with F/G or F/RF genotypes, respectively) for 4 weeks prior to initiating treatment with the randomized study drugs (i.e., none of the patients were naive to CFTR modulator therapy at the time of baseline measurements).

Clinical trial eligibility criteria

The inclusion criteria differed across the 2 studies with respect to CFTR genotypes. Study 104 enrolled patients with an F/G (including F/R117H) or an F/RF genotype. The EXPAND trial was conducted only in patients with an F/RF genotype. Given the heterogenous study population of Study 104, subgroup data were used for the ITC.

Response in the common comparator (i.e., TEZ-IVA)

Due to the different designs of Study 104 and the EXPAND trial, there are important differences in the change from baseline within the TEZ-IVA groups included in the indirect comparisons:

  • ppFEV1: 0.5% (Study 104) and 6.3% (EXPAND)

  • CFQ-R respiratory domain score: 1.7 (Study 104) and 10.1 (EXPAND)

  • BMI: 0.11 kg/m2 (Study 104) and 0.36 kg/m2 (EXPAND)

Dosing of comparators

Both ELX-TEZ-IVA and TEZ-IVA were administered in accordance with recommendations in the Canadian product monographs.29,39 However, patients in the TEZ-IVA group of Study 104 would have received this drug for a total of 12 weeks (i.e., 4 weeks in the run-in period and then 8 weeks in the double-blind phase), compared with only 8 weeks of treatment for those in the EXPAND trial.

Definitions of end points

The end points included in the ITC were similarly defined and evaluated for each of the included studies.

Timing of end point evaluation or trial duration

Both Study 104 and the EXPAND trial specified absolute change in ppFEV1 from baseline as the primary end point but differed in how the assessments were performed (through 8 weeks in Study 104 and using an average of weeks 4 and 8 in EXPAND); however, the sponsor recalculated the results using an MMRM to ensure that all analysis reflected the same approach.

Withdrawal frequency

There were few withdrawals from either of the trials included in the ITC.

Clinical trial setting

Both Study 104 and EXPAND were phase III RCTs conducted at specialized CF clinics.

Study design

Study 104 and EXPAND were similarly designed, except for the key difference between the studies: the use of a 4-week, open-label run-in period in Study 104, in which all patients received treatment with TEZ-IVA prior to randomization.

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/R117H = 1 F508del mutation and 1 R117H mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; IVA = ivacaftor; MMRM = mixed-effects model for repeated measures; ppFEV1 = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; SwCl = sweat chloride; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Summary of ITCs

Patients Aged 6 to 11 Years

The sponsor conducted a single indirect comparison for patients aged 6 to 11 years with an F/F genotype to derive relative estimates of clinical efficacy for ELX-TEZ-IVA versus LUM-IVA, ELX-TEZ-IVA versus placebo, and ELX-TEZ-IVA versus TEZ-IVA. TEZ-IVA is not currently approved by Health Canada or reimbursed by the Canadian public drug programs for use in patients aged 6 to 11 years. To conduct the primary indirect comparisons, the sponsor extracted 24-week individual patient-level data for patients with an F/F genotype from the following studies: Study 106B for ELX-TEZ-IVA (N = 29); pooled data from Study 809-109 and Study 809-011B for LUM-IVA (N = 160); and Study 661-113B (N = 61) for TEZ-IVA. Additional sensitivity analyses were performed using 8-week data. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo for absolute change from baseline through 24 weeks: || || |||||| || |||||| ||| || ||| for ppFEV1.

The primary limitations of the ITC were the difference in study design across the included studies (Studies 106B, 809-011B, and 661-113B were single-arm, open-label trials, and Studies 809-109 and 661-115 were double-blind, placebo-controlled trials) and the differences in baseline characteristics.

Patients Aged 12 Years and Older

For patients with an F/G genotype, indirect comparisons were performed for ELX-TEZ-IVA versus placebo. The direct evidence for ELX-TEZ-IVA versus IVA was derived from a subgroup analysis of Study 104, and the estimates for IVA versus placebo were derived from a meta-analysis of subgroup analyses from 3 studies: STRIVE, KONNECTION, and KONDUCT. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo for absolute change from baseline through 8 weeks: || || |||||| || |||||| ||| || ||| for ppFEV1.

For patients with an F/RF genotype, indirect comparisons were performed for ELX-TEZ-IVA versus placebo. The direct evidence for ELX-TEZ-IVA versus TEZ-IVA was derived from a subgroup analysis of Study 104, and the estimates for TEZ-IVA versus placebo were from the EXPAND trial. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with placebo for absolute change from baseline through 8 weeks: || || |||||| || |||||| ||| || ||| for ppFEV1.

The primary limitation of the ITC was the difference in study design across the included studies. The ELX-TEZ-IVA study (i.e., Study 104) included an open-label, 4-week active treatment period with TEZ-IVA or IVA prior to randomization. None of the other trials used in the ITC had a similar run-in period; therefore, the study designs, baseline values, and end point values for the common comparator were different. As both the ELX-TEZ-IVA and comparator groups in Study 104 received 4 weeks of treatment with a CFTR modulator, it is unclear if the run-in period would introduce bias into the ITC analysis.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CADTH review team.

The sponsor did not include any additional studies to address gaps in the pivotal trial evidence.

Discussion

Summary of Available Evidence

The evidence for the review of ELX-TEZ-IVA in patients aged 2 to 5 years was derived from a review of pivotal and phase III studies. CADTH has previously reviewed ELX-TEZ-IVA for the treatment of CF in patients who have at least 1 F508del mutation in the CFTR gene for patients aged 12 years and older (final recommendation issued in August 2021) and for patients aged 6 years and older (final recommendation issued in June 2022). As reflected in the Canadian product monograph, patients aged 2 to 5 years would receive ELX-TEZ-IVA as oral granules as opposed to tablets.

The current CADTH review is focused only on patients aged 2 to 5 years, and the new evidence consisted of a pivotal, open-label, single-arm trial (Study 111). The regulatory submission for ELX-TEZ-IVA is based on the extrapolation of efficacy data from older age groups to a younger population based on comparable pharmacokinetic exposures and safety. The sponsor noted that the extrapolation of efficacy was appropriate and aligned with the principles described in the International Council for Harmonisation (ICH) of Technical Requirements of Pharmaceuticals for Human Use Guidance: E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population. Specifically, the sponsor noted that the extrapolation was appropriate for the following reasons:

The clinical experts consulted by CADTH concurred with the sponsor and concluded that extrapolation of the efficacy data to patients aged 2 to 5 years was appropriate for ELX-TEZ-IVA. The experts noted that all patients with at least 1 F508del mutation would benefit from ELX-TEZ-IVA, given the mechanism of action for the drug.

The sponsor reported that an ITC was attempted to compare the clinical efficacy of ELX-TEZ-IVA in Study 111 with other relevant CFTR modulators in patients with F/F and F/MF mutations to generate the inputs needed for the cost-effectiveness analysis. The sponsor concluded that the ITC was not feasible due to the small number of patients in this age group, which reduced the power to detect differences between ELX-TEZ-IVA, LUM-IVA, and/or placebo. As such, the sponsor did not include the ITC in its submission to CADTH and used estimates from the previous CADTH submissions for patients aged 6 to 11 years (patients with F/F genotype) and patients aged 12 years and older (patients with F/G and F/RF genotypes) as assumptions within its economic model. No indirect comparison was submitted for patients with an F/MF genotype, and the sponsor used the placebo-adjusted data from Study 116 in patients aged 6 to 11 years to inform the economic model.

Interpretation of Results

Efficacy

As previously reported in CADTH reviews of ELX-TEZ-IVA, LCI is not currently used in Canadian clinical practice to evaluate lung function in patients with CF, but it has been recommended as an end point in clinical trials conducted in younger patients.8 This is because spirometry may not be sensitive enough to detect treatment differences in patients who have relatively normal lung function but may still have underlying structural abnormalities in the lungs. In Study 111, ELX-TEZ-IVA demonstrated an improvement from baseline in LCI2.5 through 24 weeks of treatment (absolute reduction = –0.83; 95% CI, –1.01 to –0.66).56 The mean improvements from baseline were observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). In previous CADTH reviews of CFTR modulators in pediatric patients (including ELX-TEZ-IVA for patients aged 6 to 11 years), the sponsor indicated that LCI is correlated with FEV1 (which has been validated as an end point) in its ability to measure airway disease. CADTH’s review of the literature found that the correlation between LCI and FEV1 was variable across studies, an observation supported by the clinical experts consulted by CADTH. Overall, the clinical experts consulted by CADTH indicated that LCI is not currently used in Canadian practice and that there is no consensus in the Canadian clinical community regarding the magnitude of improvement in LCI2.5 that would be considered clinically relevant.

Within-group change from baseline in body weight, height, and BMI is challenging to interpret for patients aged 2 to 5 years, who would be expected to experience growth over the 6-month study period. Study 111 was not powered to evaluate changes in these end points, and no statistical analyses were conducted by the sponsor. The clinical experts consulted by CADTH noted that the results from the previously reviewed studies, where ELX-TEZ-IVA demonstrated improvements from baseline in patients aged 6 to 11 years, are sufficient to conclude that ELX-TEZ-IVA would also improve or maintain growth parameters for patients aged 2 to 5 years. The clinical experts noted that patients with CF living in Canada in the target age range (i.e., 2 to 5 years) are generally well nourished in Canada as a result of early diagnosis through newborn screening and aggressive disease management through specialized clinics. As such, it was noted that the magnitude of improvement in growth parameters following initiation of ELX-TEZ-IVA would be lower in patients aged 2 to 5 years than in older patients.

Pulmonary exacerbations were included as an exploratory end point in Study 111, with no statistical analyses performed to examine change from baseline in the annual exacerbation rate. After 24 weeks of ELX-TEZ-IVA treatment, 12 patients (16.0%) each experienced 1 pulmonary exacerbation (annualized event rate = 0.32 events per year). In response to an inquiry from CADTH regarding why pulmonary exacerbations were not included as an efficacy end point with prebaseline and postbaseline evaluation of exacerbation rates, the sponsor reported that a treatment effect may be difficult to detect in Study 111 given the relative rareness of these events in younger patients relative to older patients. The clinical experts consulted by CADTH noted that the proportion of patients who reported at least 1 pulmonary exacerbation over the 24-week study period was low compared with what would be anticipated for patients aged 2 to 5 years who are not receiving a CFTR modulator. Patients enrolled in Study 111 Part B were enrolled and evaluated between July 2021 and June 2022. The clinical experts noted that exacerbation rates reported in CF clinical trials and those observed in Canadian clinical practice were generally reduced during the COVID-19 pandemic. Physical distancing and the suspension of in-person classes and daycare have been cited as contributing factors to the reduction in exacerbations. Similar observations have been reported in US, where the rate of exacerbations decreased during the COVID-19 pandemic for patients receiving ELX-TEZ-IVA and for those not receiving ELX-TEZ-IVA.57 The clinical experts emphasized that 6 months is generally insufficient to evaluate changes in exacerbation frequency as there is expected to be seasonal variation.

Overall, the clinical experts noted that ELX-TEZ-IVA would be expected to reduce exacerbation frequency and severity in the small subset of patients aged 2 to 5 years who experience frequent exacerbations. For patients who are not experiencing frequent exacerbations, ELX-TEZ-IVA would be expected to help prevent severe exacerbations as the drug will help maintain healthier airways and promote clearance of secretions. However, the clinical experts strongly emphasized that exacerbation frequency will be variable in these young patients and can be influenced by seasonality and exposure to viruses from siblings, daycare, and/or school. There is consensus that ELX-TEZ-IVA will result in meaningful improvements for patients aged 2 to 5 years but that objectively measuring changes in pulmonary exacerbations for the purposes of initiation or renewal of drug reimbursement would be challenging in clinical practice.

Study 111 was limited to patients with an F/F or F/MF genotype. No clinical studies have been conducted with ELX-TEZ-IVA in pediatric patients with F/RF or F/G genotypes; however, the clinical experts noted that ELX-TEZ-IVA would result in clinically meaningful improvements for these patients, based on the evidence reported for ELX-TEZ-IVA in adult patients with F/RF and F/G genotypes and the results in pediatric studies of patients with F/F and F/MF genotypes (both in those aged 6 to 11 years and in those aged 2 to 5 years). This is consistent with the input from patient and clinician groups, who have indicated that all patients with at least 1 F508del mutation would be likely to benefit from treatment with ELX-TEZ-IVA.

Harms

As in the previous reviews of ELX-TEZ-IVA in patients aged 6 years and older, the granular formulation of ELX-TEZ-IVA was well tolerated in the target patient population (i.e., patients aged 2 to 5 years with at least 1 F508del mutation). There have been no updates to the warnings and precautions section of the ELX-TEZ-IVA product monograph since the previous CADTH review.

Serious AEs and withdrawals due to AEs were rare in Study 111. The clinical experts consulted by CADTH noted that intolerance to ELX-TEZ-IVA has been rare in clinical practice with adolescents and adults. The clinical experts consulted by CADTH noted that patients who experience significant AEs following initial treatment with ELX-TEZ-IVA would not likely be completely discontinued from treatment; rather, treatment with ELX-TEZ-IVA would likely be interrupted and the patient would be rechallenged with the drug following resolution of the event(s). This is consistent with the input received from the clinician groups, who noted that discontinuation of therapy should be considered in patients who have clinically significant adverse effects that persist and recur after stopping and reinitiating therapy.

Similar to the development programs for the other CFTR modulators (IVA, LUM-IVA, and TEZ-IVA), patients with abnormal liver function were excluded from the phase III ELX-TEZ-IVA trials. The clinical experts consulted by CADTH noted that most patients who could be eligible for ELX-TEZ-IVA would not have hepatic impairment. The product monograph recommends that the dosage of ELX-TEZ-IVA should be adjusted in patients with moderate hepatic impairment and that the drug should not be used in patients with severe hepatic impairment.29 These recommendations are more restrictive than those in the product monographs for IVA, LUM-IVA, and TEZ-IVA,29,37,38 all of which provide dosage reduction scenarios for patients with CF who have severe hepatic impairment. The clinical experts consulted by CADTH suggested that clinicians may attempt to treat patients with severe hepatic impairment using ELX-TEZ-IVA at a reduced dosage, as opposed to using the reduced dosages of the alternative CFTR modulators, which are unlikely to provide the same level of clinical benefit.

The product monograph notes that elevated transaminases have been observed in patients treated with ELX-TEZ-IVA and recommends that ALT and AST be assessed prior to initiating treatment with ELX-TEZ-IVA, every 3 months during the first year of treatment, and annually thereafter.29 The clinical experts consulted by CADTH noted that the recommendations for monitoring would likely be followed by the clinical community. The clinical experts consulted by CADTH and the clinician groups who provided input noted that patients with CF are typically seen once every 3 months (though this has been less frequent in some cases due to the COVID-19 pandemic). As such, the recommended monitoring regimen for ELX-TEZ-IVA was not anticipated to result in a substantial increase in the number of clinic visits for patients with CF (particularly after the first year of treatment).

Similar to IVA, LUM-IVA, and TEZ-IVA, the product monograph for ELX-TEZ-IVA notes that cases of noncongenital cataracts without impact on vision have been reported in pediatric patients treated with IVA-containing regimens.29,37-39 The product monograph also notes that the patients who demonstrated these events had other risk factors (e.g., corticosteroid use or exposure to radiation); however, a possible risk attributable to treatment with IVA cannot be excluded. As such, it is recommended that pediatric patients beginning treatment with ELX-TEZ-IVA receive baseline and follow-up ophthalmological examinations.29 The clinical experts consulted by CADTH noted that children with CF currently have an ophthalmological examination prior to starting treatment with a CFTR modulator and are monitored on an ongoing basis thereafter.

The sponsor’s indirect comparisons did not investigate the comparative safety of ELX-TEZ-IVA versus IVA, LUM-IVA, or TEZ-IVA.50,51 The clinical trials included in this review demonstrated that ELX-TEZ-IVA does not appear to be associated with the respiratory AEs (e.g., dyspnea and abnormal respiration) reported in the pivotal trials with LUM-IVA.10,34,35,37,58

Other Considerations

The FDA extended the approval of ELX-TEZ-IVA to include an additional 177 mutations in the CFTR gene that have shown to be responsive to ELX-TEZ-IVA based on data from in vitro assays.30,59

Conclusion

For patients aged 2 to 5 years, a 24-week, open-label, uncontrolled trial (Study 111 Part B; N = 75) suggested that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function (decrease in LCI2.5 from baseline) and in CF biomarkers (reduction in SwCl). Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA, as the regulatory submission is based on the extrapolation of efficacy data from the studies conducted in older patients with CF (i.e., those showing some measurable level of disease manifestations at baseline). The clinical experts consulted by CADTH noted that, given its mechanism of action and the compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA would be expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. There is consensus across clinicians and patients that treatment with ELX-TEZ-IVA should be initiated as soon as possible, given the clinically meaningful benefits observed in patients who can currently access the treatment. Uncertainty remains regarding the magnitude of the beneficial effect of ELX-TEZ-IVA in very young patients with CF, and future real-world evidence may help address this uncertainty.

Study 111 was limited to patients with an F/F or F/MF genotype. No clinical studies have been conducted with ELX-TEZ-IVA in pediatric patients with F/RF or F/G genotypes; however, the clinical experts noted that ELX-TEZ-IVA would result in clinically meaningful improvements for these patients, based on the evidence reported for ELX-TEZ-IVA in adult patients with F/RF and F/G genotypes and the results in pediatric studies of patients with F/F and F/MF genotypes. This is consistent with the input from patient and clinician groups, who have indicated that all patients with at least 1 F508del mutation would be likely to benefit from treatment with ELX-TEZ-IVA.

ELX-TEZ-IVA was well tolerated in the target patient population (i.e., patients aged 2 to 5 years with at least 1 F508del mutation). Serious AEs and withdrawals due to AEs were rare in Study 111. The product monograph notes that elevated transaminases have been observed in patients treated with ELX-TEZ-IVA and recommends that ALT and AST be assessed prior to initiating treatment with ELX-TEZ-IVA, every 3 months during the first year of treatment, and annually thereafter. The clinical experts consulted by CADTH noted that the recommendations for monitoring with ELX-TEZ-IVA were not anticipated to result in a substantial increase in the number of clinic visits for patients with CF (particularly after the first year of treatment).

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28.Vertex Pharmaceuticals. Cystic Fibrosis Expert Opinion [internal sponsor's report]. 2022.

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32.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: ivacaftor (Kalydeco - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2014 Dec 19: https://www.cadth.ca/sites/default/files/cdr/complete/cdr_complete_SR0379_Kalydeco_Dec-23-14.pdf. Accessed 2023 Nov 15.

33.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: ivacaftor (Kalydeco - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2015 Nov 19: https://www.cadth.ca/sites/default/files/cdr/complete/SR0430_complete_Kalydeco_R117H_Nov-23-15_e.pdf. Accessed 2023 Nov 15.

34.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: lumacaftor/ivacaftor (Orkambi - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2016 Oct 26: https://www.cadth.ca/sites/default/files/cdr/complete/SR0471_complete_Orkambi-Oct-28-16.pdf. Accessed 2023 Nov 15.

35.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: lumacaftor/ivacaftor (Orkambi - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2018 Sep 26: https://www.cadth.ca/sites/default/files/cdr/complete/SR0559%20Orkambi%20-%20CDEC%20Final%20Recommendation%20October%204%2C%202018.pdf. Accessed 2023 Nov 15.

36.CADTH reimbursement review status: tezacaftor/ivacaftor. 2019; https://www.cadth.ca/tezacaftorivacaftor. Accessed 2023 Nov 15.

37.Orkambi®, lumacaftor/ivacaftor tablets 100 mg/125 mg and 200 mg/125 mg, lumacaftor/ivacaftor granules 100 mg/125 mg and 150 mg/188 mg [product monograph]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2018 Dec 11: https://pdf.hres.ca/dpd_pm/00048664.PDF. Accessed 2023 Nov 15.

38.Kalydeco®: ivacaftor tablets 150 mg, ivacaftor granules 50 mg per packet, 75 mg per packet [product monograph]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2019 Jan 25: https://pdf.hres.ca/dpd_pm/00049400.PDF. Accessed 2023 Nov 15.

39.Clinical Study Report: VX18-445-106. A phase 3 study evaluating the pharmacokinetics, safety, and tolerability of VX-445/TEZ/IVA triple combination therapy in cystic fibrosis subjects 6 through 11 years of age [internal sponsor's report]. Boston (MA): Vertex Pharmaceuticals Incorporated; 2020 Nov 11.

40.Goralski JL, Hoppe, J.E., Mall, M.A., McColley, S.A., McKone, E., Ramsey, B., Rayment, J.H., Robinson, P., Stehling, F., Taylor-Cousar, J.L., Tullis, E., Ahluwalia, N., Chin, A., Chu, C., Lu, M., Niu, T., Weinstock, T., Ratjen, F., Rosenfeld, M.; VX20-445-111 Study Group. Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2 Through 5 Years with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2023 Jul 1;208(1):59-67. PubMed

41.Vertex Pharmaceuticals Incorporated. NCT04537793: Evaluation of ELX/TEZ/IVA in Cystic Fibrosis (CF) Subjects 2 Through 5 Years. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/NCT04537793. Accessed 2023 Nov 15.

42.Clinical Study Report: A Phase 3 Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy in Cystic Fibrosis Subjects 2 Through 5 Years of Age [internal sponsor's report]. Toronto (ON): Vertex Pharmaceuticals Incorporated; 2022.

43.Vertex Pharmaceuticals Incorporated. NCT04545515: A study evaluating the long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis (CF) subjects 6 years and older and F/MF genotypes. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2023: https://clinicaltrials.gov/ct2/show/NCT05153317. Accessed 2023 May 18.

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45.Kent L, Reix P, Innes JA, et al. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123-138. PubMed

46.Vertex Pharmaceuticals. Protocol Number VX20-445-111, Version 3.0, Statistical Analysis Plan [internal sponsor's report]. 2022.

47.The Canadian Cystic Fibrosis registry: 2020 annual data report. Toronto (ON): Cystic Fibrosis Canada; 2022: https://www.cysticfibrosis.ca/registry/2020AnnualDataReport.pdf. Accessed 2023 May 19.

48.CADTH Reimbursement Review Clinical and Pharmacoeconomic Review Report: elexacaftor-tezacaftor ivacaftor and ivacaftor (Trikafta - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2021: https://www.cadth.ca/sites/default/files/DRR/2021/SR0673-combined-report.pdf. Accessed 2023 Nov 15.

49.CADTH Reimbursement Review Clinical and Pharmacoeconomic Review Report: elexacaftor-tezacaftor ivacaftor and ivacaftor (Trikafta - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2022: https://www.cadth.ca/sites/default/files/DRR/2022/SR0710-Trikafta_combined.pdf. Accessed 2023 May 19.

50.Drug Reimbursement Review sponsor submission: Trikafta, oral elexacaftor 50 mg / tezacaftor 25 mg / ivacaftor 37.5 mg and ivacaftor 75 mg; elexacaftor 100 mg / tezacaftor 50 mg / ivacaftor 75 mg and ivacaftor 150 mg; [internal sponsor's package]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2021 Nov 5.

51.Drug Reimbursement Review sponsor submission: Trikafta, elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg tablets and ivacaftor 150 mg tablets; elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg tablets and ivacaftor 75 mg tablets oral [internal sponsor's package]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2021 Jan 21.

52.Vertex Pharmaceuticals Incorporated. NCT04105972: A study evaluating the efficacy and safety of VX-445/tezacaftor/ivacaftor in cystic fibrosis subjects, homozygous for F508del. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/NCT04105972. Accessed 2023 Nov 15.

53.Ramsey BW, Davies J, McElvaney NG, et al. A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation. N Engl J Med. 2011;365(18):1663-1672. PubMed

54.Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015;3(7):524-533. PubMed

55.De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014;13(6):674-680. PubMed

56.Clinical Study Report: VX19-445-116. A phase 3b, randomized, placebo-controlled study evaluating the efficacy and safety of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis subjects 6 through 11 years of age who are heterozygous for the F508del mutation and a minimal function mutation (F/MF) [internal sponsor's report]. Boston (MA): Vertex Pharmaceuticals Incorporated; 2021 Aug 27.

57.Flume PA, Saiman L, Marshall B. The Impact of COVID-19 in Cystic Fibrosis. Arch Bronconeumol. 2022;58(6):466-468. PubMed

58.CADTH Common Drug Review Clinical Review Report: lumacaftor/ivacaftor (Orkambi - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2016 Jan 26: https://www.cadth.ca/sites/default/files/cdr/clinical/SR0471_Orkambi_CL_Report.pdf. Accessed 2023 Nov 15.

59.Vertex Pharmaceuticals Incorporated. Vertex announces FDA approvals of Trikafta® (elexacaftor/tezacaftor/ivacaftor and ivacaftor), Symdeko® (tezacaftor/ivacaftor and ivacaftor) and Kalydeco® (ivacaftor) for use in people with CF with certain rare mutations. 2020; https://news.vrtx.com/press-release/vertex-announces-fda-approvals-trikaftar-elexacaftortezacaftorivacaftor-and-ivacaftor. Accessed 2023 Nov 15.

60.Clinical Study Report: study 102. A phase 3, randomized, double-blind, controlled study evaluating the efficacy and safety of VX-445 combination therapy in subjects with cystic fibrosis who are heterozygous for the F508del mutation and a minimal function mutation (F/MF) [internal sponsor's report]. Toronto (ON): Vertex Pharmaceuticals Incorporated; 2019 Jul 2.

61.Clinical Study Report: study 103. A phase 3, randomized, double-blind, controlled study evaluating the efficacy and safety of VX-445 combination therapy in subjects with cystic fibrosis who are homozygous for the F508del mutation (F/F) [internal sponsor's report]. Toronto (ON): Vertex Pharmaceuticals Incorporated; 2019 Jun 18.

62.Clinical Study Report: study 104. A phase 3, randomized, double-blind, controlled study evaluating the efficacy and safety of elexacaftor combination therapy in subjects with cystic fibrosis who are heterozygous for the F508del mutation and a gating or residual function mutation (F/G and F/RF genotypes) [internal sponsor's report]. Toronto (ON): Vertex Pharmaceuticals Incorporated; 2020 Aug 28.

63.Clinical Study Report: study 109. A phase 3b, randomized, double-blind, controlled study evaluating the efficacy and safety of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis subjects, homozygous for F508del [internal sponsor's report]. Toronto (ON): Vertex Pharmaceuticals Incorporated; 2020 Oct 16.

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Appendix 1: Key Results From Studies of Patients Aged 6 to 11 Years

Note that this appendix has not been copy-edited.

Table 39: Summary of Key Results From Pediatric Studies

Analysis

Study 116

Study 106B

(N = 66)

Placebo

(N = 61)

ELX-TEZ-IVA

(N = 60)

Absolute change in ppFEV1 (%) through week 24

Baseline mean (SD)

87.2 (15.8)

91.4 (13.8)

88.8 (17.7)

Patients in analysis

59

59

59

LS mean change (SE)

–1.5 (1.5)

9.5 (1.5)

10.2 (1.2)

P value within treatment

0.2977

< 0.0001

< 0.0001

LSMD (95% CI)

Reference

11.0 (6.9, 15.1)

NA

P value versus placebo

Reference

< 0.0001

NA

Absolute change from baseline in LCI2.5 through week 24

Baseline mean (SD)

9.75 (1.95)

10.26 (2.22)

9.77 (2.68)

Patients in analysis

61

60

50

LS mean change (SE)

–0.02 (0.16)

–2.29 (0.16)

–1.71 (0.20)

P value within treatment

0.8859

< 0.0001

< 0.0001

LSMD (95% CI)

Reference

–2.26 (–2.71, –1.81)

NA

P value versus placebo

Reference

< 0.0001

NA

Absolute change from baseline CFQ-R respiratory domain through week 24a, b

Baseline mean (SD)

82.7 (14.1)

85.7 (11.7)

80.3 (15.2)

Patients in analysis

61

60

65

LS mean change (SE)

0.5 (1.6)

5.9 (1.6)

7.0 (1.1)

P value within treatment

0.7693

0.0003

< 0.0001

LSMD (95% CI)

Reference

5.5 (1.0, 10.0)

NA

P value versus placebo

Reference

0.0174

NA

Absolute change from baseline in sweat chloride through week 24a,b

Baseline mean (SD)

102.6 (8.6)

102.8 (10.0)

102.2 (9.1)

Patients in analysis

61

60

60

LS mean change (SE)

–0.9 (1.5)

–52.1 (1.5)

–60.9 (1.4)

P value within treatment

0.5241

< 0.0001

< 0.0001

LSMD (95% CI)

Reference

–51.2 (–55.3, –47.1)

NA

P value versus placebo

Reference

< 0.0001

NA

Pulmonary exacerbations

Patients with event, n (%)

16 (26.2) (AE only)

1 (1.7) (AE only)

4 (6.1)

Number of events

NA

NA

4

Event rate per year

NA

NA

0.12

Pulmonary exacerbations requiring hospitalization

Patients with event, n (%)

NA

NA

1 (1.5)

Number of events

NA

NA

1

Event rate per year

NA

NA

0.03

Pulmonary exacerbations requiring IV antibiotics

Patients with event, n (%)

NA

NA

1 (1.5)

Number of events

NA

NA

1

Event rate per year

NA

NA

0.03

Absolute change in BMI z score at week 24

Baseline mean (SD)

NA

NA

–0.16 (0.74)

Patients in analysis

NA

NA

33

LS mean (SE)

NA

NA

0.37 (0.05)

95% CI of LS mean

NA

NA

(0.26, 0.48)

P value

NA

NA

< 0.0001

Absolute change in body weight z score at week 24

Baseline mean (SD)

NA

NA

–0.22 (0.76)

Patients in analysis

NA

NA

33

LS mean (SE)

NA

NA

0.25 (0.04)

95% CI of LS mean

NA

NA

(0.16, 0.33)

P value

NA

NA

< 0.0001

Summary of AEs

At least 1 AE

57 (93.4)

48 (80.0)

65 (98.5)

WDAEs

0

1 (1.7)

1 (1.5)

AEs leading to interruption

0

7 (11.7)

1 (1.5)

Grade 3/4 AEs

2 (3.3)

2 (3.3)

1 (1.5)

SAEs

9 (14.8)

4 (6.7)

1 (1.5)

AEs of special interest

Elevated transaminases

3 (4.9)

6 (10.0)

7 (10.6)

Discontinuation

0

0

0

Interruption

0

0

0

Serious events

0

4 (6.7)

0

Any rash events

3 (4.9)

8 (13.3)

16 (24.2)

Discontinuation

0

1 (1.7)

1 (1.5)

Interruption

0

2 (3.3)

0

Serious events

0

0

0

AE = adverse event; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; SAE = serious adverse events; WDAE = withdrawal due to adverse events.

Source: Clinical Study Reports.39,56

Appendix 2: Key Results From Studies of Patients Aged 12 Years and Older

Table 40: Summary of Key Results From Pivotal and Protocol-Selected Studies

Analysis

Study 102 (F/MF)

24 weeks

Study 103 (F/F)

4 Weeks

Study 109 (F/F)

24 weeks

Study 104 (F/G and F/RF)

8 weeks

Placebo

(N = 203)

ELX-TEZ-IVA

(N = 200)

TEZ-IVA

(N = 52)

ELX-TEZ-IVA

(N = 55)

TEZ-IVA

(N = 88)

ELX-TEZ-IVA

(N = 87)

Control

(N = 126)

ELX-TEZ-IVA

(N = 132)

Absolute change in ppFEV1 (%)

BL; mean (SD)

61.3 (15.5)

61.6 (15.0)

60.2 (14.4)

61.6 (15.4)

64.2 (15.1)

63.0 (16.7)

68.1 (16.4)

67.1 (15.7)

LSM change (SE)

–0.4 (0.5)

13.9 (0.6)

0.4 (0.9)

10.4 (0.9)

1.0 (0.7)

11.2 (0.7)

0.2 (0.5)

3.7 (0.5)

LSMD (95% CI)

14.3 (12.7 to 15.8)

10.0 (7.4 to 12.6)

10.2 (8.2 to 12.1)

3.5 (2.2 to 4.7)

P value

< 0.0001 a

< 0.0001 a

< 0.0001 b

< 0.0001 b

Absolute change in CFQ-R (respiratory domain)

BL; mean (SD)

70.0 (17.8)

68.3 (16.9)

72.6 (17.9)

70.6 (16.2)

73.1 (17.6)

71.2 (19.6)

77.3 (15.8)

76.5 (16.6)

LSM change (SE)

–2.7 (1.0)

17.5 (1.0)

–1.4 (2.0)

16.0 (2.0)

1.2 (1.5)

17.1 (1.5)

1.6 (1.2)

10.3 (1.2)

LSMD (95% CI)

20.2 (17.5 to 23.0)

17.4 (11.8 to 23.0)

15.9 (11.7 to 20.1)

8.7 (5.3 to 12.1)

P value

< 0.0001 b

< 0.0001

< 0.0001 a

< 0.0001

Absolute change in BMI (kg/m2)

BL; mean (SD)

21.31 (3.14)

21.49 (3.07)

21.88 (4.12)

21.75 (3.19)

21.92 (3.89)

21.17 (3.43)

24.05 (4.71)

24.07 (4.72)

LSM change (SE)

0.09 (0.07)

1.13 (0.07)

–0.07 (0.07)

0.53 (0.07)

0.15 (0.13)

1.59 (0.13)

0.16 (0.06)

0.28 (0.06)

LSMD (95% CI)

1.04 (0.85 to 1.23)

0.60 (0.41 to 0.79)

1.44 (1.07 to 1.82)

0.13 (–0.03 to 0.29)

P value

< 0.0001 b

< 0.0001

< 0.0001

NA

Absolute change in SwCl (mmol/L)

BL; mean (SD)

102.9 (9.8)

102.3 (11.9)

90.0 (12.3)

91.4 (11.0)

89.8 (11.7)

89.0 (12.2)

56.4 (25.5)

59.5 (27.0)

LSM change (SE)

–0.4 (0.9)

–42.2 (0.9)

1.7 (1.8)

–43.4 (1.7)

–3.4 (1.2)

–46.2 (1.3)

0.7 (1.1)

–22.3 (1.1)

LSMD (95% CI)

–41.8 (–44.4 to –39.3)

–45.1 (–50.1 to –40.1)

–42.8 (–46.2 to –39.3)

–23.1 (–26.1 to –20.1)

P value

< 0.0001 b

< 0.0001 b

< 0.0001

< 0.0001

Pulmonary exacerbations

Patients with evt, n (%)

76 (37.4)

31 (15.5)

NA

NA

NA

Event rate per year

0.98

0.37

Rate ratio (95% CI)

0.37 (0.25 to 0.55)

P value

< 0.0001

Pulmonary exacerbations requiring hospitalization

Patients with evt, n (%)

27 (13.3)

7 (3.5)

NA

NA

NA

Event rate per year

0.24

0.07

Rate ratio (95% CI)

0.29 (0.14 to 0.61)

P value

< 0.0001

Pulmonary exacerbations requiring IV antibiotics

Patients with evt, n (%)

42 (20.7)

9 (4.5)

NA

NA

NA

Event rate per year

0.36

0.08

Rate ratio (95% CI)

0.22 (0.11 to 0.43)

P value

< 0.0001

Time-to-first pulmonary exacerbation

Hazard ratio (95% CI)

0.34 (0.22 to 0.52)

NA

NA

NA

P value

< 0.0001

Time-to-first pulmonary exacerbation requiring hospitalization

Hazard ratio (95% CI)

0.25 (0.11 to 0.58)

NA

NA

NA

P value

0.0011

Time-to-first pulmonary exacerbation requiring IV antibiotics

Hazard ratio (95% CI)

0.19 (0.09 to 0.39)

NA

NA

NA

P value

< 0.0001

Summary of AEs

At least 1 AE

193 (96.0)

188 (93.1)

33 (63.5)

32 (58.2)

81 (92.0)

77 (88.5)

83 (65.9)

88 (66.7)

WDAEs

0

2 (1.0)

0

0

2 (2.3)

1 (1.1)

2 (1.6)

1 (0.8)

Interruption due to AEs

10 (5.0)

19 (9.4)

0

0

1 (1.1)

2 (2.3)

3 (2.4)

5 (3.8)

Grade 3/4 AEs

15 (7.5)

19 (9.4)

1 (1.9)

0

7 (8.0)

7 (8.0)

4 (3.2)

5 (3.8)

SAEs

42 (20.9)

28 (13.9)

1 (1.9)

2 (3.6)

14 (15.9)

5 (5.7)

11 (8.7)

5 (3.8)

Most common AEs

Infective pulmonary exacerbation of CF

95 (47.3)

44 (21.8)

6 (11.5)

1 (1.8)

36 (40.9)

10 (11.5)

13 (10.3)

3 (2.3)

Sputum increased

39 (19.4)

40 (19.8)

3 (5.8)

3 (5.5)

16 (18.2)

10 (11.5)

8 (6.3)

6 (4.5)

Headache

30 (14.9)

35 (17.3)

4 (7.7)

3 (5.5)

18 (20.5)

25 (28.7)

19 (15.1)

11 (8.3)

Cough

77 (38.3)

34 (16.8)

4 (7.7)

8 (14.5)

23 (26.1)

11 (12.6)

18 (14.3)

3 (2.3)

AEs of special interest

Elevated transaminases

8 (4.0)

22 (10.9)

1 (1.9)

2 (3.6)

1 (1.1)

6 (6.9)

1 (0.8)

8 (6.1)

  Discontinuation

0

0

0

0

0

0

0

1 (0.8)

  Interruption

3 (1.5)

2 (1.0)

0

0

0

2 (2.3)

1 (0.8)

0

  Serious events

1 (0.5)

0

0

0

0

1 (1.1)

0

0

Any rash events

13 (6.5)

22 (10.9)

2 (3.8)

2 (3.6)

2 (2.3)

11 (12.6)

5 (4.0)

4 (3.0)

  Discontinuation

0

1 (0.5)

0

0

0

0

0

0

  Interruption

1 (0.5)

4 (2.0)

0

0

0

1 (1.1)

1 (0.8)

1 (0.8)

  Serious events

1 (0.5)

3 (1.5)

0

1 (1.8)

0

0

0

0

AE = adverse event; BL = baseline; CF = cystic fibrosis; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene SAE = serious adverse events; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor; URTI = upper respiratory tract infection; WDAE = withdrawal due to adverse events.

Note: This table has not been copy-edited.

aPrespecified primary end point.

bPrespecified key secondary end point.

cPost hoc analysis only reported for the indirect comparison.

Source: Clinical Study Reports60-63 and additional information provided by sponsor.64

Pharmacoeconomic Review

Abbreviations

BIA

budget impact analysis

BSC

best supportive care

CF

cystic fibrosis

CF Canada

Cystic Fibrosis Canada

ELX

elexacaftor

ELX-TEZ-IVA

elexacaftor-tezacaftor-ivacaftor and ivacaftor

F/F

homozygous for F508del mutation in the CFTR gene

F/G

1 F508del mutation and 1 gating mutation in the CFTR gene

F/MF

1 F508del mutation and 1 minimal function mutation in the CFTR gene

F/RF

1 F508del mutation and 1 residual function mutation in the CFTR gene

ICER

incremental cost-effectiveness ratio

IVA

ivacaftor

LUM-IVA

lumacaftor-ivacaftor

PEx

pulmonary exacerbation

ppFEV1

percent predicted forced expiratory volume in the first second

QALY

quality-adjusted life-year

TEZ

tezacaftor

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

Item

Description

Drug product

Elexacaftor-tezacaftor-ivacaftor and ivacaftor (Trikafta) taken orally

  • Elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg (granules) and ivacaftor 75 mg (granules)

  • Elexacaftor 80 mg–tezacaftor 40 mg–ivacaftor 60 mg (granules) and ivacaftor 59.5 mg (granules)

Submitted price

Elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg and ivacaftor 150 mg tablets OR elexacaftor 80 mg–tezacaftor 40 mg–ivacaftor 60 mg and ivacaftor 59.5 mg granules: $840 per daily dose

Indication

For the treatment of cystic fibrosis (CF) in patients aged 2 years and oldera who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Health Canada approval status

Pre-NOC

Health Canada review pathway

Priority review

NOC date

October 11, 2023

Reimbursement request

Confirmed diagnosis with CF with at least 1 F508del mutation in the CFTR gene

  • 2 to 5 years of age

Sponsor

Vertex Pharmaceuticals (Canada) Incorporated

Submission history

Previously reviewed: Yes

Elexacaftor-tezacaftor-ivacaftor (combination tablet) and ivacaftor

  • Indication: Cystic fibrosis, F508del-CFTR mutation in patients aged 6 years and older

  • Recommendation date: July 6, 2022

  • Recommendation: Reimburse with criteria and conditions, including a substantial reduction in price

NOC = Notice of Compliance.

aThis review is focused on patients aged 2 to 5 years, as per the sponsor’s reimbursement request.

Table 2: Summary of Economic Evaluation

Component

Description

Type of economic evaluation

Cost-utility analysis

Microsimulation

Target population

Patients with CF aged 2 to 5 years who have at least 1 F508del-CFTR mutation in the CFTR gene, represented by the following 4 genotypes:

  • Homozygous for F508del-CFTR (F/F)

  • Heterozygous for F508del-CFTR with minimal function mutation (F/MF)

  • Heterozygous for F508del-CFTR with a gating mutation (F/G), inclusive of the R117H mutation

  • Heterozygous for F508del-CFTR with residual function mutation (F/RF)

Treatment

ELX-TEZ-IVAa with background BSC

Comparators

  • F/F genotype: LUM-IVA with BSC, BSC alone

  • F/MF, F/RF, or F/G mutations: BSC alone

BSC for all genotypes consisted of recommended medications (such as mucolytics, inhaled and oral antibiotics, inhaled hypertonic saline, nutritional supplements, enteral tube feeding, pancreatic enzymes, antifungal agents, and corticosteroids) and physiotherapy

Perspective

Canadian publicly funded health care payer

Outcomes

QALYs, LYs

Time horizon

Lifetime (97 years)

Key data sources

  • Baseline patient characteristics were derived for each genotype separately from a number of trials of CFTR modulators in these populations.

  • Baseline mortality hazard was estimated based on age-specific mortality from a CF population survival curve derived from the literature. This survival was adjusted for changes in patient characteristics using a Cox proportional hazards model.

  • The sponsor submitted an ITC to inform placebo-adjusted estimates for acute change in ppFEV1 and mean change in weight-for-age z scores in the F/F population for patients on CFTR modulators. Data for the F/MF population were based on Study 116, where patients were aged 6 to 11 years. Data for the F/RF and F/G populations were extrapolated from trial data for patients aged 12 years and older. Patients on BSC were assumed to not experience any improvement in either outcome. In the absence of clinical data for patients aged 2 to 5 years, patients in the model were assumed to experience gains in efficacy as indicated by the ITC upon turning age 6 years.

  • The impact of treatment on the long-term reduction in the rate of ppFEV1 decline, beyond 192 weeks, was based on a propensity score–matched analysis of patients aged 12 years and older with an F/F or F/MF genotype treated with ELX-TEZ-IVA (for up to 120 weeks) in Study 105 IA3 compared with untreated control patients from the (US) Cystic Fibrosis Foundation Patient Registry. The value for patients with an F/MF genotype (89.7%) was assumed to be a suitable proxy for patients with an F/RF or F/G genotype in the absence of published long-term rate of change data on these genotypes.

Submitted results

  • F/F genotype

    • ICER vs. BSC = $399,484 per QALY gained (incremental costs = $6,714,588; incremental QALYs = 16.8)

    • ICER vs. LUM-IVA = $329,703 per QALY gained (incremental costs = $3,689,917; incremental QALYs = 11.2)

  • F/MF genotype

    • ICER vs. BSC = $429,821 per QALY gained (incremental costs = $6,820,057; incremental QALYs = 15.9)

  • F/G genotype

    • ICER vs. BSC = $389,709 per QALY gained (incremental costs = $6,614,327; incremental QALYs = 17.0)

  • F/RF genotype

    • ICER vs. BSC = $534,587 per QALY gained (incremental costs = $6,791,634; incremental QALYs = 12.7)

Key limitations

  • The long-term impact of treatment with CFTR modulators on the ppFEV1 rate of decline and PEx rates in comparison with BSC is uncertain due to a lack of evidence beyond the trial periods for any genotype or age group. This results in substantial uncertainty about the cost-effectiveness of ELX-TEZ-IVA.

  • The sponsor incorporated dynamic pricing for CFTR modulators based on an assumption of generic entry. This assumption is associated with uncertainty and likely underestimates the total costs associated with ELX-TEZ-IVA.

  • Drug acquisition costs were adjusted for patient compliance, but treatment efficacy was not. While drug wastage may occur, drugs will still be dispensed and paid for by public drug plans. This underestimated the total drug costs associated with ELX-TEZ-IVA.

  • Costs incurred by the health care system for the period over which ELX-TEZ-IVA extends survival in comparison with BSC were excluded, which underestimates the total costs associated with ELX-TEZ-IVA.

  • The sponsor adjusted disease management costs for hospital visits and pharmacotherapy for patients receiving CFTR modulators, but the cited studies did not indicate whether the results were controlled for patient ppFEV1. Therefore, the magnitude of potential cost savings is uncertain and may have been double counted.

  • The sponsor included a treatment-specific utility increment to account for the benefit of treatment with ELX-TEZ-IVA beyond its impact explained by improvements in ppFEV1 and PExs. The increment calculated by the sponsor was adjusted for ppFEV1 but not for PExs, likely leading to double counting of QALY benefits with ELX-TEZ-IVA.

  • The survival benefit predicted in the model for ELX-TEZ-IVA was overestimated and did not meet face validity.

CADTH reanalysis results

CADTH conducted a reanalysis that included the removal of the additional benefit of CFTR modulators on the long-term rate of decline in ppFEV1 and PExs; the removal of dynamic pricing; the inclusion of health care costs across the entire model time horizon; the removal of an adjustment to drug acquisition costs based on patient compliance; an assumption of equal hospital and pharmacotherapy costs between treatments; and the removal of a treatment-specific utility increment for patients on ELX-TEZ-IVA.

Results of the CADTH reanalysis are as follows:

  • F/F genotype

    • ICER vs. BSC = $1,283,744 per QALY gained (incremental costs = $10,287,657; incremental QALYs = 8.0)

    • ICER vs. LUM-IVA = $850,053 per QALY gained (incremental costs = $5,142,458; incremental QALYs = 6.0)

  • F/MF genotype

    • ICER vs. BSC = $1,311,755 per QALY gained (incremental costs = $10,387,273; incremental QALYs = 7.9)

  • F/G genotype

    • ICER vs. BSC = $1,204,386 per QALY gained (incremental costs = $10,387,077; incremental QALYs = 8.6)

  • F/RF genotype

    • ICER vs. BSC = $1,437,829 per QALY gained (incremental costs = $10,971,100; incremental QALYs = 7.6)

ELX-TEZ-IVA was not cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained in any scenario conducted by CADTH. A price reduction in excess of 94% for ELX-TEZ-IVA (for both granules and tablets) is required for ELX-TEZ-IVA to be considered cost-effective at a willingness-to-pay threshold of $50,000 for any of the genotypes when compared with BSC.

BSC = best supportive care; CF = cystic fibrosis; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; ITC = indirect treatment comparison; LUM-IVA = lumacaftor-ivacaftor; LY = life-year; PEx = pulmonary exacerbation; ppFEV1 = percent predicted forced expiratory volume in the first second; QALY = quality-adjusted life-year; vs. = versus.

aThe model assumes that patients aged 2 to 5 years receive ELX-TEZ-IVA granules, whereas patients aged 6 years and older receive ELX-TEZ-IVA tablets.

Conclusions

Results from the 24-week, open-label, uncontrolled Study 111 Part B suggest that treatment with elexacaftor-tezacaftor-ivacaftor and ivacaftor (ELX-TEZ-IVA) resulted in improvements from baseline in lung function (decrease in lung clearance index 2.5 from baseline) and cystic fibrosis (CF) biomarkers (reduction in sweat chloride) in patients aged 2 to 5 years with CF. However, as Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA in this younger population, the pharmacoeconomic review is based on the extrapolation of efficacy data from studies conducted in older patients with CF. Patients who completed Study 111 were eligible to enrol in an open-label extension study; however, interim results were not available at the time of filing the application with CADTH.

The clinical experts consulted by CADTH for the current review noted that, given the mechanism of action and compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA is expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. However, these conclusions are based on studies with a maximum follow-up period of 192 weeks, and there remains no evidence on the long-term impact of ELX-TEZ-IVA on the rate of decline in percent predicted forced expiratory volume in the first second (ppFEV1) or pulmonary exacerbations (PExs) beyond the trial periods for any genotype or age group.

Beyond uncertainty in the long-term clinical efficacy of ELX-TEZ-IVA, CADTH identified several major limitations with the submitted economic evaluation. The following were addressed in the CADTH reanalysis: the removal of an additional benefit of CFTR modulators on the long-term rate of decline in ppFEV1 and PExs; the removal of dynamic pricing for CFTR modulators; the inclusion of costs for ELX-TEZ-IVA for the period in which a survival benefit was achieved in comparison to best supportive care (BSC); the removal of an adjustment to drug acquisition costs based on patient compliance; and the removal of a treatment-specific utility increment for patients on ELX-TEZ-IVA. The results of the CADTH reanalysis were aligned with the sponsor’s, in that ELX-TEZ-IVA was not cost-effective in any of the genotype subgroups at conventionally acceptable incremental cost-effectiveness ratio (ICER) thresholds. In the CADTH base-case analyses, when compared to BSC, ELX-TEZ-IVA was associated with an ICER of $1,284,953 per quality-adjusted life-year (QALY) gained in patients who are homozygous for F508del mutation in the CFTR gene (F/F genotype); $1,451,526 per QALY gained in patients with 1 F508del mutation and 1 minimal function mutation in the CFTR gene (F/MF genotype); $1,284,853 per QALY gained in patients with 1 F508del mutation and 1 gating mutation in the CFTR gene (F/G genotype); and $1,644,869 per QALY gained in patients with 1 F508del mutation and 1 residual function mutation in the CFTR gene (F/RF genotype). Additionally, ELX-TEZ-IVA was associated with an ICER of $838,687 per QALY gained when compared to lumacaftor-ivacaftor (LUM-IVA) in the F/F genotype population.

The key drivers in the analyses were drug acquisition costs and assumptions in the long-term benefits of ELX-TEZ-IVA, which were uncertain. Treatment with ELX-TEZ-IVA was not cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained in any scenario conducted by CADTH. A price reduction in excess of 94% for ELX-TEZ-IVA (for both granules and tablets) is required for all 4 genotypes for ELX-TEZ-IVA to be considered cost-effective at this threshold in comparison with BSC. Based on a price reduction of this magnitude, the daily cost of ELX-TEZ-IVA would need to be approximately $50.40 per patient. As the majority of patients with CF aged 6 years and older living in Canada are currently being treated with ELX-TEZ-IVA, the sponsor’s submitted economic evaluation assessing the cost-effectiveness of ELX-TEZ-IVA versus BSC or LUM-IVA (for the F/F genotype only) over the entire lifetime of a patient aged 2 to 5 years does not accurately reflect the current landscape of CF treatment in Canada. The cost-effectiveness of starting ELX-TEZ-IVA for patients aged 2 to 5 years versus waiting to initiate treatment at age 6 years and older is unknown.

Stakeholder Input Relevant to the Economic Review

This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CADTH review process.

Patient group input was submitted by Cystic Fibrosis Canada (CF Canada), informed by focus groups with 6 parents of children younger than 5 years who have at least 1 copy of the F508del mutation. Data from the CF Canada 2021 patient and caregiver survey (1,200 responses) on Trikafta access, along with the Canadian Cystic Fibrosis Registry, were also used to inform the patient group input. Patients and caregivers reported that living with CF has a tremendous impact on their lives, affecting physical, psychological, social, and financial components. When asked about disease management, patients noted that managing CF requires a demanding treatment routine involving much time and effort, while frequent clinic visits and hospital stays are needed to manage the progressive and debilitating symptoms. Parents and caregivers of children with CF noted that an ideal treatment in CF would fully address the basic molecular defect in CF and restore normal chloride transport on the cell surface. No input was provided from families that had a child aged 2 to 5 years receiving ELX-TEZ-IVA. Extending access to ELX-TEZ-IVA for patients with CF aged 2 to 5 years would be congruent with the secondary prevention paradigm of CF care and may decrease the long-term burden of the disease.

Clinician input was received from CF Canada’s Accelerating Clinical Trials Network and the CF Canada Healthcare Advisory Council. Clinician input noted that the treatment paradigm for CF in children aged 2 to 5 years is lifelong. It consists of nonmodulator treatments and medications, many of which start at the time of diagnosis (including in infancy) and continue every day throughout life. The clinician input noted that, although not a cure, CFTR modulators are the first available therapies for CF targeted at correcting the basic defect in CF. However, significant unmet therapeutic needs remain for patients living with CF, as available treatments address the symptoms and complications of CF and attempt to slow down the eventual fatal progression of the disease but do not effectively address the root cause or reverse the course of the disease. Currently available therapies, such as LUM-IVA, have significant side effects and numerous drug interactions. In addition, the current standard treatments are burdensome for patients and their caregivers, which affects medication adherence as well as the mental health and quality of life of patients and caregivers. Lastly, the clinician input noted that while ELX-TEZ-IVA may not be the first therapy to address the underlying defect in CF, it still represents an improvement on existing CFTR modulator therapies, and there remains an importance of early treatment of CF to prevent disease progression and irreversible damage.

Feedback from the drug plans indicated interest on if there were any concerns with extrapolation of data from CF patients aged 6 years and older treated with ELX-TEZ-IVA to patients aged 2 to 5 years. They further requested information about the relevance of LUM-IVA in current treatment practices and how the reimbursement of ELX-TEZ-IVA may impact patients currently receiving LUM-IVA (i.e., would patients be eligible to switch, were there any special considerations, and so on). Drug plans also asked, given that patients aged 2 to 5 years would not be able to accurately complete a spirometry, what other parameters or biomarkers could be used for disease diagnosis.

Two of these concerns were addressed in the sponsor’s model:

In addition, CADTH addressed some of these concerns as follows:

CADTH was unable to address the following concerns raised from stakeholder input:

Economic Review

The current review is for ELX-TEZ-IVA for the treatment of CF in patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene.

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

The sponsor submitted a cost-utility analysis assessing ELX-TEZ-IVA in combination with BSC for the treatment of CF in patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene, represented by the F/F, F/M, F/RF, and F/G genotypes. The sponsor compared the submitted drug regimen with BSC alone in all 4 subgroups, as well as with LUM-IVA in the F/F subgroup.1 The modelled population is aligned with a subset of the Health Canada indication, which had not previously been submitted to CADTH: patients aged 2 to 5 years. CADTH has previously reviewed ELX-TEZ-IVA for the treatment of CF in patients aged 6 years and older who have at least 1 F508del mutation in the CFTR gene.2 CADTH focused its review for this submission on the population aged 2 to 5 years.

The recommended dose of ELX-TEZ-IVA is age and weight dependent. Patients aged 2 to 5 years weighing less than 14 kg are to take 1 packet of elexacaftor 80 mg–tezacaftor 40 mg–ivacaftor 60 mg granules in the morning and 1 packet of ivacaftor 59.5 mg granules in the evening.3 Patients aged 2 to 5 years weighing more than 14 kg are to take 1 packet of elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg granules in the morning and 1 packet of ivacaftor 75 mg granules in the evening.3 Patients aged 6 to 11 years weighing less than 30 kg are to take 2 tablets, each containing elexacaftor 50 mg–tezacaftor 25 mg–ivacaftor 37.5 mg in the morning and 1 tablet of ivacaftor 75 mg in the evening.3 All other patients have a recommended dose of 2 tablets, each containing elexacaftor 100 mg–tezacaftor 50 mg–ivacaftor 75 mg in the morning and 1 tablet of ivacaftor 150 mg in the evening.3 All morning and evening doses are to be taken approximately 12 hours apart with fat-containing food.3 The daily cost of treatment is $840.00 per day, or an annual cost of $306,810, based on the treatment’s list price, regardless of the strength or form. BSC was selected as the comparator treatment for all genotypes and was defined as recommended medications (such as mucolytics, inhaled and oral antibiotics, inhaled hypertonic saline, nutritional supplements, enteral tube feeding, pancreatic enzymes, antifungal agents, and corticosteroids) and physiotherapy. All patients on CFTR modulator therapies also received BSC. LUM-IVA was also included as a comparator for patients homozygous for F508del-CFTR.

The outcomes of the model included QALYs and life-years over a lifetime horizon of approximately 97 years. The analysis was undertaken from the perspective of the Canadian public health care payer.1 Discounting (1.5% per annum) was applied for both costs and outcomes, and the cycle length was 4 weeks for the first 2 years and annual for the remainder of the model time horizon.1

Model Structure

The sponsor submitted a patient-level microsimulation model (i.e., a microsimulation) used to track CF disease progression and treatment benefits for a typical patient profile of each genotype, informed by various CFTR modulator trials (Figure 1). In the sponsor’s probabilistic base case, 250 average patients per genotype were simulated and the expected costs and clinical effects of ELX-TEZ-IVA, BSC, and LUM-IVA (for the F/F genotype only) were calculated.1 This process was repeated 80 times.

At the beginning of each cycle, the model calculated a patient’s mortality risk based on a Cox proportional hazard model that linked the survival of a patient with CF to 9 risk factors: age, gender, ppFEV1, annual number of PEx, Staphylococcus aureus infection, Burkholderia cepacian infection, CF-related diabetes, weight-for-age z score, and pancreatic sufficiency status.1 For each cycle a patient remained alive, certain patient characteristics were updated, including age and treatment discontinuation for patients aged 2 to 5 years, and age, ppFEV1, weight-for age z score, PEx rate, eligibility for and occurrence of lung transplant, development of CF-related diabetes, and treatment discontinuation for patients aged 6 years and older. Long-term health impacts due to treatment were predicted using clinical outcomes such as median predicted survival, mean time spent in ppFEV1 states, cumulative change in ppFEV1, annual and lifetime PEx rates, and proportion of patients receiving a lung transplant.1 During each cycle, patients would accrue life-years and QALYs; costs were applied at the end of each run of 250 patients for efficiency gains.

Model Inputs

Baseline age-specific risk of death in the model was derived from a cohort-based survival analysis of the Canadian Cystic Fibrosis Registry reported by Stephenson et al.4 Kaplan-Meier curves from this analysis were digitized and fitted using parametric survival analysis to generate a mortality risk for the lifetime time horizon. In the sponsor’s base case, the Gompertz curve was selected as the best-fitting curve, and it was assumed that patients aged 2 to 5 years had 100% survival.1 Mortality was recalculated for each cycle using the Cox proportional hazard model developed by Liou et al. to account for the factors indicted in the Model Structure section.5 The hazard of mortality in the model was assumed to be no lower than for the general population of Canada.1

The patient characteristics used to inform the mortality risk in the model were primarily from the pooled mean baseline characteristics of CFTR modulator trials and were specific to each genotype. Baseline characteristics of age, gender, ppFEV1, and weight-for-age z score for the homozygous F/F genotype were informed by Study 809-011B and Study 809-109 (both LUM-IVA trials), the subset of patients with an F/F genotype from Study 661-113B and Study 661-115 (both tezacaftor-ivacaftor and ivacaftor [TEZ-IVA] trials), and Study 106B (ELX-TEZ-IVA trial). Patients in Study 106B, Study 661-113B, and Study 661-115 may have had a prior history of CFTR modulator use but were required to undergo a 28-day washout period before screening. Their baseline characteristics were therefore considered by the sponsor to be reflective of a CFTR modulator–naive population for the homozygous F/F genotype.6-10 Study 106B and Study 116 (both ELX-TEZ-IVA trials) were further used to inform baseline patient characteristics for the F/MF population.9,11 ENVISION, KONNECTION, and KONDUCT (all trials of IVA monotherapy) were used to inform the characteristics of the F/G population, where patients were not required to have an F508del-CFTR mutation on the second allele.12-14 Lastly, Study 661-113B and Study 661-115 were used to inform the baseline characteristics of the F/RF population.6,8 The baseline rate of PExs requiring IV antibiotics and/or hospitalization was informed by Whiting et al.15 CF-related diabetes status at baseline was based on data from the UK Cystic Fibrosis Registry.16 Patients were assumed not to be at risk of developing CF-related diabetes before age 6, and the annual incidence of CF-related diabetes was applied across all genotypes. It was assumed that the risk of developing CF-related diabetes was equal for patients receiving a CFTR modulator and for those receiving BSC alone.

As noted previously, age, ppFEV1, PExs, and weight-for-age z score were updated at the beginning of each model cycle. Clinical efficacy inputs were derived from the relevant studies. Since ppFEV1 was not available for patients aged 2 to 5 years, the sponsor assumed that lung function, according to ppFEV1, is not tracked until patients turn 6 years in the model, at which point ppFEV1 data from patients aged 6 to 11 years was used. As the assignment of baseline mortality hazards in the model was based on a CFTR modulator–naive population, the analysis required placebo-adjusted estimates of clinical efficacy for CFTR modulators where there were gaps in the available direct evidence. Placebo-adjusted estimates were derived, where necessary, using an indirect treatment comparison with individual patient-level data from relevant phase III randomized controlled trials.1,17

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Patients on BSC alone were expected to not have any acute increases in ppFEV1 and were assumed to have a long-term decline in ppFEV1 in line with a study by Leung et al.19 The same rate of decline was applied to all genotypes, except the heterozygous F/RF genotype as they are typically thought to have a milder form of disease and thus a slower rate of decline. In the absence of data on the reduction in the rate of ppFEV1 decline in patients treated with CFTR modulators from ages 2 to 5 years versus patients receiving BSC, the reduction in the rate of ppFEV1 decline was assumed be the rate observed in the registry-matched analysis conducted in patients aged 12 years or older. Patients were assumed to avoid a proportion of lung function decline before the age of 6 years.1 Patients receiving ELX-TEZ-IVA during the maintenance period were assumed to sustain their acute improvements for 192 weeks, based on the results of Study 105. There was no maintenance period for TEZ-IVA. During the post-acute maintenance period, patients on ELX-TEZ-IVA were modelled to have an 89.7% reduction in the rate of ppFEV1 decline compared with patients receiving BSC, with the exception of patients with an F/F genotype, who had an 86.4% reduction in the rate of ppFEV1 decline.1 Patients on LUM-IVA were assumed to experience a 42% reduction in the rate of ppFEV1 decline compared to patients receiving BSC, based on retrospective observational studies.20-22

The baseline rate of occurrence of PExs each cycle after a patient turned 6 years was based on the patient’s ppFEV1 and age, according to a formula derived by Goss and Burns, and was not genotype specific.23 Due to data availability and as a simplifying assumption, PExs were not estimated for patients aged 2 to 5 years. For patients aged 6 to 11 years, CFTR modulators were also assumed to have no treatment effect on PExs requiring IV antibiotics and/or hospitalizations as the observed PEx event rate of ELX-TEZ-IVA remained low over 120 weeks (24 weeks in Study 106B plus an additional 96 weeks in Study 107, an open-label extension study). Once patients on CFTR modulators turned age 12 years, their rate of PExs was adjusted by a rate ratio derived by the sponsor. This rate was based on an assumed additional treatment impact on PExs beyond those impacts explained by improvements in ppFEV1 in patients treated with CFTR modulators, as captured in the Goss and Burns. formula. To account for the potential double counting of the benefit due to the better ppFEV1 observed with CFTR modulators, the sponsor attempted to calibrate the PEx rate ratio for patients receiving a CFTR modulator. Patients on CFTR modulators had their rate of PExs adjusted such that the resulting relative rate of PExs between patients receiving a CFTR modulator and those receiving BSC alone matched the treatment effect on PExs requiring IV antibiotics and/or hospitalizations observed in the pivotal trials.

Patients treated with a CFTR modulator were assumed to experience an acute change in weight-for-age z score from baseline. The magnitude and duration of the acute change was informed by age-specific and genotype-specific clinical trial data. After the initial change was applied upon model entry, a patient’s weight-for-age z score was assumed to remain consistent for the remainder of the simulation.1 Patients with an F/F genotype receiving TEZ-IVA were assumed to have an increase in their weight-for-age z score, applied at age 6 years based on Study 115.24 Patients on BSC alone were expected to not have any acute increases in their weight-for-age z score.

The sponsor’s model also accounted for treatment discontinuation and compliance. Discontinuation rates for the model period corresponding to the trial duration period were obtained from the relevant phase III trials; open-label extension studies were used to inform a “post-acute” phase of the model, in which no patients discontinued treatment.1 Upon CFTR discontinuation, patients were modelled to no longer receive benefits; however, they retained the acute increase in ppFEV1 and weight-for-age z score they had achieved up until the point of discontinuation. In the post-acute period, patients who had discontinued treatment had the same ppFEV1 decline as the age-dependent values of their BSC counterparts. The sponsor further considered treatment compliance to inform treatment costs over the acute period (first 24 weeks).1 Compliance rates from Study 111 in the combined F/F and F/MF population were applied for all genotypes. Patients on TEZ-IVA had compliance rates aligned with Study 115. Treatment compliance in the post-acute period was set to 93% across all CFTR modulators regardless of genotype.1 Compliance was assumed to have no impact on treatment efficacy and to only affect the costs associated with CFTR modulators.

The sponsor-submitted economic model also considered lung transplant and adverse events. The sponsor aligned the rate of lung transplant and mortality risk following transplant with the previous CADTH submission.25 In the base-case analysis, patients with a ppFEV1 threshold of 30% were eligible for lung transplant and the probability of receiving a transplant was 4.6%.1 Adverse events in the model were based on the relevant phase III trials for the respective ages, genotypes, and CFTR modulators.

Costs considered in the model included drug acquisition, monitoring, disease management, pharmacotherapy, diagnostic tests, PExs, adverse events, and lung transplants. The cost of ELX-TEZ-IVA was submitted by the sponsor, whereas the prices of LUM-IVA were obtained from the Ontario Exceptional Access Program formulary.26 For CFTR modulators, including ELX-TEZ-IVA, the sponsor employed a dynamic pricing approach, in which the introduction of a first generic into the market after loss of patent exclusivity would lead to a 25% reduction in the prices of all drugs, and the entry of a second generic would further reduce prices by 50%. These assumptions were based on a pan-Canadian Pharmaceutical Alliance office framework for pricing expectations upon generic entry. Additional costs associated with CFTR modulator use included monitoring costs, consisting of liver function tests and ophthalmologist visits, as per the product monographs, with the costs obtained from the Ontario Schedule of Benefits.27

Annual CFTR modulator monitoring costs were applied as indicated in each CFTR modulator’s associated product monograph.3,28,29 Disease management costs were also captured to include clinician visits, hospitalizations, infection prevention, and management of comorbidities. Such costs were applied in the model by disease severity (based on ppFEV1 thresholds) and were further divided into PEx and non-PEx event costs. Health care resource use associated with routine disease management costs was informed by a sponsor-commissioned burden of illness study and supplemental 2014 data from the Canadian CF Registry.1 Physician and laboratory unit costs were informed by the Ontario Schedule of Benefits; hospitalization costs were derived from a study by Skolnik et al.27,30,31 Informed by published literature suggesting patients on CFTR modulators have reduced CF-related inpatient admission and outpatient IV and antibiotic use, the sponsor adjusted disease management costs for patients on CFTR modulators.32,33 As a result, differential annual inpatient costs and annual pharmacotherapy costs were estimated for patients on BSC alone and for patients on CFTR modulators. The sponsor also excluded disease management costs for patients on CFTR modulators after the similar patient on BSC had died in a given simulation: the patients on CFTR modulators only incurred CFTR modulator therapy costs for the remainder of the time horizon. Lung transplant costs were obtained from Alberta Health Services, with follow-up costs obtained from the literature.34,35 The cost of each adverse event was assumed to be equal to the cost of a single general practitioner assessment.27 All costs were reported in 2023 Canadian dollars.

In the absence of utilities based on a generic instrument (e.g., EQ-5D), the sponsor used an equation developed by Solem et al.,36 which included ppFEV1 and PExs as predictors of an EQ-5D index utility score. For this calculation, each PEx was assumed to last 21.7 days, based on the TRAFFIC and TRANSPORT trials.36 For patients beginning treatment aged 2 to 5 years, the model assumes a utility value regardless of CFTR modulator treatment until the age of 6 years.1 The sponsor also included a treatment-specific utility increment only for patients receiving ELX-TEZ-IVA, as it was felt that the equation by Solem et al. did not capture the impact of treatment on nonrespiratory outcomes. Post–lung transplant utility values were obtained from a study by Whiting et al.15 No disutilities related to adverse events were included in the model, as they were assumed to have minimal impact on patient quality of life.

Summary of Sponsor’s Economic Evaluation Results

All analyses were run probabilistically, with 250 average patients individually simulated for 80 iterations for the base-case and scenario analyses. The deterministic and probabilistic results were similar. The probabilistic findings are presented in the following section. The sponsor’s base case is based on publicly available list prices for comparators.

Base-Case Results

The sponsor presented results by genotype. For the F/F genotype, ELX-TEZ-IVA was associated with an incremental cost of $3,689,917 and incremental QALYs of 11.2 when compared with LUM-IVA, for an ICER of $329,703 per QALY gained. Compared to BSC, ELX-TEZ-IVA was associated with an incremental cost of $6,714,588 and incremental QALYs of 16.8, for an ICER of $399,484 per QALY gained. For the F/MF genotype, when compared to BSC, ELX-TEZ-IVA was associated with an incremental cost of $6,820,057 and incremental QALYs of 15.9, for an ICER of $429,821 per QALY gained. For the F/G genotype, ELX-TEZ-IVA was associated with an incremental cost of $6,614,327 and incremental QALYs of 17.0, for an ICER of $389,709 per QALY gained versus BSC. For the F/RF genotype, ELX-TEZ-IVA was associated with an incremental cost of $6,791,634 and incremental QALYs of 12.7, for an ICER of $534,587 per QALY gained compared to BSC.

The sponsor also combined all genotypes and presented a weighted ICER by their prevalence and by comparator market share. The overall weighted ICER was $419,571 per QALY gained (incremental costs = $6,716,950; incremental QALYs = 16.0) in comparison with the relevant standard of care.

Table 3: Summary of the Sponsor’s Economic Evaluation Results by Genotype

Drug

Total costs ($)

Incremental costs ($)

Total QALYs

Incremental QALYs

ICER ($/QALY)

Homozygous for F508del-CFTR (F/F)

BSC

973,938

Reference

25.0

Reference

Reference

ELX-TEZ-IVA

7,688,526

6,714,588

41.8

16.8

399,484

LUM-IVA

3,998,609

Reference

30.6

Reference

Reference

ELX-TEZ-IVA

7,688,526

3,689,917

41.8

11.2

329,703

Heterozygous for F508del-CFTR (F/MF)

BSC

788,521

Reference

25.3

Reference

Reference

ELX-TEZ-IVA

7,608,578

6,820,057

41.2

15.9

429,821

Heterozygous for F508del-CFTR (F/G)

BSC

1,080,162

Reference

24.8

Reference

Reference

ELX-TEZ-IVA

7,694,489

6,614,327

41.8

17.0

389,709

Heterozygous for F508del-CFTR (F/RF)

BSC

737,607

Reference

27.9

Reference

Reference

ELX-TEZ-IVA

7,529,241

6,791,634

40.6

12.7

534,587

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; LUM-IVA = lumacaftor-ivacaftor; QALY = quality-adjusted life-year; vs. = versus.

Source: Sponsor’s pharmacoeconomic submission.1

Sensitivity and Scenario Analysis Results

The sponsor conducted several scenario analyses pertaining to different discounting values, pricing scenarios for CFTR modulators, and efficacy estimates by using the lung clearance index and adopting a societal perspective (i.e., considering caregiver utility increments and indirect costs resulting from productivity loss due to PExs). The scenario that assumed static pricing for LUM-IVA and ELX-TEZ-IVA had the largest impact, where price reductions for CFTR modulator therapies occurred at the end of patent exclusivity in the base case. This scenario analysis resulted in a weighted ICER of $697,562.

CADTH Appraisal of the Sponsor’s Economic Evaluation

CADTH identified several key limitations to the sponsor’s analysis that have notable implications for the economic analysis:

Table 4: Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission)

Sponsor’s key assumption

CADTH comment

Survival for patients between the ages of 2 and 5 years is 100%.

Reasonable. Clinical expert feedback received by CADTH noted that while survival for this age group may not be 100%, mortality would not be due to CF; thus, it is likely a reasonable simplifying assumption.

An acute increase in ppFEV1 due to ELX-TEZ-IVA for patients aged 12 years and older with an F/G or F/RF genotype is reflective of the pediatric population.

Reasonable. Based on feedback received by clinical experts, the mechanism of action is expected to be identical in younger children.

Patients aged 2 to 5 years who begin treatment with a CFTR modulator experience an acute increase in ppFEV1 immediately upon turning age 6 years.

Reasonable, according to clinical experts consulted by CADTH.

The risk of developing CF-related diabetes is the same for patients on CFTR modulators and patients on BSC.

Reasonable, according to clinical experts consulted by CADTH.

After an initial change, a patient’s weight-for-age z score is assumed to remain constant for the rest of the model time horizon.

Uncertain. Clinical expert feedback received by CADTH noted that while likely reasonable, the value of a weight-for-age z score increase would likely be uncertain once a younger patient transitions to adulthood.

Rate of lung transplant for patients with ppFEV1 < 40% is 4.6%.

Reasonable. According to clinical experts consulted by CADTH, lung transplant rates have decreased in recent years.

BSC = best supportive care; CF = cystic fibrosis; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ppFEV1 = percent predicted forced expiratory volume in the first second.

CADTH Reanalyses of the Economic Evaluation

Base-Case Results

The CADTH base case was derived by making changes in model parameter values and assumptions, in consultation with clinical experts. CADTH undertook a stepped analysis, incorporating each change detailed in Table 5 into the sponsor’s model to highlight the impact of each change. Each genotype is presented separately. The summary results of the CADTH reanalyses for the F/F genotype are presented in Table 6. The results for the F/MF, F/RF, and F/G genotypes are presented in Appendix 4.

Table 5: CADTH Revisions to the Submitted Economic Evaluation

Stepped analysis

Sponsor’s value or assumption

CADTH value or assumption

Changes to derive the CADTH base case

1. Reduction in rate of ppFEV1 decline compared with BSC (after 192 weeks)

ELX-TEZ-IVA (F/F): 86.4%

ELX-TEZ-IVA (other genotypes): 89.7%

LUM-IVA: 42%

No reduction in rate of ppFEV1 decline

2. Pulmonary exacerbation rate ratio with CFTR modulators compared to BSC

ELX-TEZ-IVA: 0.31

LUM-IVA: 0.46

1 for all CFTR modulators

3. Dynamic pricing of CFTR modulators

25% price reduction after 16 years for ELX-TEZ-IVA, 6 years for IVA, and 8 years for LUM-IVA

50% price reduction after 17 years for ELX-TEZ-IVA, 7 years for IVA, and 9 years for LUM-IVA

No price reduction over model time horizon

4. Patient compliance rate in post-acute period

93%

100%

5. Disease management costs during period of survival benefit while on ELX-TEZ-IVA

Not included

Included

6. ELX-TEZ-IVA impact on inpatient and pharmacotherapy costs (beyond impact on ppFEV1)

Annual inpatient costs

  • BSC

    • ppFEV1 ≥ 70%: $4,163

    • ppFEV1 ≥ 40% to 69%: $7,273

    • ppFEV1 < 40%: $9,600

  • CFTR modulator

    • ppFEV1 ≥ 70%: $791

    • ppFEV1 ≥ 40% to 69%: $1,382

    • ppFEV1 < 40%: $1,824

Annual pharmacotherapy costs

  • BSC

    • ppFEV1 ≥ 70%: $7,834

    • ppFEV1 ≥ 40% to 69%: $9,280

    • ppFEV1 < 40%: $9,562

  • CFTR modulator

    • ppFEV1 ≥ 70%: $6,071

    • ppFEV1 ≥ 40% to 69%: $7,192

    • ppFEV1 < 40%: $7,411

Annual inpatient costs

  • All comparators

    • ppFEV1 ≥ 70%: $4,163

    • ppFEV1 ≥ 40% to 69%: $7,273

    • ppFEV1 < 40%: $9,600

Annual pharmacotherapy costs

  • All comparators

    • ppFEV1 ≥ 70%: $7,834

    • ppFEV1 ≥ 40% to 69%: $9,280

    • ppFEV1 < 40%: $9,562

7. Treatment-specific utility increment for ELX-TEZ-IVA

Increment of 0.09 included

No utility increment

CADTH base case

Reanalysis 1 + 2 + 3 + 4 + 5 + 6 + 7

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; IVA = ivacaftor; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second.

Results from the CADTH base-case analysis showed that for the F/F genotype, ELX-TEZ-IVA was associated with incremental costs of $5,307,519 and incremental QALYs of 6.3 when compared with LUM-IVA, for an ICER of $838,687 per QALY gained. Compared to BSC, ELX-TEZ-IVA was associated with an incremental cost of $10,408,124 and incremental QALYs of 8.1, for an ICER of $1,284,953 per QALY gained. In the heterozygous F/MF genotype, ELX-TEZ-IVA was associated with incremental costs and incremental QALYs of $10,278,140 and 7.1, respectively, for an ICER of $1,451,526 per QALY gained, compared to BSC. In the heterozygous F/G genotype, ELX-TEZ-IVA was associated with $10,312,005 of incremental costs and 8.0 incremental QALYs compared to BSC, resulting in an ICER of $1,284,853 per QALY gained. Lastly, in the heterozygous F/RF genotype, $10,931,906 in incremental costs and 6.6 in incremental QALYs were observed for ELX-TEZ-IVA compared to BSC, for an ICER of $1,644,869 per QALY gained. All analyses were based on publicly available prices. Full results of the CADTH base case can be found in Table 7, with disaggregated results for all genotypes available in Appendix 4.

The sponsor’s model further produced an overall ICER, weighted for each genotype and the relative market shares of the available comparators. The weighted ICER was $1,301,071 per QALY gained. The change to the sponsor’s base case that had the greatest impact on the results was the removal of dynamic pricing due to the introduction of generic options, emphasizing the impact of drug acquisition costs as a key driver of the model.

Table 6: Summary of the Stepped Analysis of the CADTH Reanalysis Results (F/F Genotype)

Stepped analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

Sponsor’s base case (deterministic)

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

7,753,763

42.8

381,905

LUM-IVA

3,999,638

30.5

Reference

ELX-TEZ-IVA

7,753,763

42.8

306,571

CADTH reanalysis 1: ppFEV1 decline

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

6,752,116

35.6

546,295

LUM-IVA

3,720,571

27.3

Reference

ELX-TEZ-IVA

6,752,116

35.6

363,389

CADTH reanalysis 2: pulmonary exacerbation rate ratio

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

7,779,104

42.7

384,842

LUM-IVA

4,025,042

30.3

Reference

ELX-TEZ-IVA

7,779,104

42.7

302,161

CADTH reanalysis 3: dynamic pricing

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

12,332,427

42.8

640,106

LUM-IVA

6,170,089

30.5

Reference

ELX-TEZ-IVA

12,332,427

42.8

503,232

CADTH reanalysis 4: compliance in the post-acute phase

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

8,307,701

42.8

413,142

LUM-IVA

4,258,058

30.5

Reference

ELX-TEZ-IVA

8,307,701

42.8

330,704

CADTH reanalysis 5: disease management costs during survival benefit period

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

7,905,129

42.8

390,441

LUM-IVA

4,147,587

30.5

Reference

ELX-TEZ-IVA

7,905,129

42.8

306,850

CADTH reanalysis 6: inpatient and pharmacotherapy costs

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

7,888,312

42.8

389,492

LUM-IVA

4,103,321

30.5

Reference

ELX-TEZ-IVA

7,888,312

42.8

309,092

CADTH reanalysis 7: treatment-specific utility for ELX-TEZ-IVA

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

7,753,763

40.8

429,241

LUM-IVA

3,999,638

30.5

Reference

ELX-TEZ-IVA

7,753,763

40.8

364,833

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7): deterministic

BSC

981,477

25.1

Reference

ELX-TEZ-IVA

11,390,106

33.1

1,290,470

LUM-IVA

6,116,136

26.8

Reference

ELX-TEZ-IVA

11,390,106

33.1

829,744

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7): probabilistic

BSC

973,938

25.0

Reference

ELX-TEZ-IVA

11,382,063

33.1

1,284,953

LUM-IVA

6,074,544

26.7

Reference

ELX-TEZ-IVA

11,382,063

33.1

838,687

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; QALY = quality-adjusted life-year.

Table 7: Summary of the CADTH Base-Case Results by Genotype

Drug

Total costs ($)

Incremental costs ($)

Total QALYs

Incremental QALYs

ICER ($/QALY)

Homozygous for F508del-CFTR (F/F)

BSC

973,938

Reference

25.0

Reference

Reference

ELX-TEZ-IVA

11,382,063

10,408,124

33.1

8.1

1,284,953

LUM-IVA

6,074,544

Reference

26.7

Reference

Reference

ELX-TEZ-IVA

11,382,063

5,307,519

33.1

6.3

838,687

Heterozygous for F508del-CFTR (F/MF)

BSC

788,521

Reference

25.3

Reference

Reference

ELX-TEZ-IVA

11,066,661

10,278,140

32.4

7.1

1,451,526

Heterozygous for F508del-CFTR (F/G)

BSC

1,080,162

Reference

24.8

Reference

Reference

ELX-TEZ-IVA

11,392,167

10,312,005

32.8

8.0

1,284,853

Heterozygous for F508del-CFTR (F/RF)

BSC

737,607

Reference

27.9

Reference

Reference

ELX-TEZ-IVA

11,669,512

10,931,906

34.5

6.6

1,644,869

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; LUM-IVA = lumacaftor-ivacaftor; QALY = quality-adjusted life-year.

Scenario Analysis Results

Price reduction analyses were conducted using the sponsor and CADTH base cases, assuming proportional price reductions for ELX-TEZ-IVA (Table 8) for the summary of price reductions. Appendix 4 provides full price reduction analyses for individual genotypes (i.e., F/F, F/MF, F/G, and F/RF) and all genotypes combined (weighted by prevalence and market shares). Note for the F/F genotype comparison with LUM-IVA are also presented. Using the weighted population CADTH base-case analysis, a price reduction in excess of 94% is required for ELX-TEZ-IVA to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY in comparison with BSC for all genotypes. The price reduction required varies by genotype but is smallest for the F/F genotype and is greatest for the F/RF genotype.

Table 8: CADTH Price Reduction Analyses

Analysis

ICER for ELX-TEZ-IVA vs. BSC ($/QALY)

Price reduction

Sponsor base case

CADTH reanalysis

Homozygous for F508del-CFTR (F/F)

No price reduction

381,905

1,290,470

90%

1,355

107,112

95%

Dominant

41,370

99%

Dominant

Dominant

Heterozygous for F508del-CFTR (F/MF)

No price reduction

406,979

1,429,803

90%

11,996

130,410

95%

Dominant

58,222

99%

Dominant

471

Homozygous for F508del-CFTR (F/G)

No price reduction

368,537

1,295,357

90%

Dominant

100,086

95%

Dominant

33,682

99%

Dominant

Dominant

Homozygous for F508del-CFTR (F/RF)

No price reduction

502,800

1,578,493

90%

20,812

146,693

95%

Dominant

67,148

99%

Dominant

3,513

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Note: All price reduction analysis was conducted deterministically, unless otherwise stated.

CADTH also undertook a series of scenario analyses to determine the impact of alternative assumptions on the cost-effectiveness of ELX-TEZ-IVA. These scenarios included the following:

The results of the CADTH scenario analyses are available in Table 9 for the F/F genotype and in Appendix 4 for the F/MF, F/RF, and F/G genotypes. These scenarios highlighted the impact of assuming additional benefit with ELX-TEZ-IVA despite a lack of supporting evidence: none of the scenarios for the F/F genotype population produced an ICER below $836,939 per QALY gained when compared to BSC. These scenario analyses are driven by the high drug acquisition costs with ELX-TEZ-IVA, which offset the estimated QALY gains.

Table 9: CADTH Scenario Analysis Summary — F/F Genotype

Scenario analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

1. Slower rate of decline in ppFEV1

BSC

973,938

25.0

Reference

ELX-TEZ-IVA

13,472,245

40.0

832,726

LUM-IVA

6,899,343

30.2

Reference

ELX-TEZ-IVA

13,472,245

40.0

676,763

2. Long-term reduction in pulmonary exacerbations included for CFTR modulators

BSC

973,938

25.0

Reference

ELX-TEZ-IVA

11,425,272

33.7

1,198,260

LUM-IVA

6,067,537

27.3

Reference

ELX-TEZ-IVA

11,425,272

33.7

836,939

3. Inclusion of treatment-specific utility increment for patients on ELX-TEZ-IVA

BSC

973,938

25.0

Reference

ELX-TEZ-IVA

11,382,063

34.6

1,078,743

LUM-IVA

6,074,544

26.7

Reference

ELX-TEZ-IVA

11,382,063

34.6

673,822

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; LUM-IVA = lumacaftor-ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second; QALY = quality-adjusted life-year.

Issues for Consideration

Overall Conclusions

Results from the 24-week, open-label, uncontrolled Study 111 Part B suggest that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function (decrease in lung clearance index 2.5 from baseline) and CF biomarkers (reduction in sweat chloride) in patients aged 2 to 5 years with CF. However, as Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA in this younger population, the pharmacoeconomic review is based on the extrapolation of efficacy data from studies conducted in older patients with CF. Patients who completed Study 111 were eligible to enrol in an open-label extension study; however, interim results were not available at the time of filing the application with CADTH.

As noted in CADTH’s previous review of ELX-TEZ-IVA for patients with CF aged 6 to 11 years,25 the clinical evidence submitted by the sponsor demonstrated that ELX-TEZ-IVA was associated with statistically and clinically significant improvements in acute ppFEV1 and weight-for-age z scores compared with relevant comparators in patients aged 6 to 11 years with F/F or F/MF genotypes. Although no clinical studies were conducted with ELX-TEZ-IVA in pediatric patients with F/RF or F/G genotypes, the clinical expert feedback received during the review noted that ELX-TEZ-IVA would result in clinically meaningful improvements for these patients, based on the evidence reported for ELX-TEZ-IVA in adolescent and adult patients with the F/RF and F/G genotypes and the results of studies of pediatric patients with the F/F and F/MF genotypes. Similar results were reported for patients aged 12 years and older regarding the acute change in ppFEV1 in all genotypes.39

The clinical experts consulted by CADTH for the current review noted that, given the mechanism of action and compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA is expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. However, these conclusions are based on studies with a maximum follow-up of 192 weeks, and there remains no evidence on the long-term impact of ELX-TEZ-IVA on the rate of decline in ppFEV1 and PExs rates beyond the trial period for any genotype or age group.

Beyond uncertainty in the long term clinical efficacy of ELX-TEZ-IVA, CADTH identified several major limitations with the submitted economic evaluation. The following were addressed in the CADTH reanalysis: the removal of an additional benefit of CFTR modulators on the long-term rate of decline in ppFEV1 and PExs; the removal of dynamic pricing for CFTR modulators; the inclusion of costs for ELX-TEZ-IVA for the period in which a survival benefit was achieved in comparison to BSC; the removal of an adjustment to drug acquisition costs based on patient compliance; and the removal of a treatment-specific utility increment for patients on ELX-TEZ-IVA. The results of the CADTH reanalysis were aligned with the sponsor’s, in that ELX-TEZ-IVA was not cost-effective in any of the genotype subgroups at conventionally acceptable ICER thresholds. In the CADTH base-case analyses, when compared to BSC, ELX-TEZ-IVA was associated with an ICER of $1,284,953 per QALY gained in the F/F genotype, $1,451,526 per QALY gained in the F/MF genotype, $1,284,853 per QALY gained in the F/G genotype, and $1,644,869 per QALY gained in the F/RF genotype. Additionally, ELX-TEZ-IVA was associated with an ICER of $838,687 per QALY gained when compared to LUM-IVA in the F/F genotype population.

The key drivers in the analyses were drug acquisition costs and assumptions in the long-term benefits of ELX-TEZ-IVA, which were uncertain. Treatment with ELX-TEZ-IVA was not cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained in any scenario conducted by CADTH. A price reduction in excess of 94% for ELX-TEZ-IVA (for both granules and tablets) is required for all 4 genotypes for ELX-TEZ-IVA to be considered cost-effective at this threshold in comparison with BSC. Based on a price reduction of this magnitude, the daily cost of ELX-TEZ-IVA would be approximately $50.40 per patient. As the majority of patients with CF aged 6 years and older are currently being treated with ELX-TEZ-IVA, the sponsor’s submitted economic evaluation assessing the cost-effectiveness of ELX-TEZ-IVA compared to BSC or LUM-IVA (for the F/F genotype only) over the entire lifetime of a patient aged 2 to 5 years does not accurately reflect the current landscape of CF treatment. The cost-effectiveness of starting ELX-TEZ-IVA for patients aged 2 to 5 years versus waiting to initiate treatment at age 6 years or older is unknown.

References

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2.pan-Canadian Oncology Drug Review Committee (pERC) final recommendation: Elexacaftor-TezacaftorIvacaftor and Ivacaftor (Trikafta). Ottawa (ON): CADTH; 2021: https://www.cadth.ca/sites/default/files/DRR/2021/SR0673%20Trikafta%20-%20CADTH%20Final%20Rec%20Revised.pdf. Accessed 2023 Jun 28.

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7.Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. PubMed

8.Davies JC, Sermet-Gaudelus I, Naehrlich L, et al. A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. J Cyst Fibros. 2021;20(1):68-77. PubMed

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17.Indirect Treatment Comparison for Epcoritamab in Patients with Relapsed or Refractory Large B-cell Lymphoma based on EPCORE NHL-1 trial [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Epkinly (epcoritamab), 4 mg in 0.8 mL [5mg/mL] and 48 mg in 0.8 mL [60 mg/mL], for injection. New York (NY): OPEN Health; 2023 Mar 10.

18.Mall MA, Brugha R, Gartner S, et al. Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study. Am J Respir Crit Care Med. 2022;206(11):1361-1369. PubMed

19.Leung GJ, Cho TJ, Kovesi T, Hamid JS, Radhakrishnan D. Variation in lung function and nutritional decline in cystic fibrosis by genotype: An analysis of the Canadian cystic fibrosis registry. J Cyst Fibros. 2020;19(2):255-261. PubMed

20.Loukou I, Moustaki M, Plyta M, Douros K. Long-term clinical outcome of cystic fibrosis paediatric patients presenting with meconium ileus. Acta Paediatr. 2020;109(12):2738-2739. PubMed

21.Ejiofor LCK, Mathiesen IHM, Jensen-Fangel S, et al. Patients with cystic fibrosis and advanced lung disease benefit from lumacaftor/ivacaftor treatment. Pediatr Pulmonol. 2020;55(12):3364-3370. PubMed

22.Muilwijk D, Zomer DD, Gulmans V, Ent CK. P055 Real-world trends in long-term clinical outcomes of lumacaftor/ivacaftor. Journal of Cystic Fibrosis. 2020;19:S70-S71.

23.Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis. Thorax. 2007;62(4):360-367. PubMed

24.McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4):325-335. PubMed

25.Drug Reimbursement Review pharmacoeconomic report: Elexacaftor-TezacaftorIvacaftor and Ivacaftor (Trikafta) for Cystic fibrosis, F508del-CFTR mutation, 6 years and older. Ottawa (ON): CADTH; 2022: https://www.cadth.ca/sites/default/files/DRR/2022/SR0710-Trikafta_combined.pdf. Accessed 2023 Jul 10.

26.Exceptional Access Program (EAP). Toronto (ON): Ontario Ministry of Health; Ontario Ministry of Long-Term Care; 2022: http://www.health.gov.on.ca/en/pro/programs/drugs/odbf/odbf_except_access.aspx. Accessed 2023 Jun 24.

27.Schedule of benefits for physician services under the Health Insurance Act: (January 25, 2022 (effective July 1, 2022)). Toronto (ON): Ontario Ministry of Health; 2022: https://www.health.gov.on.ca/en/pro/programs/ohip/sob/physserv/sob_master.pdf.

28.Kalydeco: Ivacaftor tablets 150 mg, Oral Ivacaftor granules 25 mg per packet, 50 mg per packet, 75 mg per packet, Oral [product monograph]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2022.

29.Orkambi: Lumacaftor / Ivacaftor Tablets 100 mg / 125 mg, Oral, Lumacaftor / Ivacaftor Tablets 200 mg / 125 mg, Oral Lumacaftor / Ivacaftor Granules 75 mg / 94 mg, Oral, Lumacaftor / Ivacaftor Granules 100 mg / 125 mg, Oral Lumacaftor / Ivacaftor Granules 150 mg / 188 mg, Oral [product monograph]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2023.

30.Schedule of benefits for laboratory services: effective July 1, 2020. Toronto (ON): Ontario Ministry of Health; 2020: http://www.health.gov.on.ca/en/pro/programs/ohip/sob/lab/lab_mn2020.pdf. Accessed 1800 Jan 1.

31.Skolnik K, Ronksley P, Pendharkar S, Wick J, Quon BS, Williamson T. Hospitalization-related costs for canadian cystic fibrosis patients [conference abstract]. Pediatr Pulmonol. 2018;53.

32.Feng LB, Grosse SD, Green RF, Fink AK, Sawicki GS. Precision Medicine In Action: The Impact Of Ivacaftor On Cystic Fibrosis-Related Hospitalizations. Health Aff (Millwood). 2018;37(5):773-779. PubMed

33.Hassan M, Bonafede MM, Limone BL, Hodgkins P, Suthoff ED, Sawicki G. Reduction in pulmonary exacerbations (PEx) after initiation of ivacaftor: a retrospective cohort study among patients with cystic fibrosis (CF) treated in real-world settings [conference abstract]. Journal of Cystic Fibrosis. 2016;15:S58.

34.Vasiliadis HM, Collet JP, Penrod JR, Ferraro P, Poirier C. A cost-effectiveness and cost-utility study of lung transplantation. J Heart Lung Transplant. 2005;24(9):1275-1283. PubMed

35.Government of Alberta. Alberta Interactive Health Data Application. Average cost of lung transplant procedure in 2017/2018. 2019; http://www.ahw.gov.ab.ca/IHDA_Retrieval/redirectToURL.do?cat=201&subCat=486. Accessed 2023 Jun 8.

36.Solem CT, Vera-Llonch M, Tai M, O’Callaghan L. Pulmonary Exacerbations, Lung Dysfunction, And Eq-5d Measures In Adolescents And Adults With Cystic Fibrosis And Homozygous For The F508del-Cftr Mutation. Value Health. 2016;19(3):A116-A117.

37.Lee T, Sawicki GS, Altenburg J, et al. Effect of elexacaftor/tezacaftor/ivacaftor on annual rate of lung function decline in people with cystic fibrosis. J Cyst Fibros. 2023;22(3):402-406. PubMed

38.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: Elexacaftor-TezacaftorIvacaftor and Ivacaftor (Trikafta): Treatment of cystic fibrosis in patients aged 6 years and older who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator gene. Ottawa (ON): CADTH; 2022: https://www.cadth.ca/sites/default/files/DRR/2022/SR0710%20Trikafta%20-%20CADTH%20Final%20Rec-meta.pdf. Accessed 2023 Jun 20.

39.Drug Reimbursement Review pharmacoeconomic report: Elexacaftor-TezacaftorIvacaftor and Ivacaftor (Trikafta) for Cystic fibrosis, F508del CFTR mutation. Ottawa (ON): CADTH; 2021: https://www.cadth.ca/sites/default/files/DRR/2021/SR0673-combined-report.pdf. Accessed 2023 Jul 10.

40.Budget Impact Analysis [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Epkinly (epcoritamab), 4 mg in 0.8 mL [5mg/mL] and 48 mg in 0.8 mL [60 mg/mL], for injection. Pointe-Claire (QC): AbbVie Corporation; 2023 Nov 14.

Appendix 1: Cost Comparison Table

Note that this appendix has not been copy-edited.

The comparators presented in the following table have been deemed to be appropriate based on feedback from clinical expert(s). Comparators may be recommended (appropriate) practice or actual practice. Existing Product Listing Agreements are not reflected in the table and as such, the table may not represent the actual costs to public drug plans.

Table 10: CADTH Cost Comparison Table for CFTR Modulator Therapies for Cystic Fibrosis for Patients Aged 2 to 5 Years

Treatment

Strength / concentration

Form

Price ($)

Recommended dosagea

Daily cost ($)

Annual cost ($)

Elexacaftor- tezacaftor- ivacaftor and ivacaftor (Trikafta)

100 mg / 50 mg/ 75 mg and 75 mg

80 mg/ 40 mg/ 60 mg and 59.5 mg

Granules Packet

420.0000b

One granule packet (containing elexacaftor 100 mg - tezacaftor 50 mg - ivacaftor 75 mg or elexacaftor 80 mg - tezacaftor 40 mg - ivacaftor 60 mg) taken in the morning and 1 granule packet (ivacaftor 75 mg or ivacaftor 59.5 mg) taken in the evening approximately 12 hours apart, with fat-containing food

840.00

306,810

100 mg/ 50 mg/

75 mg and 150 mg

50 mg/ 25 mg/

37.5 and 75 mg

Tablets

Two tablets (each containing elexacaftor 100 mg - tezacaftor 50 mg - ivacaftor 75 mg or elexacaftor 50 mg - tezacaftor 25 mg - ivacaftor 37.5 mg) taken in the morning and 1 tablet (ivacaftor 150 mg or ivacaftor 75 mg) taken in the evening approximately 12 hours apart, with fat-containing food

CFTR modulator therapies

Lumacaftor-ivacaftor (Orkambi)

100 mg/125 mg

Granules

170.5357

One packet twice daily

682.14

249,152

Note: All prices are from the Ontario Exceptional Access Program formulary (accessed June 2023)26 unless otherwise indicated, and do not include dispensing fees. Annual costs are based on 365.25 days per year.

aRecommended dosages are from the respective product monographs.3,29

bSponsor-submitted price.1

Appendix 2: Submission Quality

Note that this appendix has not been copy-edited.

Table 11: Submission Quality

Description

Yes/No

Comments

Population is relevant, with no critical intervention missing, and no relevant outcome missing

Yes

No comment

Model has been adequately programmed and has sufficient face validity

No

Model lacks transparency with regards to programming

Model structure is adequate for decision problem

Yes

No comment

Data incorporation into the model has been done adequately (e.g., parameters for probabilistic analysis)

Yes

No comment

Parameter and structural uncertainty were adequately assessed; analyses were adequate to inform the decision problem

Yes

No comment

The submission was well organized and complete; the information was easy to locate (clear and transparent reporting; technical documentation available in enough details)

Yes

No comment

Appendix 3: Additional Information on the Submitted Economic Evaluation

Note that this appendix has not been copy-edited.

Figure 1: Model Structure

The microsimulation model structure submitted by the sponsor illustrating the flow of patients through different health states.

Source: Sponsor’s pharmacoeconomic submission.1

Appendix 4: Additional Details on the CADTH Reanalyses and Sensitivity Analyses of the Economic Evaluation

Note that this appendix has not been copy-edited.

Detailed Results of CADTH Base Case

Table 12: Disaggregated Summary of CADTH’s Economic Evaluation Results (Deterministic) — F/F Genotype

Parameter

ELX-TEZ-IVA

LUM-IVA

Incremental

ELX-TEZ-IVA

BSC

Incremental

Discounted LYs

Total

34.6

28.8

5.7

34.6

26.9

7.6

Discounted QALYs

Total

34.2

28.2

6.0

34.2

26.2

8.0

Discounted costs ($)

Total

11,203,814

6,061,356

5,142,458

11,203,814

916,157

10,287,657

Drug acquisition cost

10,437,275

5,156,352

5,280,923

10,437,275

0

10,437,275

Non–PEx-related disease management costs

504,690

485,342

19,347

504,690

492,515

12,175

PEx-related costs

258,165

417,205

–159,040

258,165

421,210

–163,046

Lung transplant costs

0

0

0

0

0

0

Adverse event cost

3,527

2,277

1,250

3,527

2,432

1,095

Monitoring cost

157

180

–23

157

0

157

Indirect costs

0

0

0

0

0

0

ICER ($/QALY)

850,053

1,283,744

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/F = homozygous for F508del mutation in the CFTR gene; LY = life-year; PEx = pulmonary exacerbations; QALY = quality-adjusted life-year.

Table 13: Disaggregated Summary of CADTH’s Economic Evaluation Results (Deterministic) — F/MF Genotype

Parameter

ELX-TEZ-IVA

BSC

Incremental

Discounted LYs

Total

34.9

27.2

7.7

Discounted QALYs

Total

34.7

26.7

7.9

Discounted costs ($)

Total

11,129,360

742,088

10,387,273

Drug acquisition cost

10,532,547

0

10,532,547

Non–PEx-related disease management costs

495,432

442,792

52,640

PEx-related costs

96,961

296,833

–199,872

Lung transplant costs

0

0

0

Adverse event cost

4,263

2,463

1,800

Monitoring cost

158

0

158

Indirect costs

0

0

0

ICER ($/QALY)

1,311,755

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LY = life-year; PEx = pulmonary exacerbations; QALY = quality-adjusted life-year.

Table 14: Disaggregated Summary of CADTH’s Economic Evaluation Results (Deterministic) — F/G Genotype

Parameter

ELX-TEZ-IVA

BSC

Incremental

Discounted LYs

Total

35.2

27.1

8.1

Discounted QALYs

Total

34.9

26.2

8.6

Discounted costs ($)

Total

11,395,429

1,008,352

10,387,077

Drug acquisition cost

10,641,712

0

10,641,712

Non–PEx-related disease management costs

521,095

511,913

9,182

PEx-related costs

228,337

493,520

–265,182

Lung transplant costs

0

470

–470

Adverse event cost

4,126

2,450

1,676

Monitoring cost

159

0

159

Indirect costs

0

0

0

ICER ($/QALY)

1,204,386

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; LY = life-year; PEx = pulmonary exacerbations; QALY = quality-adjusted life-year.

Table 15: Disaggregated Summary of CADTH’s Economic Evaluation Results (Deterministic) — F/RF Genotype

Parameter

ELX-TEZ-IVA

BSC

Incremental

Discounted LYs

Total

36.9

29.6

7.3

Discounted QALYs

Total

36.8

29.2

7.6

Discounted costs ($)

Total

11,718,395

747,296

10,971,100

Drug acquisition cost

11,143,534

0

11,143,534

Non–PEx-related disease management costs

496,796

466,103

30,692

PEx-related costs

73,585

278,350

–204,764

Lung transplant costs

0

0

0

Adverse event cost

4,318

2,842

1,476

Monitoring cost

161

0

161

Indirect costs

0

0

0

ICER ($/QALY)

1,437,829

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; LY = life-year; PEx = pulmonary exacerbations; QALY = quality-adjusted life-year.

Table 16: Summary of the Stepped Analysis of the CADTH Reanalysis Results (Deterministic) — F/MF Genotype

Stepped analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

Sponsor’s base case (deterministic)

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

7,663,343

42.2

406,979

CADTH reanalysis 1 – ppFEV1 decline

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

6,639,136

34.9

608,529

CADTH reanalysis 2 – pulmonary exacerbation rate ratio

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

7,663,082

42.0

412,396

CADTH reanalysis 3 – dynamic pricing

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

12,156,915

42.2

673,180

CADTH reanalysis 4 – compliance in the post-acute phase

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

8,210,525

42.2

439,395

CADTH reanalysis 5 – disease management costs during survival benefit period

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

7,806,674

42.2

415,470

CADTH reanalysis 6 – inpatient and pharmacotherapy costs

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

7,798,275

42.2

414,973

CADTH reanalysis 7 – treatment-specific utility for ELX-TEZ-IVA

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

7,663,343

40.3

458,604

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (deterministic)

BSC

793,354

25.3

Reference

ELX-TEZ-IVA

11,058,871

32.5

1,429,803

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (probabilistic)

BSC

788,521

25.3

Reference

ELX-TEZ-IVA

11,066,661

32.4

1,451,526

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LY = life-year; QALY = quality-adjusted life-year; ppFEV1 = percent predicted forced expiratory volume in the first second.

Table 17: Summary of the Stepped Analysis of the CADTH Reanalysis Results (Deterministic) — F/G Genotype

Stepped analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

Sponsor’s base case (deterministic)

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

7,773,682

42.9

368,537

CADTH reanalysis 1 – ppFEV1 decline

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

6,741,011

35.5

529,192

CADTH reanalysis 2 – pulmonary exacerbation rate ratio

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

7,761,414

42.6

375,063

CADTH reanalysis 3 – dynamic pricing

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

12,369,724

42.9

621,931

CADTH reanalysis 4 – compliance in the post-acute phase

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

8,328,927

42.9

399,150

CADTH reanalysis 5 – disease management costs during survival benefit period

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

7,929,684

42.9

377,138

CADTH reanalysis 6 – inpatient and pharmacotherapy costs

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

7,907,190

42.9

375,898

CADTH reanalysis 7 – treatment-specific utility for ELX-TEZ-IVA

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

7,773,682

40.9

413,940

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (deterministic)

BSC

1,089,164

24.8

Reference

ELX-TEZ-IVA

11,313,664

32.7

1,295,357

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (probabilistic)

BSC

1,080,162

24.8

Reference

ELX-TEZ-IVA

11,392,167

32.8

1,284,853

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/MF = 1 F508del mutation and 1 gating mutation in the CFTR gene; LY = life-year; QALY = quality-adjusted life-year; ppFEV1 = percent predicted forced expiratory volume in the first second.

Table 18: Summary of the Stepped Analysis of the CADTH Reanalysis Results (Deterministic) — F/RF Genotype

Stepped analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

Sponsor’s base case (deterministic)

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

7,574,624

41.5

502,800

CADTH reanalysis 1 – ppFEV1 decline

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

6,918,294

36.9

689,212

CADTH reanalysis 2 – pulmonary exacerbation rate ratio

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

7,596,250

41.4

508,813

CADTH reanalysis 3 – dynamic pricing

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

11,966,983

41.5

825,242

CADTH reanalysis 4 – compliance in the post-acute phase

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

8,113,294

41.5

542,344

CADTH reanalysis 5 – disease management costs during survival benefit period

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

7,688,854

41.5

511,186

CADTH reanalysis 6 – inpatient and pharmacotherapy costs

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

7,723,595.

41.5

513,736

CADTH reanalysis 7 – treatment-specific utility for ELX-TEZ-IVA

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

7,574,624

39.7

582,928

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (deterministic)

BSC

725,405

27.9

Reference

ELX-TEZ-IVA

11,726,690

34.9

1,578,493

CADTH base case

(1 + 2 + 3 + 4 + 5 + 6 + 7) (probabilistic)

BSC

737,607

27.9

Reference

ELX-TEZ-IVA

11,669,512

34.5

1,644,869

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; F/MF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; LY = life-year; QALY = quality-adjusted life-year; ppFEV1 = percent predicted forced expiratory volume in the first second.

Scenario Analyses

Table 19: CADTH Price Reduction Analysis — F/F Genotype

Analysis

ICER ($/QALY) for ELX-TEZ-IVA vs. LUM-IVA

ICER ($/QALY) for ELX-TEZ-IVA vs. BSC

Price reduction

Sponsor base case

CADTH reanalysis

Sponsor base case

CADTH reanalysis

No Price Reduction

306,571

829,744

381,905

1,290,470

10%

245,340

662,894

339,621

1,158,986

20%

184,109

496,044

297,338

1,027,502

40%

61,647

162,345

212,771

764,533

60%

Dominant

Dominant

128,205

501,565

70%

Dominant

Dominant

85,921

370,080

80%

Dominant

Dominant

43,638

238,596

90%

Dominant

Dominant

1,355

107,112

95%

Dominant

Dominant

Dominant

41,370

99%

Dominant

Dominant

Dominant

Dominant

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; LUM-IVA = lumacaftor-ivacaftor; QALY = quality-adjusted life-year; vs. = versus.

Table 20: CADTH Price Reduction Analysis — F/MF Genotype

Analysis

ICER ($/QALY) for ELX-TEZ-IVA vs. BSC

Price reduction

Sponsor base case

CADTH reanalysis

No Price Reduction

406,979

1,429,803

10%

363,092

1,285,426

20%

275,318

996,672

40%

187,544

707,918

60%

143,657

563,541

70%

99,770

419,164

80%

55,883

274,787

90%

11,996

130,410

95%

Dominant

58,222

99%

Dominant

471

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/MF = heterozygous for F508del and 1 minimal function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 21: CADTH Price Reduction Analysis — F/G Genotype

Analysis

ICER ($/QALY) for ELX-TEZ-IVA vs. BSC

Price reduction

Sponsor base case

CADTH reanalysis

No Price Reduction

368,537

1,295,357

10%

327,103

1,162,549

20%

244,233

896,933

40%

161,363

631,317

60%

119,928

498,510

70%

78,493

365,702

80%

37,058

232,894

90%

Dominant

100,086

95%

Dominant

33,682

99%

Dominant

Dominant

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/G = heterozygous for F508del and 1 gating mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 22: CADTH Price Reduction Analysis — F/RF Genotype

Analysis

ICER ($/QALY) for ELX-TEZ-IVA vs. BSC

Price reduction

Sponsor base case

CADTH reanalysis

No Price Reduction

502,800

1,578,493

10%

449,246

1,419,404

20%

342,137

1,101,226

40%

235,029

783,048

60%

181,475

623,959

70%

127,920

464,870

80%

74,366

305,782

90%

20,812

146,693

95%

Dominant

67,148

99%

Dominant

3,513

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/RF = heterozygous for F508del and 1 residual function mutation in the CFTR gene; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 23: CADTH Price Reduction Analysis — Weighted Analysis, All Genotypes Combined

Analysis

ICER ($/QALY) for ELX-TEZ-IVA vs. standard of care

Price reduction

Sponsor base case

CADTH reanalysis

No price reduction

399,060

1,355,183

10%

355,170

1,216,867

20%

267,389

940,234

40%

179,609

663,601

60%

135,719

525,285

70%

91,829

386,969

80%

47,938

248,652

90%

4,048

110,336

95%

Dominant

41,178

99%

Dominant

Dominant

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 24: CADTH Scenario Analysis Summary — F/MF Genotype

Scenario analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

1. Slower rate of decline in ppFEV1

BSC

788,521

25.3

Reference

ELX-TEZ-IVA

13,285,699

39.4

886,656

2. Long-term reduction in pulmonary exacerbations included for CFTR modulators

BSC

788,521

25.3

Reference

ELX-TEZ-IVA

11,121,006

32.9

1,355,482

3. Inclusion of treatment-specific utility increment for patients on ELX-TEZ-IVA

BSC

788,521

25.3

Reference

ELX-TEZ-IVA

11,066,661

33.8

1,202,824

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 25: CADTH Scenario Analysis Summary — F/G Genotype

Scenario analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

1. Slower rate of decline in ppFEV1

BSC

1,080,162

24.8

Reference

ELX-TEZ-IVA

13,478,005

39.9

821,473

2. Long-term reduction in pulmonary exacerbations included for CFTR modulators

BSC

1,080,162

24.8

Reference

ELX-TEZ-IVA

11,417,054

33.5

1,190,243

3. Inclusion of treatment-specific utility increment for patients on ELX-TEZ-IVA

BSC

1,080,162

24.8

Reference

ELX-TEZ-IVA

11,392,167

34.4

1,071,801

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Table 26: CADTH Scenario Analysis Summary — F/RF Genotype

Scenario analysis

Drug

Total costs ($)

Total QALYs

ICER ($/QALY)

1. Slower rate of decline in ppFEV1

BSC

737,607

27.9

Reference

ELX-TEZ-IVA

13,082,606

38.9

1,121,384

2. Long-term reduction in pulmonary exacerbations included for CFTR modulators

BSC

737,607

27.9

Reference

ELX-TEZ-IVA

11,665,696

34.8

1,580,648

3. Inclusion of treatment-specific utility increment for patients on ELX-TEZ-IVA

BSC

737,607

27.9

Reference

ELX-TEZ-IVA

11,669,512

36.0

1,338,537

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; vs. = versus.

Appendix 5: Submitted Budget Impact Analysis and CADTH Appraisal

Note that this appendix has not been copy-edited.

Table 27: Summary of Key Take-Aways

Key take-aways of the budget impact analysis

  • CADTH identified the following key limitations with the sponsor’s analysis:

    • The sponsor’s adjustment of drug costs by a compliance rate for patients underestimates drug costs and the resulting budget impact.

    • The sponsor’s estimate of the proportion of patients switching treatments from LUM-IVA to ELX-TEZ-IVA upon ELX-TEZ-IVA reimbursement may be underestimated.

    • There is uncertainty regarding the proportion of patients with public drug coverage.

  • The CADTH reanalysis assumed 100% compliance for all drugs. In the CADTH base case, the reimbursement of ELX-TEZ-IVA for the treatment of CF in patients who are 2 to 5 years old with at least 1 F508del-CFTR mutation is expected to be $42,404,017 in Year 1, $46,295,984 in Year 2, and $48,029,320 in Year 3. Therefore, the 3-year total is $136,729,321.

  • A CADTH scenario analysis found the budget impact to be sensitive to assumptions around the proportion of patients with public drug coverage.

Summary of Sponsor’s Budget Impact Analysis

The sponsor submitted an epidemiology-based budget impact analysis (BIA), assessing the expected budgetary impact of reimbursing ELX-TEZ-IVA plus BSC for the treatment of CF patients who are 2 to 5 years of age with at least 1 F508del-CFTR mutation. The analysis was conducted from the perspective of the Canadian public drug plans over a 3-year time horizon (from 2024 to 2026, with 2023 as the base year). Only drug acquisition costs were included. The BIA considered a reference scenario where only LUM-IVA (only available in Ontario, Alberta, Saskatchewan, and the Non-Insured Health Benefits for F/F patients) was available while the new drug scenario included both ELX-TEZ-IVA and LUM-IVA. All patients were assumed to receive background BSC, therefore costs associated with BSC were not considered. The sponsor’s estimates of expected ELX-TEZ-IVA utilization were based on internal estimates, whereas the market size was primarily based on data generated from the CF Canada patient registry and further reduced based on the proportion of patients covered by provincial formularies. Key inputs to the BIA are documented in Table 28.

Additionally, the sponsor made the following key assumptions:

Figure 2: Sponsor’s Estimation of the Size of the Eligible Population (Ontario Example)

A flow diagram estimating the size of the eligible population used for the budget impact analysis (Ontario specific).

Source: Sponsor’s budget impact submission.40

Table 28: Summary of Key Model Parameters

Parameter

Sponsor’s estimate (reported as year 1 / year 2 / year 3)

Target population

Number of patients eligible for drug under review

179 / 183 / 186

Market Uptake (3 years)

Uptake (reference scenario)

   LUM-IVA

   BSC

2% / 2% / 2%

98%/ 98%/ 98%

Uptake (new drug scenario)

   ELX-TEZ-IVA

   LUM-IVA

   BSC

77%/ 83%/ 85%

2% / 1% / 0%

22%/ 16%/ 15%

Cost of treatment (per patient)

Annual treatment cost, adjusted for 93% compliance

   ELX-TEZ-IVA

   LUM-IVA

   BSC

$285,333

$231,712

$0

BSC = best supportive care; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; LUM-IVA = lumacaftor-ivacaftor.

Note: Values may not sum to 100% due to rounding.

Summary of the Sponsor’s BIA Results

Results of the sponsor’s base case BIA estimated that the reimbursement of ELX-TEZ-IVA for the treatment of CF patients who are 2 to 5 years old with at least 1 F508del-CFTR mutation would be $39,435,735 in Year 1, $43,055,265 in Year 2, and $44,667,268 in Year 3. Therefore, the 3-year incremental budget impact would be $127,158,268.

The sponsor conducted several sensitivity analyses to assess the impact of different compliance rates, predicted utilization rates of ELX-TEZ-IVA and IVA, increasing the size of the eligible patient population, and the inclusion of pharmacy upcharges and dispensing fees. All had a large impact on results, with the largest impact associated with the scenario analyses assuming a 10% increase in either eligible population size or market uptake upon ELX-TEZ-IVA availability. Both scenario analyses were associated with a 3-year budget impact of $139,924,982. Another scenario of note is that assuming 100% compliance, where the 3-year incremental budget impact was $136,729,321.

CADTH Appraisal of the Sponsor’s BIA

CADTH identified several key limitations to the sponsor’s analysis that have notable implications on the results of the BIA:

CADTH Reanalyses of the BIA

Table 29: CADTH Revisions to the Submitted Budget Impact Analysis

Stepped analysis

Sponsor’s value or assumption

CADTH value or assumption

Corrections to sponsor’s base case

None

Changes to derive the CADTH base case

1. Patient compliance

93%

100%

CADTH base case

Reanalysis 1

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; LUM-IVA = lumacaftor-ivacaftor.

The results of the CADTH stepwise reanalysis are presented in summary format in Table 30 and a more detailed breakdown is presented in Table 31.

Based on the CADTH base case, the budget impact of the reimbursement of ELX-TEZ-IVA for the treatment of CF in patients who are 2 to 5 years of age with at least 1 F508del-CFTR mutation is expected to be $42,404,017 in Year 1, $46,295,984 in Year 2, and $48,029,320 in Year 3. Therefore, the 3-year total is $136,729,321. Scenario analyses were conducted around the proportion of patients expected to have public drug coverage. The 3-year budget impact totals for these analyses were $105,176,400 and $210,352,801 when 50% and 100% of patients were assumed to have public coverage, respectively.

Table 30: Summary of the CADTH Reanalyses of the BIA

Stepped analysis

Three-year total

Submitted sponsor base case

$127,158,268

CADTH base case

$136,729,321

BIA = budget impact analysis.

Table 31: Detailed Breakdown of the CADTH Reanalyses of the BIA

Stepped analysis

Scenario

Year 0 (current situation)

Year 1

Year 2

Year 3

Three-year total

Submitted sponsor base case

Reference

$324,491

$329,944

$335,488

$341,126

$1,006,559

New drug

$324,491

$39,765,679

$43,390,753

$45,008,394

$128,164,827

Budget impact

$0

$39,435,735

$43,055,265

$44,667,268

$127,158,268

CADTH base case

Reference

$348,915

$354,778

$360,740

$366,803

$1,082,321

New drug

$348,915

$42,758,795

$46,656,724

$48,396,123

$137,811,642

Budget impact

$0

$42,404,017

$46,295,984

$48,029,320

$136,729,321

CADTH scenario analysis: 94% price reduction

Reference

$348,915

$354,778

$360,740

$366,803

$1,082,321

New drug

$348,915

$2,899,019

$2,968,951

$2,903,767

$8,771,738

Budget impact

$0

$2,544,241

$2,608,211

$2,536,965

$7,689,417

CADTH scenario: 50% public coverage

Reference

$268,396

$272,906

$277,493

$282,156

$832,555

New drug

$268,396

$32,891,381

$35,889,788

$37,227,787

$106,008,955

Budget impact

$0.00

$32,618,474

$35,612,295

$36,945,631

$105,176,400

CADTH scenario: 100% public coverage

Reference

$536,792

$545,813

$554,985

$564,312

$1,665,109

New drug

$536,792

$65,782,761

$71,779,575

$74,455,573

$212,017,910

Budget impact

$0

$65,236,949

$71,224,590

$73,891,262

$210,352,801

BIA = budget impact analysis.

Ethics Review

Abbreviations

CF

cystic fibrosis

CFTR

cystic fibrosis transmembrane conductance regulator

ELX-TEZ-IVA

elexacaftor-tezacaftor-ivacaftor and ivacaftor

Summary

Ethical considerations identified in this review included those related to the following:

Objective

To identify and describe the ethical considerations associated with the use of ELX-TEZ-IVA in the treatment of CF in patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene, including considerations related to the disease context, evidentiary basis, use of the therapy, and considerations relevant to health systems.

Research Questions

This report addresses the following research questions:

Methods

To identify ethical considerations relevant to the use of ELX-TEZ-IVA in the treatment of CF in patients aged 2 to 5 years who have at least 1 F508del mutation in the CFTR gene, this ethics report was driven by relevant questions identified in the EUnetHTA Core Model 3.0,1 Ethics Analysis Domain,1 and supplemented by relevant questions from the Equity Checklist for HTA (ECHTA).2 These guiding questions were organized to respond to the research questions posed and to investigate ethical considerations related to:

Data Collection: Review of Project Inputs and Literature

Data to inform this ethics report were drawn from the identification of ethical considerations (e.g., values, norms, or implications related to the harms, benefits, and implications for equity, justice, and resource allocation, and ethical considerations in the evidentiary basis) in the patient and clinician group, clinical expert, and drug program input collected by CADTH to inform this review, as well as from a complementary search of the published literature. Ongoing collaboration and communication with CADTH reviewers working on the clinical and economic reviews for this submission also assisted in the clarification and identification of ethical considerations.

Review of Project Inputs

During this CADTH review, a single reviewer collected and considered input from 6 main sources related to ethical considerations relevant to the research questions guiding this ethics report. In addition to published literature, this report considered the following sources:

Literature Search Methods

An information specialist conducted a literature search using key resources, including MEDLINE via Ovid, Philosopher’s Index via Ovid, PsycInfo via Ovid, the Cumulative Index to Nursing and Allied Health Literature via EBSCO, and Scopus. Google Scholar was searched to find additional materials not captured in the major bibliographic databases. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Trikafta along with searches for cystic fibrosis and the F508del mutations of the CFTR gene.

CADTH-developed search filters were applied to limit retrieval to citations related to ethical concepts or considerations and qualitative studies. Search terms for equity were also applied to the main concepts to capture additional articles. Duplicates were removed by manual deduplication in Endnote. Retrieval was limited to the English language. The search was completed on June 7, 2023.

Literature Screening and Selection

Literature retrieved according to the search and selection methods detailed above was screened in 2 stages. First, the titles and abstracts of the citations retrieved were screened for relevance by a single reviewer. Articles were identified and retrieved for full-text review by a single reviewer if their titles or abstracts identified ethical considerations or provided normative analysis (i.e., focusing on “what ought to be” through argumentation) or empirical research (i.e., focusing on “what is” through observation) of ethical considerations related to the experiences, incidence, diagnosis, treatment, or outcomes of CF or related to the evidence on, use of, or implications of ELX-TEZ-IVA for patients with CF. In the second stage, full-text publications categorized as “retrieve” were reviewed by the same reviewer. Texts that included substantive information meeting the aforementioned criteria were included in the review, and reports that did not meet these criteria were excluded. As a parallel process, other sources drawn from relevant bibliographies, relevant key concepts, and consultation with experts or other CADTH reviewers were retrieved and reviewed using the selection criteria listed previously.

Data Analysis

Data analysis was driven by the 4 research questions guiding this report and included the collection, coding, and thematic analysis of data drawn from the literature and project inputs. The reviewer conducted 2 iterative cycles of coding and analysis in NVivo, a qualitative analysis software program, to abstract, identify, and synthesize relevant ethical considerations from the literature and from relevant project inputs.

In the initial coding phase, publications and input sources were reviewed for ethical content (e.g., claims related to potential harms, benefits, equity, justice, resource allocation, and ethical issues in the evidentiary basis). Once identified, claims related to ethical content were coded using methods of qualitative description.3 In the second coding phase, major themes and subcodes were identified through repeated reading of the data3 and were summarized into thematic categories within each guiding domain or research question. If the ethical content did not fit into these categories or into the domains outlined in the research questions, this was noted, as were discrepancies or conflicts in ethical considerations or values identified between project sources or within thematic categories. Data analysis was iterative, and the themes identified in the literature, in project inputs, and during consultations with clinical experts were used to further refine and reinterpret the ethical considerations identified.

The data collected and analyzed from these sources were thematically organized and described according to the 4 research questions driving this report. The results of this analysis and its limitations and conclusions are described in the following sections.

Results

Description of Included Sources

Data to inform this ethics report were drawn from a review of clinician group input, drug program input, and consultation with clinical experts engaged by CADTH for this review. All the clinical experts were active in relevant clinical roles in Canada, and all had experience treating patients with CF. A description and summary of these sources are included in the CADTH Clinical Review Report.

The literature search identified 223 results, and the grey literature search identified 19 additional results, for a total of 242 results. Following title and abstract screening, 209 citations were excluded and 33 potentially relevant publications from the electronic searches were retrieved for full-text review. Of the potentially relevant publications, 12 were excluded because they did not discuss ethical considerations of CF or ELX-TEZ-IVA. A total of 21 publications met the inclusion criteria and were included in this report. An additional 4 articles were identified in a manual search of the references of eligible articles.

A total of 25 publications were used to inform this report. Of these publications, 10 publications discussed ethical considerations in the context of CF, including in relation to diagnosis and treatment; 8 publications discussed patient and/or family and caregiver experiences in the context of CF; 5 publications were selected to provide a broader understanding of diversity in clinical trials; and 2 publications were selected to provide a broader understanding of the context of ethical considerations relating to drugs for rare diseases. Details regarding the characteristics of included publications are reported in Table 1.

Key Ethical Considerations

Diagnosis, Current Treatment Landscape, and Experiences of CF

As noted in the clinical report, the incidence of CF in Canada is approximately 1 per 3,600 live births.4 Approximately 4,300 people with CF live in Canada, of which 8% are children aged 2 to 5 years.4 Of these children, approximately 87% have at least 1 copy of the F508del mutation of the CFTR gene, making them eligible for ELX-TEZ-IVA pending Health Canada approval.5

CF is a multiorgan genetic disorder caused by dysfunction in the CFTR gene.6 This disease primarily impacts the respiratory system, leading to progressive lung damage. It additionally affects the gastrointestinal and reproductive systems.7,8 CF is currently incurable, but substantial improvements have been seen in survival prognosis, with the median age of survival estimated to be 57.3 years in people with CF in Canada.9 Key factors influencing prognosis include duration of time to diagnosis and treatment initiation, lung disease severity, nutritional and socioeconomic conditions, and mental well-being.10

Diagnosis

The introduction of newborn screening for CF across Canada has significantly altered the diagnostic approach for this disease, as newborns with positive screening results are referred for further diagnostic testing. Newborn screening in Canada involves drawing a small sample of blood from the infant’s heel. If there is a positive or inconclusive result, the patient is referred to a CF clinic for further testing. A sweat chloride test is administered, which measures the amount of chloride in a person’s sweat. If the results indicate 60 mmol/L or greater, CF is confirmed.

The establishment of a newborn screening program for CF in Canada and the US has led to improved health outcomes and long-term growth outcomes for patients with CF.11-13 Screening results, however, are not always clear because there have been instances when individuals present with symptoms indicative of CF but they were either were not screened due to the absence of newborn screening or they received a false-negative result during newborn screening.14,15 Such circumstances can result in delayed diagnosis, irreversible progression of the disease, and delayed access to early treatment.16,17 The clinical experts consulted by CADTH noted that misdiagnosis and underdiagnosis of CF are rare in Canada, with most cases confirmed by 1 month of age on average, and most false-negatives resolved and accurately diagnosed by 1 year of age following the development of symptomatic CF.

In addition, CF has historically been perceived as a condition primarily impacting white individuals of European ancestry,18 despite also impacting individuals in other regions, such as the Middle East, Asia, and Latin America.17 This perception is ethically concerning because it can lead to tacit health care practitioner racial bias that can result in delayed diagnosis for patients of non-Caucasian or non-European ancestry. Canadian practitioners need to be aware of this when treating patients born outside of Canada who may not have undergone newborn screening for CF in their country of birth and thus may be undiagnosed. Increasing awareness of CF is also important for patients of non-European descent and their caregivers; US research indicates that these populations have significantly less knowledge and awareness of CF than non-Hispanic white patients.19

Current Treatment Landscape

Clinician input described the treatment approach for CF in children (aged 2 to 5 years) as lifelong. As noted in the clinical report, nonmodulator therapies include high-calorie, high-fat, and high-protein diets; digestive medications; and airway clearance treatments, most of which are initiated at the time of diagnosis. Frequently prescribed medications in CF include antibiotics, mucolytics, bronchodilators, pancreatic enzymes, fat-soluble vitamins, insulin for individuals with CF-related diabetes, and ursodiol for liver disease.

As previously stated, CF is caused by mutations in the CFTR gene. There are more than 2,000 CFTR mutations currently documented.20 Since the introduction of CFTR modulator therapy nearly a decade ago, the treatment of CF has undergone significant transformation, leading to health outcome improvements for individuals with CF. CFTR modulators are mutation-specific therapies. For some mutations, early initiation of CFTR modulators has shown interruption of disease progression in multiple systems.21 The clinical benefits of CFTR modulators include improved lung function, reduced frequency of pulmonary exacerbations, improved weight or body mass index, and enhanced quality of life.21-23

ELX-TEZ-IVA has demonstrated improvements in health outcomes and quality of life in children aged 6 years and older and adults with CF.22,24-26 Additionally, clinician group input noted that ELX-TEZ-IVA is a more efficacious therapy for patients with CF who have at least 1 copy of the F508del mutation than other previously approved CFTR modulators. Furthermore, ELX-TEZ-IVA has the potential to delay disease progression and the need for additional procedures.

ELX-TEZ-IVA is used to treat up to 90% of patients with CF in Canada5 and is already approved for use with, and publicly reimbursed across Canada for, patients with CF who have at least 1 F508del mutation and are aged 6 years and older. Patients with other rare genetic mutations resulting in CF do not currently have access to most approved modulator treatments in Canada. However, there are some exceptions, such as patients with a gating mutation (G551D) who can access ivacaftor once they are aged 6 years or older. The research and development of CFTR modulators for children with rare genotypes who are currently ineligible for ELX-TEZ-IVA due to gene mutation requirements may help expand access to CFTR therapy in a more diverse patient population.27

Because CF is a multiorgan disease, it requires multiple health care professionals for surveillance and management. The clinical experts consulted by CADTH and caregiver perspectives in the literature highlight a need for ELX-TEZ-IVA among children with CF aged 2 to 5 years. This is due to the role ELX-TEZ-IVA can play in the prevention of disease progression, loss of livable years, suffering, while also improving quality of life. The clinical experts noted that there were no data to support withholding the initiation of CFTR modulator treatment until clinical symptoms of CF have developed in children, especially as children younger than 6 years could still develop structural lung disease while presenting as asymptomatic.28,29

Patient, Family, and Caregiver Experiences of CF

Upon learning of a CF diagnosis, caregivers reportedly experience a traumatic response, which can include extended periods of shock and distress and ongoing feelings of loss and grief, followed by a process of adjustment.30-32 Caregivers’ lack of knowledge about CF can further exacerbate this traumatic response.31

CF presents with a wide range of clinical manifestations, varying in severity among individuals, and includes chronic lung infections, progressive deterioration of lungs, progressive loss of lung function, and early mortality. Common complications from CF include digestion difficulties, malnutrition, the development of vitamin deficiencies due to the inability to effectively absorb nutrients, chronic lung infections, CF-related diabetes, and sinus infections.33

Prior to the introduction of CFTR modulators, pediatric treatments for CF included airway clearance techniques and nebulized mucolytics, which need to be maintained for life.34 As per the patient group input, the management of CF necessitates a demanding treatment routine. As the disease advances, it requires an increasing amount of time and effort, and frequent clinic visits and hospital stays to cope with the progressive and debilitating symptoms. Some children have described alternate treatments to be tedious and time-consuming. Caregivers echoed these sentiments, with some reporting that their entire life was dictated by managing their child’s various treatments. Upon initiating ELX-TEZ-IVA, both caregivers and adolescents (aged 12 to 18 years) alike expressed astonishment and disbelief at the significant reduction in treatment burden in addition to the life-changing benefits.34

Ethics of Evidence and Evaluation of ELX-TEZ-IVA

As discussed in detail in the CADTH Clinical Report for this review, ELX-TEZ-IVA was evaluated in Study 111, a 24-week, open-label, phase III, nonrandomized, single-arm, 2-part study. Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA in patients aged 2 to 5 years with at least 1 F508del mutation in the CFTR gene. However, as discussed in the following section, the regulatory submission is based on the extrapolation of efficacy data from studies conducted in older patients with CF, as the assessment of efficacy was not a primary objective in Study 111 and assessments of efficacy outcome measures in patients aged 2 to 5 years can be challenging. As discussed in the clinical review, ELX-TEZ-IVA was well tolerated in study participants, with few serious adverse events. The product monograph notes that elevated transaminases (alanine transaminase and aspartate transaminase) have been observed in patients treated with ELX-TEZ-IVA, requiring periodic and ongoing monitoring to understand any potential risks to the liver.

Considerations Related to the Extrapolation of Efficacy

Extrapolation is the practice of making predictions or inferences about outcomes beyond available data. In the context of this CADTH review, and as discussed further in the CADTH Clinical Review Report, this involves extending the efficacy findings from 1 age group (e.g., patients aged 12 years and older) to estimate potential efficacy outcomes in another age group (e.g., patients aged 2 to 5 years). Extrapolation is frequently required in the approval of new medications where preapproval trials cannot encompass all patient subpopulations, age groups, and comorbidities due to study limitations and to the need to avoid exposing vulnerable patient populations, such as children, to unnecessary research.35 Extrapolation is thus commonly used for pediatric therapies to increase availability of information for pediatric use and regulatory approval.36 However, using limited clinical data to generalize a treatment’s efficacy across a wide range of patients may not always be clinically appropriate because this approach may overestimate or underestimate a drug’s efficacy and safety during routine use.35 Concerns about generalizability arise when factors such as patient age, sex, and race or ethnicity may not have been adequately represented during preapproval trials.35 Careful consideration of these differences is particularly important when applying extrapolated data to the pediatric population.35 In the context of this report, developmental stages, physiological changes, and genetic variations should be carefully considered.

The clinical experts consulted by CADTH noted that the assessment of outcome measures in evaluating the efficacy of ELX-TEZ-IVA for children with CF aged 2 to 5 years is challenging. The clinical experts and published literature noted that this population is unable to consciously perform coordinated efforts, such as spirometry, which is used to assess lung function in clinical practice.21 Sedation may be required to perform lung function assessments, which presents ethical concerns regarding risks and recovery (e.g., respiratory depression, allergic reactions, aspiration, inadequate sedation, and, in rare cases, death).21 Moreover, establishing the effectiveness of interventions may require several years in children with minimal disease.21

As noted in the CADTH Clinical Review Report, Study 111 suggested that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function and CF biomarkers; however, uncertainty remains about the magnitude of the treatment effect and its comparative effectiveness based on currently available evidence. Nonetheless, the clinical experts noted that, given the efficacy data in patients aged 6 years and older, ELX-TEZ-IVA would be expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation. They noted that there are no physiological differences between children aged 2 to 5 years and adolescents or adults that would affect the underlying disease pathology or mechanism of action of CFTR modulators. Additionally, they noted they would raise these considerations when discussing the use of extrapolated data with families or caregivers concerning the use of ELX-TEZ-IVA. For example, the clinical experts stated that CFTR modulators are associated with a significant decrease in pulmonary exacerbations, reducing hospital admissions, and that, over time, each pulmonary exacerbation results in irreversible lung damage. Consequently, the primary objective in discussing extrapolation with caregivers is to highlight the importance of preventing pulmonary exacerbations. Furthermore, the experts noted that there is evidence suggesting that structural changes can occur early in the disease course, including before the age of 6 years. The goal is therefore to initiate medication early, even before symptoms manifest, recognizing that there might be underlying processes occurring that are not visible or measurable in routine clinical practice.

The clinical experts noted that CF registries may be 1 option for collecting long-term data on the safety and efficacy of ELX-TEZ-IVA in children aged 2 to 5 years but that use of these data to inform reimbursement decisions may be limited because important indicators, such as liver function tests, are not submitted. Rather, such information is known by treating clinicians. Other registry data, such as number of exacerbations, hospital stays, and days of antibiotics, can provide some information, but not a complete picture. The clinical experts stated that, in the absence of traditional outcome measures evaluating response to ELX-TEZ-IVA, they would look at improvement or stabilization in the frequency and severity of pulmonary exacerbations and body mass index to evaluate efficacy, which are not considered reliable indicators of the medication’s benefits in the target patient population. This fact has important implications for renewal criteria for reimbursement by the public drug programs. For example, the CADTH clinical experts have recommended that sweat chloride testing not be used to determine ELX-TEZ-IVA response for the purposes of drug reimbursement, which is consistent with the clinical expert input from previous reviews of ELX-TEZ-IVA in older patients (aged 6 to 11 years and 12 years and older). This decision is because sweat chloride testing does not provide a reliable prediction of clinically significant outcomes; rather, it reflects the mechanism of action of CFTR modulators like ELX-TEZ-IVA.

Clinical experts also highlighted the challenges in accessing sweat chloride testing in certain jurisdictions due to the variability in receiving test results within different time frames and significant concerns regarding the health care system’s ability to accommodate repeated sweat chloride testing for all patients with at least 1 F508del mutation. Because children aged 2 to 5 years will likely not be able to demonstrate such improvements in overt measurable ways, the clinical experts noted that prescribing decisions (e.g., whether to prescribe, renew, or discontinue the medication) would be based on an assessment by the treating specialist clinician. The clinical experts recommended relying on writing clinical letters to support renewals, especially if children have complex care needs (e.g., developmental delays) and cannot perform pulmonary function tests.

Representativeness in Research Participation

Although the randomized controlled trial that informed the Health Canada decision to grant children (aged 6 to 11 years) access to ELX-TEZ-IVA was broadly representative of the patient population most commonly affected by CF,37 there was underrepresentation of racialized groups because participants in Study 111 were primarily white. The primary reason for this is because CF disproportionately affects non-Hispanic white people. Nonetheless, the inclusion of racialized populations in clinical trials is a crucial step toward addressing health inequities and facilitating better access to advancements in CF therapies,38 especially because trial participation is often seen as a quicker path to accessing innovative therapies such as ELX-TEZ-IVA.39 Additionally, diverse clinical trial participation can produce higher-quality biomedical knowledge and ensure fairness for potential participants.38 Lack of interest in trial participation among racialized populations is not the root of this disparity, and research participation can be improved by employing research staff with cultural competence who use community involvement in the research process, such as in developing consent forms, translating documents, and using community liaisons for recruitment.40

Considerations for Pharmacoeconomic Assessments

The lack of long-term efficacy and comparative effectiveness data has implications for the pharmacoeconomic assessment of ELX-TEZ-IVA because it limits the ability to accurately model and assess its cost-effectiveness. This limitation, which may impact cost-effectiveness analyses for drugs for rare diseases more generally, presents challenges for assessing the opportunity costs — or forgone benefits — associated with reimbursing and resourcing a particular intervention over others.41 Understanding opportunity costs is important for informing resource allocation decisions at a health system level.

Ethical Considerations in the Use of ELX-TEZ-IVA

Balancing Benefits and Harms

As previously stated, there is evidence supporting the benefits of using ELX-TEZ-IVA for children and youth aged 6 years and older and for adults.37,42-44 Despite evidentiary limitations, such as the absence of direct evidence of efficacy in patients aged 2 to 5 years, as well as the absence of long-term safety and comparative effectiveness data for this age group, the clinical experts noted that they would recommend prescribing ELX-TEZ-IVA for children aged 2 to 5 years, given the expected benefits of preventive treatment in relation to structural lung damage, the lack of effective alternatives, and the generally favourable safety and tolerability profile in this age group. As an orally administered medication, ELX-TEZ-IVA is accessible and easy to administer for patients or their caregivers, including relative to alternate therapies. Moreover, as noted by the clinical experts and in the literature, there are additional anticipated benefits for patients and their caregivers, including lesser treatment-associated burden on patients and caregivers, decreases in hospitalizations, and equity-associated benefits for patients of lower socioeconomic status.

The clinical experts noted that the side effects of ELX-TEZ-IVA in a pediatric population are reportedly minimal (e.g., elevated liver enzymes and creatine kinase). Long-term evidence on the benefits of this drug is limited for all age groups. The lack of long-term efficacy data on ELX-TEZ-IVA is reportedly raising questions among practitioners and patients alike regarding the sustainability of its benefits in terms of health outcomes and quality of life.34,45 This knowledge gap has implications for the assessment of ELX-TEZ-IVA as it may limit the ability to accurately model and assess its cost-effectiveness. The clinical experts stated that they did not anticipate any physiological differences between children aged 2 to 5 years and older children that would differentially affect the use or efficacy of ELX-TEZ-IVA. However, they noted that younger children with CF face specific vulnerabilities, such as being more susceptible to the impacts of viral illnesses before vaccination and potential consequences arising from the re-emergence of vaccine hesitancy, which could heighten their susceptibility to preventable diseases and result in pulmonary exacerbations.

Additionally, while clinical experts acknowledged the expected benefits associated with the use of ELX-TEZ-IVA, they noted that patients or caregivers may be inclined to reduce or discontinue other treatments due to improvements experienced following the use of ELX-TEZ-IVA, which could lead them to believe that they no longer require additional therapy. This observation aligns with recent research findings.34 As patients with CF may be required to undertake more than 10 complex daily treatments, which can take more than 2 hours a day,27 treatment adherence may become challenging to children who reportedly do not feel affected by CF after taking ELX-TEZ-IVA.34

Sex-related disparities in the outcomes of individuals with CF, including in response to CFTR modulator treatment, have also been reported in other age groups, with female patients exhibiting a higher rate of pulmonary exacerbations and requiring lung transplant at an earlier stage than male patients.46 If ELX-TEZ-IVA is reimbursed for children aged 2 to 5 years, postmarket monitoring of its efficacy across sexes may be warranted to better inform decisions around treatment and overall care for both female and male patients in this age group.

Socioeconomic Considerations

It is reported that low socioeconomic status negatively impacts the social determinants of health of people living with CF.47-50 The clinical experts underscored the positive influence that ELX-TEZ-IVA could have on children with CF from low socioeconomic backgrounds. Notably, the experts emphasized the enhanced equity and improved health outcomes resulting from a decreased treatment burden after transitioning to the orally administered medication, taken twice a day. For instance, children with CF who are living in poverty often face psychosocial challenges, which can hinder their ability to adhere to numerous treatment obligations. However, following the introduction of ELX-TEZ-IVA, these children have shown significant improvements in their overall well-being and treatment management.

Health System Considerations

The reimbursement of ELX-TEZ-IVA for CF raises ethical considerations related to health systems as well as resource considerations, including opportunity costs, the sustainability of Canadian health care budgets, and the shifting use of health care resources as a result of implementation. Clinical experts consulted by CADTH highlighted that initiation of ELX-TEZ-IVA would be expected to increase the use of health care resources (e.g., frequent clinic visits; additional blood work, extended time for treatment education; and more examinations, follow-up appointments, and associated treatment costs) for all age groups. However, they expected that, following the initial treatment period, the burden on health systems would gradually diminish as there would be a reduction in required treatments beyond ELX-TEZ-IVA and a decrease in pulmonary exacerbations and associated hospitalization costs.34,45

Expensive drugs for rare diseases, such as ELX-TEZ-IVA, raise ethical considerations related to distributive justice and equitable access, the sustainability of health care budgets, and the fair pricing of pharmaceuticals.41,51 As a highly expensive medication, the clinical experts noted that the cost of ELX-TEZ-IVA, and CFTR modulators in general, could present a challenge to provincial drug budgets because, although the population of patients with CF may be small within a jurisdiction, the cost of reimbursing ELX-TEZ-IVA could have a disproportionate budget impact on provincial formularies. Reimbursing high-cost drugs for rare diseases, such as ELX-TEZ-IVA for CF, requires consideration of the opportunity costs associated with reimbursing, or not, a therapy over other therapies or services (e.g., including primary and preventive care) and raises questions about the fair and equitable allocation of scarce health care resources.50 The assessment of the opportunity costs of implementing ELX-TEZ-IVA for children aged 2 to 5 years is further complicated by the evidentiary uncertainty about the magnitude and durability of its therapeutic effect.

The clinical experts also noted that inconsistencies in pharmaceutical insurance coverage or reimbursement of ELX-TEZ-IVA within Canada could present access-related delays or challenges for patients (and their families). For example, they noted that families with private drug coverage that did not reimburse very-high-cost therapies such as ELX-TEZ-IVA could be faced with the decision of removing a dependent child from their parents’ insurance plan to access ELX-TEZ-IVA if it was otherwise reimbursed through a provincial drug plan.

Limitations

There is very little published literature that discusses ethical considerations related to the use of ELX-TEZ-IVA for the treatment of CF in a pediatric population, given both the rarity of the disease and the novelty of the drug under review for children aged 2 to 5 years. Nonetheless, this does not imply that ethical considerations in the context of ELX-TEZ-IVA for the treatment of CF are absent. This review of ethical considerations draws from additional resources collected in the course of this Reimbursement Review, including clinician and drug program input, discussion with clinical experts, and engagement with CADTH clinical and pharmacoeconomic review teams, to provide a more comprehensive understanding of the ethical considerations related to the use of ELX-TEZ-IVA for the treatment of CF.

Although this ethics report drew on expert input, it is possible that more direct engagement with key stakeholders (e.g., direct interviews with patients, caregivers, family members, and decision-makers) on their specific experiences with CF and/or ELX-TEZ-IVA could have offered additional relevant ethical considerations or domains of analysis.

Conclusion

Input from patient groups, clinician groups, and provincial drug programs, as well as direct engagement with clinical experts and published literature, were reviewed for ethical considerations relevant to the use of ELX-TEZ-IVA in patients aged 2 to 5 years with CF. Ethical considerations in the context of CF emphasized the physical and psychosocial burden of CF on patients, families, and caregivers. Clinical trial evidence indicated that ELX-TEZ-IVA was well tolerated in study participants aged 2 to 5 years, with few serious adverse events, although there is a recommendation for ongoing monitoring of liver enzymes. However, as the trial was not primarily designed to assess efficacy, the determination of efficacy in patients aged 2 to 5 years for the purposes of regulatory approval was extrapolated from studies conducted in older patients with CF. Extrapolation may offer benefits such as avoiding exposing vulnerable patients, such as children, to unnecessary research and extending access to therapy in patient populations that may be difficult to study or cannot be studied in clinical trials. However, extrapolation also presents potential risks if efficacy is not generalizable and thus overestimates or underestimates real-world effectiveness across different populations. Long-term monitoring is required to understand the long-term safety, efficacy, and comparative effectiveness of ELX-TEZ-IVA in patients aged 2 to 5 years. However, the clinical experts noted that, given the efficacy data in patients aged 6 years and older, they expected ELX-TEZ-IVA to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. As a result, the clinical experts suggested they would recommend prescribing ELX-TEZ-IVA for children aged 2 to 5 years, given the expected benefits of preventive treatment in relation to structural lung damage, the lack of effective alternatives, and the generally favourable safety and tolerability profile in this age group. Ethical considerations for health systems related to the use of ELX-TEZ-IVA for patients aged 2 to 5 years highlight challenges in funding decisions and in assessments of opportunity costs for expensive drugs for rare diseases as well as the need to address potential inequities in access due to inconsistent reimbursement and/or insurance coverage across and within jurisdictions in Canada.

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Appendix 1: Details of Included Publications

Note that this appendix has not been copy-edited.

Table 1: Details of Included Publications

First author (year)

Publication type

Objective

Key ethical considerations

Funding source

Almulhem (2022)34

Qualitative interview study

To explore the opinions of children with CF, their parents or caregivers, and health care professionals on the impact of ELX-TEZ-IVA, airway clearance techniques, and nebulized treatments.

  • Benefits of ELX-TEZ-IVA include significant reduction in treatment burden.

  • Lack of long-term efficacy data on ELX-TEZ-IVA caused concern regarding sustainability of its benefits.

  • Benefits of ELX-TEZ-IVA can lead to treatment adherence challenges.

Funded as part of a PhD studentship

Aspinall (2022)45

Qualitative interview study

To explore the effects Kaftrio has on an individual’s perception of reality and to what extent the modulator has changed their life beyond just the physical aspects.

  • Two individuals reported discontinuing treatment due to physiological and psychological side effects.

  • Lack of long-term efficacy data on ELX-TEZ-IVA caused concern regarding sustainability of its benefits.

  • Benefits of ELX-TEZ-IVA include a decrease in pulmonary exacerbations and associated hospitalization costs.

Knowledge Economy Skills Scholarships (KESS)

Bailey (2018)47

Review

To explore the ethical issues associated with conducting research in the population of people with CF who experience health disparities, and to propose recommendations to address ethical issues.

  • Declining participation in a clinical trial could result in receiving suboptimal clinical care.

  • There is a tendency for individuals (including children) with CF to automatically agree to research participation.

  • Potential confusion may arise when a CF researcher simultaneously fulfills the role of a clinician. The potential for manipulation arising from power dynamics during role confusion can be harmful to patient participants.

None reported

Dingus Keuhlen (2021)32

Mixed methods study

To explore, analyze, and expand upon the lived experiences of caregivers raising children with CF and the connection to the systemic influences contributing to their elevated rates of psychological symptoms.

Caregivers experience elevated levels of anxiety and depression while raising their children (aged 0 to 6 years) with CF.

None reported

Dobra (2021)39

Survey study

To understand how the CF community thinks slots in competitive trials should be allocated across the UK and whether this should be driven by clinical need or patients’ engagement or adherence or if it should be random.

Inclusion of racialized populations in clinical trials is a crucial step toward addressing health inequities and facilitating better access to advancements in CF therapies because participation is often seen as a quicker path to accessing ELX-TEZ-IVA.

Cystic Fibrosis Trust through the Clinical Trials Accelerator Platform

Dobra (2022)21

Review

To explore why it is important to involve children in research.

  • Increased recognition and awareness of CF in African populations may result in earlier identification and improved outcomes.

  • Establishing the effectiveness of ELX-TEZ-IVA may require several years in children as they may be asymptomatic.

National Institutes of Health Research through a predoctoral fellowship (NIHR300407)

Guo (2022)28

Economic analysis

To estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment.

Delays in accessing ELX-TEZ-IVA can cause tangible impacts on health outcomes.

None reported

Hutchins (2022)19

Survey study

To comparatively explore disease-specific experiences and cultural contributions for persons with CF from racialized populations.

Some racialized populations have significantly less knowledge about CF compared to their non-Hispanic Caucasian counterparts.

Georgia Association of Genetic Counselors student grant

King (2022)27

Review

To review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extrapulmonary manifestations of CF.

Although drug development for patients who are ineligible for ELX-TEZ-IVA due to gene mutation requirements are reportedly ongoing, there are currently no modulator treatments clinically available for this population.

None reported

McGarry (2016)40

Review

To evaluate the representation of racialized populations in pharmacology clinical trials for CF.

Racialized populations are underrepresented in clinical trials of pharmaceutical agents for CF.

National Institute of General Medical Sciences grants 5T32GM007546 to 35 andUL1TR001422

McGarry (2017)48

Review

To compare longitudinal pulmonary function between Hispanic and non-Hispanic white patients with CF.

Low socioeconomic status negatively impacts the social determinants of health of people living with CF.

Cystic Fibrosis Research Institute, National Institutes of Health, Cystic Fibrosis Foundation, and National Science Foundation

Owusu (2020)17

Retrospective case-controlled study

To describe and compare the presentation and outcomes of Black African children with CF to those with p.Phe508del genotype.

In the absence of newborn screening, Black African children with CF tend to receive a later diagnosis.

  • Black African children with CF are more likely to experience malnourishment at diagnosis than children with p.Phe508del genotype.

  • Increased recognition and awareness of CF in African populations may result in earlier identification and improved outcomes.

African Paediatric Fellowship Programme, University of Cape Town, and National Research Foundation of South Africa

Silva-Filho (2016)18

Commentary

To assess the current CF situation in some Latin American countries and make suggestions for possible directions for future focus.

CF has historically been perceived as a condition primarily impacting individuals of Caucasian or European ancestry, but the disease is also found in other regions, such as the Middle East, Asia, and Latin America.

Novartis Pharma AG

Stanojevic (2021)29

Pharmacoeconomic study

To estimate the potential impact of ELX-TEZ-IVA on morbidity and mortality, and the impact of delayed access.

Delays in accessing ELX-TEZ-IVA can cause tangible impacts on health outcomes.

Cystic Fibrosis Canada

Vaidyanathan (2022)15

Database study

To characterize CF in Asian subgroups to address disparities such as delayed diagnosis and poor prognosis.

Newborn screening of CF is less effective among racialized populations.

Stanford University School of Medicine

Wang (2023)46

Observational longitudinal study

To examine the differences between sexes in pulmonary exacerbations, ppFEV1, BMI, and Pseudomonas aeruginosa before and after treatment with ELX-TEZ-IVA at a large CF centre in the US.

Males experienced a more significant decrease in pulmonary exacerbations than females following use of ELX-TEZ-IVA.

None reported

Wright (2022)16

Commentary

To discuss health disparities, reflecting on authors’ experiences in delayed diagnosis of CF based on race and bias in health care practitioners.

An African American man experienced a lifetime of distress, physical suffering, frequent hospital visits, multiple diagnoses, and inappropriate surgeries because of delayed diagnosis due to the belief that CF only affects non-Hispanic white people.

None reported

Zampoli (2023)50

Review

To highlight the current global inequity in access to CFTR drugs and its impact on widening disparities between high-income countries and low- and middle-income countries in CF outcomes and survival.

  • Low socioeconomic status negatively impacts the social determinants of health of people living with CF.

  • Treating a relatively small number of individuals with CF using expensive CFTR modulators can pose a conflict in terms of resource allocation.

None reported

BMI = body mass index; CF = cystic fibrosis; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; ppFEV1 = percent predicted forced expiratory volume in the first second.

Stakeholder Input

Patient Input

Cystic Fibrosis Canada

About Cystic Fibrosis Canada

Since being founded by parents in 1960, Cystic Fibrosis Canada has grown into a leading organization with a central role engaging people living with cystic fibrosis, parents and caregivers, volunteers, researchers and healthcare professionals, government and donors. We have advanced research and care that has quadrupled life expectancy. We work together to change lives through treatment, re