CADTH Reimbursement Review

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

Sponsor: Vertex Pharmaceuticals (Canada) Incorporated

Therapeutic area: Cystic fibrosis, F508del-CFTR mutation, 6 years and older

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Trikafta consists of a fixed-dose combination tablet containing elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) co-packaged with a tablet containing ivacaftor (ELX-TEZ-IVA). It is available in 2 dosage strengths:

• ELX 50 mg, TEZ 25 mg, and IVA 37.5 mg co-packaged with a tablet containing IVA 75 mg

• ELX 100 mg, TEZ 50 mg, and IVA 75 mg co-packaged with a tablet containing IVA 150 mg.

ELX-TEZ-IVA is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 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 protein that results in CF.¹ The Canadian Cystic Fibrosis patient registry reported that 4,344 Canadians were living with CF in 2019. Of these, 87.8% carried at least 1 F508del mutation (47.1% were homozygous and 40.7% were heterozygous).

This is the second submission to CADTH for ELX-TEZ-IVA. CADTH previously reviewed ELX-TEZ-IVA for the treatment of CF in patients aged 12 years and older who have at least 1 F508del mutation in the CFTR gene, the CADTH Canadian Drug Expert Committee (CDEC) recommended that ELX-TEZ-IVA be reimbursed with conditions.² The sponsor has requested the following reimbursement criteria for the current submission for ELX-TEZ-IVA:

• Initiation criteria: Patients aged 6 years and older should have a confirmed diagnosis with CF with at least 1 F508del mutation in the CFTR gene.

• First renewal: In addition to the previously recommended criteria for the 12-and-older population whereby the physician must provide evidence of continued treatment benefit in at least 1 of the predefined criteria (i.e., lung function, pulmonary exacerbations, hospitalizations, body mass index [BMI] and Cystic Fibrosis Questionnaire–Revised [CFQ-R]) after 6 months of treatment with ELX-TEZ-IVA, the sponsor recommends adding a reduction in sweat chloride to the renewal criteria.

• Subsequent renewals annually: The physician must provide evidence of continued treatment benefit with ELX-TEZ-IVA for subsequent renewal of reimbursement.

Both the initial submission for ELX-TEZ-IVA (12 years and older) and the current submission (6 years and older) were accepted as priority reviews by Health Canada.

The objective of this review was to evaluate the beneficial and harmful effects of ELX-TEZ-IVA at recommended dosages for the treatment of patients aged 6 years and older with cystic fibrosis and 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 review of ELX-TEZ-IVA is available on the CADTH website (under the Patient Input and Clinician Input sections).

Patient Input

Three patient groups, Cystic Fibrosis Canada (CF Canada), the Canadian Cystic Fibrosis Treatment Society, and CF Get Loud, responded to CADTH’s call for patient input for both the initial CADTH review of ELX-TEZ-IVA (i.e., for patients 12 years of age and older) and for the current review of ELX-TEZ-IVA, which is focused on patients 6 years of age and older.

The patient groups emphasized that CF has a tremendous impact on those living with the condition, their loved ones, and on 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. Patients may suffer from pulmonary exacerbations requiring weeks of hospitalization and IV antibiotics. Malnutrition is another consequence of CF, and those living with the condition are often underweight and may require a feeding tube for supplemental nutrition. Patients may also suffer from CF-related comorbidities, such as CF-related diabetes and CF-related liver disease. In addition to the decline of the physical health of patients with CF, many suffer from the unseen effects of CF. These include, but are not limited to, depression, anxiety, and hopelessness. The mental anguish caused by the ever-present awareness of 1’s mortality cannot be expressed in words and is often not quantified. Parents and caregivers have an overwhelming desire to do something to help their loved ones.

Managing CF requires a demanding treatment routine with regular visits to specialized CF clinics. As the disease progresses, even more time and effort are needed to manage the progressive and debilitating symptoms. The condition has a significant impact on patients’ day-to-day quality of life, affecting life decisions that include education, career, travel, relationships, and family planning.

Patients with CF and their loved ones are seeking treatments that can change the trajectory of the disease and improve both life expectancy and quality of life. Improved outcomes include retaining or increasing lung function, improving digestive health and energy levels, and minimizing symptoms of CF. Patients want to avoid hospital admissions, reduce the need for invasive medical procedures, and minimize the treatment burden of daily therapies. They also wish to avoid the adverse effects of therapies, such as osteoporosis, antimicrobial resistance, and CF-related diabetes or liver dysfunction.

Patient groups emphasized the importance of early and aggressive treatment of CF with a focus on maintaining health and slowing or preventing disease progression. They noted that even those children with CF who appear healthy (e.g., with a percent predicted forced expiratory volume in 1 second [ppFEV₁] of 100%) are subjected to an aggressive therapeutic regimen of physiotherapy and antibiotic treatments in addition to special diets and frequent clinic visits. All patient groups stressed that it is important to start treatment with ELX-TEZ-IVA as soon as possible to prevent the irreversible damage that can be caused by CF. The patient groups referenced the initial CADTH recommendation for ELX-TEZ-IVA, noting that they believe the reimbursement conditions are too restrictive, particularly the requirement that patients demonstrate a ppFEV₁ of less than 90% to be eligible. The patient groups reported that they believe all patients with at least 1 F508del mutation can benefit from treatment with ELX-TEZ-IVA.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

Similar to the input from the patient groups, the clinical experts consulted by CADTH indicated that there are significant unmet therapeutic needs for patients living with CF. None of the treatments that are currently available can meet the most important goals of therapy, which include prolonging survival, preventing the need for lung transplantation, slowing the decline in lung function over time, or 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.

The clinical experts anticipate that ELX-TEZ-IVA would be used as a preventive therapy with the goal of initiating treatment before a patient develops significant lung disease. The clinical experts noted that ELX-TEZ-IVA could be used in every patient who meets the Health Canada–approved indication, regardless of their current or past treatment regimens. In clinical practice, eligible patients would be identified based on their CFTR genotype; however, no practical method is available to predict who will be most likely to respond to ELX-TEZ-IVA. The patients who are most in need of treatment with ELX-TEZ-IVA include patients with moderate to severe lung disease (e.g., ppFEV₁ ≤ 60%), patients whose BMI is less than or equal to 20 kg/m², patients with frequent pulmonary exacerbations, and those experiencing a rapid decline in forced expiratory volume in 1 second (FEV₁). However, it could be argued that all patients, including those with mild lung disease or who are pre-symptomatic, could benefit from treatment when considering the long-term outcomes and the goal of preventing severe outcomes.

The clinical experts noted that the magnitude of improvement with ELX-TEZ-IVA is far greater than with any other currently available treatments for CF (including all other CFTR modulators). ELX-TEZ-IVA would replace earlier CFTR modulators that are significantly less effective (e.g., lumacaftor-ivacaftor (LUM-IVA) [Orkambi] and tezacaftor-ivacaftor and IVA (TEZ-IVA) [Symdeko]) and patients currently receiving those drugs would likely be switched to ELX-TEZ-IVA.

The following end points are routinely assessed in Canadian clinical practice: lung function (e.g., spirometry measures such as forced expiratory volume in 1 second [FEV₁]), nutrition and growth (e.g., BMI, BMI z score, and BMI percentile), hospital admissions and outpatient treatments for pulmonary exacerbations, and pulmonary exacerbation frequency per year. The magnitude of improvement in CF outcomes that would be considered clinically significant depends on the baseline status of the patient. After initiating treatment with ELX-TEZ-IVA, those with less-severe or more-advanced disease may show smaller changes from baseline in commonly measured end points, but still experience clinically relevant improvements (e.g., stabilization). For ppFEV₁, an improvement of 5% or more would typically be considered clinically meaningful for most patients in Canadian clinical practice. The experts noted that an increase in BMI should only be viewed as a goal of therapy if the patient is malnourished at the time of initiating therapy. Increasing the BMI of a patient who is in the normal range or overweight may pose challenges and should not be viewed as a desirable outcome for evaluating the response to a treatment such as ELX-TEZ-IVA.

Treatment with ELX-TEZ-IVA would most likely be interrupted or discontinued because of adverse events (AEs) or progression to lung transplant. The most likely known AE that would result in discontinuation is development of persistent liver enzyme abnormalities.

The clinical experts noted that prescribing and monitoring of ELX-TEZ-IVA should be done in an adult or pediatric CF clinic.

Clinician Group Input

Three groups of clinicians provided input for the initial CADTH review of ELX-TEZ-IVA (the Canadian Cystic Fibrosis Clinic Directors, CF Canada’s Accelerating Clinical Trials Network, and The Toronto Adult CF Clinic) and 2 groups provided input for the current review (CF Canada’s Accelerating Clinical Trials Network and the Canadian Cystic Fibrosis Clinic Directors/CF Canada Health Care Advisory Council). The input from the clinician groups identified the same unmet medical needs for patients with CF and potential place in therapy for ELX-TEZ-IVA as the clinical experts consulted by CADTH. Similar to the clinical experts consulted by CADTH, the clinician groups noted that the impact of ELX-TEZ-IVA has been dramatic and life-altering for the patients who have received the treatment through Health Canada’s Special Access Programme, compassionate access mechanisms, or clinical trials (including those involving patients who have advanced lung disease).

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 affect the implementation of a CADTH recommendation for ELX-TEZ-IVA:

• lack of availability of multiple-breath washout testing in most Canadian CF clinics

• potential implementation challenges if recommended reimbursement criteria were different for patients aged 6 to 11 years and those 12 years and older.

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

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Patients Aged 6 to 11 Years

Description of Studies

The evidence identified in the current review of ELX-TEZ-IVA that addressed the expanded patient population (i.e., those between the ages of 6 and 11 years) included: a 24-week, double-blind, placebo-controlled randomized controlled trial (RCT) in patients who were heterozygous for the F508del mutation and who had 1 minimal function mutation in the CFTR gene (F/MF) (Study 116; N = 121) and a 24-week, pivotal, single-arm trial in patients homozygous for the F508del mutation in the CFTR gene (F/F) and patients with F/MF (Study 106B; N = 66). The treatment periods were 24 weeks in Study 116 and Study 106B and both studies included a screening phase (up to 28 days) and a safety follow-up phase (approximately 4 weeks or entry into an open-label extension [OLE] phase study). Study 106B is the second phase of a 2-part study (Part A consisted of a 28-day screening period, a 15-day, single-arm, open-label treatment period, and a 28-day safety follow-up period). Part B was initiated after completion of the internal review of the data in Part A that was used to confirm or adjust the doses to be evaluated in Part B. In accordance with recommended dosage for ELX-TEZ-IVA in Canada, this report focuses on Part B (i.e., Study 106B).

The inclusion and exclusion criteria for the included RCTs were similar except for the CFTR genotypes (i.e., only F/MF in Study 116 and F/F or F/MF in Study 106B) and the thresholds for ppFEV₁ (≥ 70% in Study 116 and ≥ 40% in Study 106B) and a score of 2.5 on the lung clearance index (LCI) (≥ 7.5 in Study 116 and not specified for Study 106). Similar to the trials conducted in adult and adolescent patients, patients in Study 116 and 106B were required to have stable CF disease in the opinion of the investigator at the time of screening. The trials 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, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease less than 4 weeks before their first dose of the study drug. Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.

The primary end point of Study 116 was absolute change from baseline in LCI_2.5; secondary end points were absolute change from baseline in sweat chloride, CFQ-R respiratory domain scores, and CFQ-R non-respiratory domain scores. All efficacy end points in Study 106B were considered secondary objectives; the primary end point was safety and tolerability. The end points included absolute changes from baseline in the following: ppFEV₁, LCI_2.5, CFQ-R, BMI, BMI z score, weight, weight z score, height, and height z score. In addition, descriptive statistics were provided for pulmonary exacerbations and hospitalization in Study 106B.

Efficacy Results

In Study 116, treatment with ELX-TEZ-IVA was associated with an increase from baseline in ppFEV₁ compared with placebo through 24 weeks as measured by a least squares mean difference (LSMD) of 11.0% (95% confidence interval [CI], 6.9 to 15.1). Improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were higher at all time points throughout the study. In Study 106B, treatment with ELX-TEZ-IVA resulted in a within-group increase in ppFEV₁ through 24 weeks (least squares [LS] mean change = 10.2%; 95% CI, 7.9 to 12.6; P < 0.0001). Improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were greater than baseline at all time points throughout the 24-week treatment period.

In Study 116, treatment with ELX-TEZ-IVA was associated with a reduction in LCI_2.5 through 24 weeks compared to placebo (LSMD = −2.26; 95% CI, −2.71 to −1.81; P < 0.0001). Patients in Study 106 demonstrated a within-group reduction in LCI_2.5 through 24 weeks (LS mean change = −1.71; 95% CI, −2.11 to −1.30; P < 0.0001). Improvements (reduction) in LCI_2.5 with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were reduced at all time points throughout both studies.

Pulmonary exacerbations were only captured as AEs in Study 116. The percentage of patients with at least 1 pulmonary exacerbation was greater in the placebo group compared with the ELX-TEZ-IVA group (26.2% versus 1.7%). Pulmonary exacerbations were included as an exploratory end point in Study 106B, in which the annual event rate for overall pulmonary exacerbations was 0.12 events per year. Event rates for pulmonary exacerbations requiring hospitalization and/or IV antibiotic therapy were each 0.03 events per year. There were no statistical comparisons for event rates pre- and post-treatment with ELX-TEZ-IVA.

In Study 116, treatment with ELX-TEZ-IVA was associated with improved health-related quality of life (HRQoL) as measured with the CFQ-R respiratory domain score from baseline compared with placebo through 24 weeks (LSMD = 5.5; 95% CI, 1.0 to 10.0; P = 0.0003). In Study 106B, patients demonstrated an increase from baseline CFQ-R respiratory domain scores through 24 weeks (LS mean absolute change = 7.0; 95% CI, 4.7 to 9.2; P < 0.0001). Changes from baseline in the non-respiratory domains of the CFQ-R were assessed as exploratory end points in Study 106B (but not in Study 116). Scores in non-respiratory domains of the CFQ-R showed a numerical increase from baseline; however, no statistical analyses were conducted.

Absolute change from baseline in sweat chloride through 24 weeks was a secondary end point of Study 116. The ELX-TEZ-IVA group demonstrated statistically significant reductions in sweat chloride compared with the placebo group through 24 weeks (LSMD = −51.2 mmol/L; 95% CI, −55.3 to −47.1). In Study 106B, treatment with ELX-TEZ-IVA resulted in a statistically significant within-group reduction in sweat chloride through 24 weeks. The LS mean absolute change in sweat chloride from baseline through 24 weeks was −60.9 mmol/L (95% CI, −63.7 to −58.2; P < 0.0001).

Harms Results

In Study 116, the overall percentage of patients who experienced 1 or more AEs was greater in the placebo group (93.4%) compared to the ELX-TEZ-IVA group (80.0%). The AEs that were reported in at least 5% of patients in the ELX-TEZ-IVA group and occurred at a frequency 5% or higher than in the placebo group were headache (30.0% versus 19.7%, respectively), rash (10.0% versus 4.9%, respectively), and a positive Staphylococcus test result (6.7% versus 1.6% respectively). Infective pulmonary exacerbations were reported as AEs more commonly in the placebo group compared with the ELX-TEZ-IVA group (26.2% versus 1.7%, respectively). Adverse events were more commonly reported in Study 106B compared with the ELX-TEZ-IVA group of Study 116 (e.g., 1 or more AEs were reported in 98.5% of patients in Study 106B compared with 80.0% in Study 116). In Study 116, 4 patients (6.7%) in the ELX-TEZ-IVA group and 9 patients (14.8%) in the placebo group had 1 or more serious adverse events (SAEs). In Study 106B, a single patient (1.5%) had 3 SAEs (metapneumovirus infection, pneumonia, and rhinovirus infection). In Study 116, a single patient (1.7%) in the ELX-TEZ-IVA group had an AE of a rash that led to study drug discontinuation. No patients in the placebo group discontinued the study drug. In Study 106B, a single patient had an AE of an erythematous rash that led to treatment discontinuation.

Critical Appraisal

Randomization in Study 116 was performed using an appropriate methodology with adequate allocation concealment (i.e., interactive web response system [IWRS]) and stratification based on relevant prognostic factors (i.e., baseline lung function [LCI_2.5 < 10 versus ≥ 10] and baseline weight [< 30 kg versus ≥ 30 kg]). Baseline and demographic characteristics were generally similar across the ELX-TEZ-IVA and placebo groups in Study 116. A higher percentage of patients in the ELX-TEZ-IVA group had a baseline ppFEV1 of greater than 90% (60.0% versus 45.9% for the placebo group) and a lower percentage had a baseline ppFEV1 of less than 70% (6.7% versus 16.4%, respectively). As those with normal lung function (i.e., > 90%) would be less likely to demonstrate short-term improvements in ppFEV₁ due to the ceiling effect, this could bias the results for change in ppFEV₁ through 24 weeks against ELX-TEZ-IVA.

The study treatments were administered in a double-blind manner in Study 116 and open-label in Study 106. The AE profiles of ELX-TEZ-IVA and the comparators were unlikely to compromise blinding in the study. The exception could be the increased percentage of patients who experienced a rash in the ELX-TEZ-IVA group (13.3% versus 4.9% with placebo); however, this was not expected to seriously affect treatment blinding. Similar to the previously reviewed trials in adults and adolescents, few pediatric patients discontinued either Study 116 (99.2% completion) or Study 106B (97.0% completion). The studies were relatively short in duration, which may in part explain the high percentage of patients who completed. Adherence was reported to be 99% across both Study 116 and Study 106B. In accordance with the study protocols, the use of concomitant medications remained stable throughout the treatment period for all treatment groups. Pulmonary exacerbations in pediatric patients were only evaluated as efficacy end points in the 24-week single-arm trial (Study 106B). The placebo-controlled trial (Study 116) only reported pulmonary exacerbations as AEs. The primary and key secondary end points were analyzed without statistical testing procedures to control the potential for type I error, and the results should therefore be interpreted with caution due to the risk of inflated type I error.

The diagnostic criteria used to screen patients for Study 116 and Study 106 were identical to those used in Study 102, Study 103, and Study 109 for those at least 12 years of age. As noted in the previous CADTH review of ELX-TEZ-IVA, these criteria are consistent with Canadian clinical practice for diagnosing patients with CF who are homozygous for the F508del-CFTR mutation. The Clinical experts consulted by CADTH indicated that the exclusion of patients with a ppFEV₁ of less than 70% does not affect the generalizability of Study 116, as these patients are less common in the Canadian pediatric CF population.

Study 106B included outcomes that are considered to be important to patients with CF based on patient group input: respiratory function (i.e., LCI and ppFEV₁), nutritional status and growth (e.g., weight, height, and BMI), HRQoL (CFQ-R), and clinical events (e.g., pulmonary exacerbations). The primary efficacy end point in Study 116 (i.e., LCI_2.5) differed from that used in the adolescent and adult trials (i.e., ppFEV₁). This is reflective of regulatory guidance, which advises that spirometry may not be sensitive enough to detect treatment differences in children with CF. Younger patients with CF may exhibit spirometry values that are within the normal range, but underlying structural deficiencies within the lungs may be detectable using alternative evaluations (e.g., LCI).

The use of placebo as the comparator in Study 116 is appropriate as no other CFTR modulators are currently approved in Canada for use in the treatment of patients with CF aged 6 to 11 years with an F/MF genotype. The absence of a control group in Study 106B limits the ability to interpret the results of the study. In both studies, ELX-TEZ-IVA (or matching placebo in Study 116) 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 116 and 106B were reasonably reflective of the Canadian CF population.

Patients Aged 12 Years and Older

Description of Studies

Four double-blind, phase III RCTs were included in the CADTH systematic review: 1 placebo-controlled trial conducted in patients with the F/MF genotype (Study 102 [N = 405]), 2 active-controlled trials in patients with the F/F genotype (Study 103 [N = 107] and Study 109 [N = 107]), and 1 active-controlled trial in patients who were heterozygous for the F508del mutation and a residual function mutation (F/RF) or who were heterozygous for the F508del mutation and a gating mutation (F/G) (Study 104; N = 259).

The double-blind treatment periods were 24 weeks in duration in Study 102 and Study 109, 8 weeks in Study 104, and 4 weeks in Study 103. Study 103, Study 104, and Study 109 all included a 28-day active-treatment run-in period during which all patients with either an F/F or F/RF genotype received treatment with TEZ-IVA (Study 103, Study 109, and the F/RF subgroup of patients in Study 104) and patients with an F/G genotype received treatment with IVA (F/G subgroup of patients in Study 104). Patients were subsequently randomized to receive ELX-TEZ-IVA or to remain on the active treatment administered during the run-in period. All the studies included a screening phase (up to 28 days) and a safety follow-up phase (approximately 4 weeks or entry into an OLE phase study).

The inclusion and exclusion criteria for the included RCTs were similar except for the CFTR genotypes (i.e., F/MF, F/F, F/G, or F/RF). Patients were required to have stable CF disease in the opinion of the investigator and a ppFEV₁ of between 40% and 90% at the time of screening. The trials excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus. Patients were also ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease less than 4 weeks before the first dose of the study drug. Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL) abnormal liver function, or abnormal renal function.

Efficacy Results

Patients With F/MF Genotype (Study 102): Treatment with ELX-TEZ-IVA was associated with a statistically significant absolute increase from baseline in ppFEV₁ compared with placebo at 4 weeks (LSMD = 13.8%; 95% CI, 12.1 to 15.4; P < 0.0001) and 24 weeks (LSMD = 14.3%; 95% CI, 12.7 to 15.8; P < 0.0001). Improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were higher at all time points throughout the study. Results for change from baseline in ppFEV₁ were generally consistent across all subgroup analyses, including those based on age (12 to < 18 years or ≥ 18 years) and ppFEV₁ at screening (< 70% or ≥ 70%). The sponsor conducted an additional post hoc subgroup analysis for the subset of patients with a ppFEV₁ below 40% at baseline (16 of 203 [7.9%] in the placebo group and 18 of 200 [9.0%] in the ELX-TEZ-IVA group), in which the absolute difference in ppFEV₁ with ELX-TEZ-IVA versus placebo was 15.2% (95% CI, 7.3 to 23.1) at 4 weeks and 18.4% (95% CI, 11.5 to 25.3) at 24 weeks.

Treatment with ELX-TEZ-IVA was associated with a lower rate of pulmonary exacerbations compared with placebo (rate ratio = 0.37; 95% CI, 0.25 to 0.55). Similarly, treatment with ELX-TEZ-IVA was associated with lower rates of pulmonary exacerbations requiring hospitalization (rate ratio = 0.29; 95% CI, 0.14 to 0.61) and pulmonary exacerbations requiring IV antibiotic therapy (rate ratio = 0.22; 95% CI, 0.11 to 0.43). Hazard ratios (HRs) favoured ELX-TEZ-IVA over placebo for time to first pulmonary exacerbation (HR = 0.34; 95% CI, 0.22 to 0.52), time to first pulmonary exacerbation requiring hospitalization (HR = 0.25; 95% CI, 0.11 to 0.58), and time to first pulmonary exacerbation requiring IV antibiotics (HR = 0.19; 95% CI, 0.09 to 0.39).

Treatment with ELX-TEZ-IVA was associated with a statistically significant improvement in BMI at 24 weeks compared with placebo (LSMD = 1.04 kg/m²; 95% CI, 0.85 to 1.23; P < 0.0001). In patients less than 20 years of age (n = 145), those treated with ELX-TEZ-IVA demonstrated improvements in BMI z scores compared with placebo (LSMD = 0.30; 95% CI, 0.17 to 0.43). Similarly, the ELX-TEZ-IVA group demonstrated greater improvement in body weight at 24 weeks compared with the placebo group (LSMD = 2.9 kg; 95% CI, 2.3 to 3.4).

Treatment with ELX-TEZ-IVA was associated with a statistically significant and clinically meaningful improvement in CFQ-R respiratory domain scores from baseline compared with placebo through 24 weeks (LSMD = 20.2; 95% CI, 17.5 to 23.0).

The ELX-TEZ-IVA group demonstrated statistically significant reductions in sweat chloride compared with the placebo group at 4 weeks (LSMD = −41.2 mmol/L; 95% CI, −44.0 to −38.5) and 24 weeks (LSMD = −41.8; 95% CI, −44.4 to −39.3).

The Treatment Satisfaction Questionnaire for Medication (TSQM) was included as an exploratory end point for patients between the ages of 12 and 17 years. The difference in change from baseline favoured ELX-TEZ-IVA compared with placebo in the domains for global satisfaction (LSMD = 11.9; 95% CI, 1.8 to 22.0) and effectiveness (LSMD = 14.4; 95% CI, 3.5 to 25.4). The TSQM was not included as an end point in Study 109.

Patients With F/F Genotype (Study 103 and Study 109): In Study 103, treatment with ELX-TEZ-IVA was associated with a statistically significant and clinically meaningful increase from baseline in ppFEV₁ compared with TEZ-IVA at 4 weeks (LSMD = 10.0%; 95% CI, 7.4 to 12.6; P < 0.0001). Improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were higher at all time points throughout the study. The results for change from baseline in ppFEV₁ were generally consistent across all subgroup analyses. A post hoc subgroup analysis from Study 103 suggested that the magnitude of the observed treatment effect (LS mean = 7.8%; 95% CI, 4.8 to 10.8) for CFTR modulator–experienced patients is less than that for CFTR-modulator–naive patients (LS mean = 13.2%; 95% CI, 8.5 to 17.9). In Study 109, treatment with ELX-TEZ-IVA was associated with a statistically significant absolute increase from baseline in ppFEV₁ compared with TEZ-IVA through 24 weeks (LSMD = 10.2%; 95% CI, 8.2 to 12.1; P < 0.0001).

Pulmonary exacerbations were only captured as AEs in Study 103 and Study 109. The percentage of patients with 1 or more pulmonary exacerbations was greater in the TEZ-IVA group compared with the ELX-TEZ-IVA group in both studies.

Compared with TEZ-IVA, treatment with ELX-TEZ-IVA was associated with improvements in BMI at 4 weeks in Study 103 (LSMD = 0.60 kg/m²; 95% CI, 0.41 to 0.79) and body weight at 4 weeks (LSMD = 1.6 kg; 95% CI, 1.0 to 2.1). Changes from baseline in BMI and body weight were not investigated in Study 109.

Treatment with ELX-TEZ-IVA was associated with a statistically significant and clinically meaningful improvement in CFQ-R respiratory domain scores from baseline compared with TEZ-IVA at 4 weeks in Study 103 (LSMD = 17.4; 95% CI, 11.8 to 23.0) and through 24 weeks in Study 109 (LSMD = 15.9; 95% CI, 11.7 to 20.1).

The ELX-TEZ-IVA group experienced statistically significant reductions in sweat chloride compared with the TEZ-IVA group at 4 weeks (LSMD = −45.1 mmol/L; 95% CI, −50.1 to −40.1) in Study 103 and through 24 weeks in Study 109 (LSMD = −42.8; 95% CI, −46.2 to −39.3; P < 0.0001).

The TSQM was included as an exploratory end point in Study 103 for patients between the ages of 12 and 17 years. The ELX-TEZ-IVA group demonstrated improvements compared with the TEZ-IVA group in the domains for global satisfaction (LSMD = 11.9; 95% CI, 1.8 to 22.0) and effectiveness (LSMD = 14.4; 95% CI, 3.5 to 25.4). The TSQM was not included as an end point in Study 109.

Patients With F/G and F/RF Genotypes (Study 104): Treatment with ELX-TEZ-IVA was associated with a statistically significant within-group improvement in ppFEV1 through 8 weeks (LS mean change = 3.7%; 95% CI, 2.8 to 4.6; P < 0.0001). Treatment with ELX-TEZ-IVA was associated with a statistically significant improvement in ppFEV₁ compared to the control group (LSMD = 3.5%; 95% CI, 2.2 to 4.7; P < 0.0001). Subgroup analyses based on the comparator group (patient genotype) demonstrated absolute improvements in ppFEV₁ with ELX-TEZ-IVA versus IVA (LSMD = 5.8; 95% CI, 3.5 to 8.0) and versus TEZ-IVA (LSMD = 2.0; 95% CI, 0.5 to 3.4).

Pulmonary exacerbations were only captured as AEs. Compared with the pooled control group (TEZ-IVA and IVA), fewer ELX-TEZ-IVA-treated patients reported 1 or more pulmonary exacerbations (10.3% versus 2.3%, respectively).

Mean BMI increased in both the pooled control group (LS mean = 0.16 kg/m²; standard error [SE] = 0.06) and the ELX-TEZ-IVA group (LS mean = 0.28 kg/m²; SE = 0.06]) with no statistically significant difference between the groups (LSMD = 0.13 kg/m²; 95% CI, −0.03 to 0.29).

The ELX-TEZ-IVA group experienced a statistically significant increase in CFQ-R respiratory domain scores from baseline (LS mean within-group change = 10.3; 95% CI, 8.0 to 12.7; P < 0.0001). Treatment with ELX-TEZ-IVA also resulted in an increase in CFQ-R respiratory domain scores compared to the pooled TEZ-IVA and IVA control groups (LSMD = 8.7; 95% CI, 5.3 to 12.1; P < 0.0001). Subgroup analyses demonstrated similar effect sizes for ELX-TEZ-IVA compared with IVA in patients with an F/G genotype (LSMD = 8.9; 95% CI, 3.8 to 14.0; P = 0.0008) and for ELX-TEZ-IVA compared with TEZ-IVA in patients with an F/RF genotype (LSMD = 8.5; 95% CI, 4.0 to 13.1; P = 0.0003). No statistical analyses were performed for changes from baseline in the non-respiratory domains of the CFQ-R.

The ELX-TEZ-IVA group demonstrated a statistically significant decrease in sweat chloride from baseline (LS mean = −22.3 mmol/L; 95% CI, −24.5 to −20.2; P < 0.0001). Treatment with ELX-TEZ-IVA also resulted in a decrease in sweat chloride from baseline compared to the pooled control group (LSMD = −23.1 mmol/L; 95% CI, −26.1 to −20.1; P < 0.0001).

Harms Results

Patients With F/MF Genotype (Study 102): The overall percentage of patients who experienced 1 or more AEs was 96.0% in the placebo group and 93.1% in the ELX-TEZ-IVA group. The percentage of patients who experienced 1 or more SAEs was 20.9% in the placebo group and 13.9% in the ELX-TEZ-IVA group. Pulmonary exacerbations were the most reported SAE and were more frequent in the placebo group compared with the ELX-TEZ-IVA group (16.4% versus 5.4%, respectively). Few other SAEs were reported for more than 1 patient in each treatment group. Two withdrawals due to adverse events (WDAEs) were reported in the ELX-TEZ-IVA group (1.0%) and none were reported in the placebo group. The reasons for discontinuation from the ELX-TEZ-IVA group included portal hypertension (0.5.%) and rash (0.5%).

Patients With F/F Genotype (Study 103 and 109): The overall percentages of patients who experienced 1 or more AEs in Study 103 and Study 109 were 63.5% and 88.5% in the TEZ-IVA groups, respectively, compared with 58.2% and 92.0% in the ELX-TEZ-IVA groups, respectively. The percentage of patients who experienced 1 or more SAEs was 15.9% in the TEZ-IVA group compared with 5.7% in the ELX-TEZ-IVA group of Study 109. The difference between the groups was due to a greater percentage of patients in the TEZ-IVA group experiencing a pulmonary exacerbation compared with the ELX-TEZ-IVA group (11.4% versus 1.1, respectively). Serious AEs were rare in the 4-week Study 103 and reported for only 1 patient in the TEZ-IVA group (pulmonary exacerbation) and 2 patients in the ELX-TEZ-IVA group (pulmonary exacerbation and rash) (1.9% versus 3.6%, respectively). No WDAEs were reported in either the TEZ-IVA or ELX-TEZ-IVA groups in Study 103. In Study 109, WDAEs were reported for 2 patients (2.3%) in the TEZ-IVA group (compulsive disorder and psychotic disorder) and 1 patient (1.1%) in the ELX-TEZ-IVA group (anxiety and depression).

Patients With F/G and F/RF Genotypes (Study 104): The overall percentage of patients who experienced 1 or more AEs was 66.7% in the ELX-TEZ-IVA group and 65.9% in the control group. The percentage of patients who experienced 1 or more SAEs was 8.7% in the control group compared with 3.8% in the ELX-TEZ-IVA group. The difference between the groups was due to a greater percentage of patients in the control group experiencing a pulmonary exacerbation that was classified as an SAE compared with the ELXTEZ-IVA group (5.6% versus 1.5%, respectively). There were 2 WDAEs in the control group (1.6%; pulmonary exacerbation, and anxiety and depression) and 1 in the ELX-TEZ-IVA group (0.8%; elevated alanine transaminase [ALT] and aspartate transaminase [AST] levels).

Critical Appraisal

Randomization was stratified based on relevant prognostic factors (i.e., age, sex, baseline ppFEV₁, and prior CFTR-modulator use [in Study 104]).^5,6,10,11 Baseline and demographic characteristics were generally well balanced across the treatment groups in each of the included studies. Study treatments were administered in a double-blind manner, with all groups issued the same number of tablets each day. The AE profile of ELX-TEZ-IVA and the comparators was unlikely to compromise blinding in any of the included trials. Few patients discontinued the trials (the completion rate ranged from 96.8% to 100%), although the studies were relatively short in duration, which may partly explain the high percentage of patients who completed.^5,6,10,11 Adherence with the study treatments was reported to be greater than 99% across all treatment groups in the included trials.^5,6,10,11 In accordance with the study protocols, the use of concomitant medications remained stable throughout the treatment period for all treatment groups. The only exceptions were the lower usage rates of some antibiotics for pulmonary exacerbations in the ELX-TEZ-IVA group relative to the placebo group in Study 102 (this difference was attributable to the efficacy of ELX-TEZ-IVA for reducing pulmonary exacerbations relative to placebo). The primary and key secondary end points were analyzed with statistical testing procedures that controlled the type I error rate, and all end points within the statistical testing hierarchies were statistically significant.

The diagnostic criteria used in Study 103 and Study 109 were consistent with Canadian clinical practice for identifying patients with CF who are homozygous for the F508del-CFTR mutation. The gating and residual function mutations that were used to select patients for inclusion in Study 104 were consistent with the approved indications for TEZ-IVA and IVA in Canada.^7,12,13 Because there were no widely accepted criteria for defining minimal function mutations in the CFTR gene, identification of patients with minimal function mutations in Study 102 relied on a novel approach designed by the sponsor (i.e., in vitro response to TEZ, IVA, or TEZ-IVA).⁵ The clinical experts consulted by CADTH noted that terms “residual function” and “minimal function” are not currently used in Canadian clinical practice. Because patients with CF with more-severe lung disease (e.g., ppFEV₁ < 40% at screening) or a normal ppFEV₁ at screening (≥ 90%) were excluded from the studies,^5,6,10,11 the results of the included studies are applicable primarily to patients with moderate (FEV₁ of 40% to 69%) to mild (FEV₁ of 70% to 89%) lung disease. As patients with advanced lung disease are an important subgroup with a high level of unmet medical need, CADTH supplemented this review with additional evidence from observational studies to address this important gap in the RCT evidence.

Study 103, Study 104, and Study 109 included an open-label, 4-week, active-treatment period with TEZ-IVA or IVA before randomization. As such, these trials were essentially investigating switching to ELX-TEZ-IVA from either TEZ-IVA or IVA compared with remaining on TEZ-IVA for patients with an F/F or F/RF genotype or remaining on IVA for patients with an F/G genotype. As TEZ-IVA is not widely reimbursed in Canada, the switching design limits the generalizability of the studies directly to the Canadian setting. To address this potential gap in the evidence, the sponsor supplied CADTH with indirect comparisons to provide an estimate of ELX-TEZ-IVA versus placebo for those with an F/F or F/RF genotype.

Indirect Comparisons

Patients Aged 6 to 11 Years

Description of Studies

The sponsor conducted a single indirect comparison for patients ages 6 to 11 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-level patient data for those with an F/F genotype from the following studies: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||VVVVVVVVVVVV. Additional sensitivity analyses were performed using 8-week data.

Efficacy Results

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; |||||||||||||||||||||||||||||||||||||||| for LCI_2.5; |||||||||||||||||||||||||||||||||||||||| for BMI z score; and |||||||||||||||||||||||||||||||||||||||| for the CFQ-R respiratory domain. The sponsor reported the following indirect estimates of effect for ELX-TEZ-IVA compared with LUM-IVA for absolute change from baseline through 24 weeks: ||||||||||||||||||||||||||||| for ppFEV₁; |||||||||||||||||||||||||||||||||||||||| for LCI_2.5; |||||||||||||||||||||||||||||||||||||||| for BMI z score; and |||||||||||||||||||||||||||||||||||||||| for the CFQ-R respiratory domain.

Harms Results

The indirect comparison filed by the sponsor did not include any comparisons for AEs.

Critical Appraisal: The primary limitation of the indirect treatment comparison (ITC) was the difference in study design across the included studies ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||VVVVVVVVVVVV.

Patients Aged 12 Years and Older

Description of Studies

The sponsor conducted indirect comparisons to derive relative estimates of the clinical efficacy for ELX-TEZ-IVA compared to local standard of care in the F/F, F/RF and F/G populations, given the absence of RCTs. Although head-to-head trials were conducted for ELX-TEZ-IVA versus TEZ-IVA (for patients with F/F or F/RF genotypes) and IVA (for patients with an F/G genotype), the sponsor conducted indirect comparisons to derive estimates of effect for ELX-TEZ-IVA versus LUM-IVA for patients with an F/F genotype and ELX-TEZ-IVA versus placebo for those an F/F, F/G, or F/RF genotype. A literature search conducted by CADTH did not identify any additional published indirect comparisons that included the patients, interventions, and outcomes identified in the protocol for CADTH’s review of ELX-TEZ-IVA.

All the sponsor’s indirect comparisons were conducted using the Bucher method for continuous end points. The sponsor stated that the Bucher method was considered the most appropriate approach for these indirect comparisons because of the 4-week active-treatment run-in periods in the ELX-TEZ-IVA trials. As the studies for TEZ-IVA, LUM-IVA, and IVA all enrolled patients who were naive to CFTR-modulator treatment, the baselines were not considered sufficiently comparable to the ELX-TEZ-IVA studies to conduct a meta-analysis of individual patient data.

Efficacy Results

For patients with an F/F genotype, indirect comparisons were performed for ELX-TEZ-IVA versus placebo and ELX-TEZ-IVA versus LUM-IVA. The direct evidence for ELX-TEZ-IVA versus TEZ-IVA was from Study 104 (the direct estimate for TEZ-IVA versus placebo) was from the EVOLVE trial, and the direct estimate for LUM-IVA versus placebo was derived from a meta-analysis of the TRAFFIC and TRANSPORT trials. 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; |||||||||||||||||||||||||||||||||||| for BMI; and |||||||||||||||||||||||||||||||||||| for the CFQ-R respiratory domain.

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 data 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 BMI; and |||||||||||||||||||||||||||||||||||| for the CFQ-R respiratory domain.

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; |||||||||||||||||||||||||||||||||||| for BMI; and |||||||||||||||||||||||||||||||||||| for the CFQ-R respiratory domain.

Harms Results

The indirect comparison filed by the sponsor did not include any comparisons for AEs.

Critical Appraisal

The primary limitation of the indirect comparisons was the difference in study design across the included studies. The ELX-TEZ-IVA studies (i.e., Study 104 and Study 109) included an open-label, 4-week, active-treatment period with TEZ-IVA or IVA before randomization. As none of the other trials used in the indirect comparisons had a similar run-in period, the study designs, baseline values, and the end-point values for the common comparator were different. As both the ELX-TEZ-IVA and the comparator groups of Study 104 and Study 109 received 4 weeks of treatment with a CFTR-modulator, the direction of any potential bias associated with the run-in period is uncertain.

Other Relevant Evidence

CADTH also reviewed additional studies that did not meet the eligibility criteria of the systematic review but may address important gaps in the evidence from the pivotal and supportive RCTs. These included 2 long-term extension-phase studies (Study 107 and Study 105), 2 indirect comparisons submitted by the sponsor, 2 observational studies that evaluated the use of ELX-TEZ-IVA in patients with advanced lung disease, 1 study that modelled the potential impact of ELX-TEZ-IVA on CF-related morbidity and mortality, and 3 observational studies that included a subset of patients with normal lung function at the time of initiating treatment with ELX-TEZ-IVA.

Long-Term Extension Studies

Patients Aged 6 to 11 Years

Study 107 is an ongoing, multi-centre, OLE study that enrolled patients who completed Study 106 (children with CF who are 6 years of age and older with either an F/F genotype or F/MF genotype). Two participants discontinued the study drug before week 24 of Study 106 and did not enter Study 107. Interim results were reported after all patients (n = 64) had completed the 24-week visit.

Efficacy Results

Treatment resulted in improvements in all measures consistent with Study 106. Compared to baseline values of Study 106, ELX-TEX-IVA treatment improved ppFEV₁ (9.5%; SE = 1.3), sweat chloride concentration (−64.7 mmol/L; SE = 1.7), CFQ-R respiratory domain score (12.9 points; SE = 1.2), BMI (1.27 kg/m²; SE = 0.15), BMI z score (0.34; SE = 0.06), and LCI_2.5 (−1.91; SE = 0.18) at the extension study week 24 interim analysis. Overall, in the 24-week pivotal study and through the week 24 interim analysis of the OLE study, 5 children (7.6%) had protocol-defined pulmonary exacerbations, with an observed annual rate of pulmonary exacerbations of 0.07. There were no CF-related hospitalizations in either the pivotal study or through the week 24 interim analysis of the OLE study.

Harms Results

Most patients (79.7%) reported AEs that were either mild (51.6%) or moderate (28.1%) in severity. The most common AEs were upper respiratory tract infections (14.1%), headaches (10.9%), and vomiting (10.9%). There were no discontinuations through the week 24 interim analysis.

Critical Appraisal

Study 107 is an extension of Study 106 that had been critically appraised earlier. The findings from this interim analysis were retrieved from a poster presentation at the North American Cystic Fibrosis Conference. As no further details were provided by the sponsor, CADTH could not fully critically appraise this study at the time of this review.¹⁴ Two patients discontinued the study drug before week 24 and did not enter the OLE study but no explanation for their withdrawal was provided. Issues with the generalizability of these data are the same as for the parent double-blind study.

Patients Aged 12 Years and Older

Study 105 is an ongoing, open-label, uncontrolled trial that enrolled patients who had completed Study 102 or 103 (patients with either an F/MF or an F/F genotype). Interim results were reported for 24 weeks of follow-up for Study 102 patients and 36 weeks for Study 103 patients (data cut-off of October 2019).¹⁵ Results from the week 96 interim analysis were presented at the North American Cystic Fibrosis Conference.¹⁶ A total of 506 patients were enrolled in the extension study (n = 400 for Study 102 and n = 107 for Study 102) and 42 participants prematurely discontinued treatment before the week 96 visit. Reasons for discontinuing include AEs (n = 8), pregnancy (n = 6), refusal of further dosing (n = 9), commercial drug availability (n = 12), and other reasons (n = 7).

Efficacy Results

Among patients previously enrolled in Study 102, the absolute change from baseline to week 24 in ppFEV₁ was similar for patients who switched from placebo to ELX-TEZ-IVA (14.9%; 95% CI, 13.5 to 16.3) and for those who remained on ELX-TEZ-IVA (14.3%; 95% CI, 12.9% to 15.7%) during the extension study. Patients previously enrolled in Study 103 reported an absolute change from baseline to week 36 in ppFEV₁ of 12.8% (95% CI, 10.1 to 15.4) and 11.9% (95% CI, 9.3 to 14.5) during the extension study, for patients previously treated with TEZ-IVA and ELX-TEZ-IVA, respectively.

During treatment with ELX-TEZ-IVA, the annual event rate for pulmonary exacerbations was 0.27 (95% CI, 0.19 to 0.39) for those previously treated with placebo and 0.32 (95% CI, 0.24 to 0.44) for those previously treated with ELX-TEZ-IVA in Study 102, and 0.30 (95% CI, 0.20 to 0.45) for those previously enrolled in Study 103.

The LS mean change from baseline to week 24 for the CFQ-R respiratory domain was 19.2 (95% CI, 16.7 to 21.7) for those switched from placebo to ELX-TEZ-IVA (Study 102), and 20.1 (95% CI, 17.6 to 22.6) for those who received ongoing ELX-TEZ-IVA treatment. The LS mean change was 13.8 (95% CI, 8.9 to 18.8) and 14.3 (95% CI, 9.5 to 19.2), respectively, for patients from Study 103 who were switched from TEZ-IVA to ELX-TEZ-IVA and those treated with ELX-TEZ-IVA in both study periods.

The absolute change in BMI from baseline to week 24 (Study 102) or week 36 (Study 103) ranged from an LS mean of 1.2 kg/m² to 1.3 kg/m². The change from baseline in BMI z scores was reported for patients who were 20 years of age or younger at the start of the parent studies. The point estimate for the LS mean change from baseline in z scores ranged from 0.30 to 0.43 across the different treatment populations.

Among patients previously enrolled in Study 102, the absolute change from week 24 to week 96 in the ppFEV₁ was similar for patients who switched from placebo to ELX-TEZ-IVA (absolute change = 15.2%; 95% CI, 13.6 to 16.7) and for those who remained on ELX-TEZ-IVA (absolute change = 14.3%; 95% CI, 12.7 to 15.8) during the extension study. Patients previously enrolled in Study 103 reported an absolute change from week 4 to week 96 in the ppFEV₁ of 12.4% (95% CI, 9.6 to 15.1) and 11.5% (95% CI, 8.8 to 14.2) during the extension study for patients previously treated with TEZ-IVA and ELX-TEZ-IVA, respectively.

The estimated mean pulmonary exacerbation rate per 48 weeks for participants with F/MF genotypes was 0.21 (95% CI, 0.17 to 0.26) for the week 96 interim analysis compared with 0.98 in the placebo group of the F/MF parent study. The estimated mean pulmonary exacerbation rate per 48 weeks for participants with the F/F genotype was 0.21 (95% CI, 0.14 to 0.30) for the week 96 interim analysis. Because part of this OLE study overlapped with the COVID-19 pandemic, restrictions on social interactions likely contributed to reductions in pulmonary exacerbations for patients with CF.

For patients previously enrolled in Study 102, the absolute change from week 24 to extension-period week 96 in the CFQ-R respiratory domain was 20.1 points (95% CI, 17.5 to 22.6) for those switched from placebo to ELX-TEZ-IVA, and 21.7 points (95% CI, 19.1 to 24.1) for those who received ongoing ELX-TEZ-IVA treatment. The absolute change was 15.6 points (95% CI, 11.0 to 20.1) and 18.0 points (95% CI, 13.6 to 22.5) for patients from Study 103 who were switched from TEZ-IVA to ELX-TEZ-IVA and those treated with ELX-TEZ-IVA, respectively, in both study periods. The absolute change in BMI from week 24 (Study 102) or week 4 (Study 103) to week 96 ranged from 1.3 kg/m² to 1.9 kg/m². The absolute change in sweat chloride concentration from week 24 (study 102) or week 4 (study 103) to week 96 ranged from −45.8 mmol/L to −49.7 mmol/L in patients previously enrolled in Study 102 or 103.

Harms Results

Most patients (93%) reported 1 or more AEs during the extension study. The most reported AEs were infective pulmonary exacerbation of CF (25%), cough (23%), oropharyngeal pain (15%) and nasopharyngitis (14%). Seven patients (1.4%) stopped treatment due to AEs and 80 patients (16%) experienced 1 or more SAEs.

Most patients (98%) reported 1 or more AEs during the extension study (586 events per 100 person-years). The most reported events were infective pulmonary exacerbations of CF (38%), coughing (36%), oropharyngeal pain (26%), headaches (25%) and nasopharyngitis (23%). Eleven patients (2.2%) stopped treatment due to AEs, 126 patients (25%) experienced an SAE, and grade 3 or 4 AEs were reported by 84 (17%).

Critical Appraisal

Study 105 is an ongoing, uncontrolled, open-label trial that enrolled patients who had completed Study 102 or Study 103. As this was an unblinded study, patients’ expectations of treatment may have biased the reporting of subjective outcomes, such as respiratory symptoms (as measured by the CFQ-R) or harms. Extension studies are often limited by selection bias, as only patients who are tolerant to treatment and complete the parent studies are eligible to enrol. For Study 105, the risk of selection bias may be low, given that only 7 patients (1.4%) out of the 513 randomized in the parent studies were not enrolled or treated in the extension study. During the first 24 weeks of follow-up, discontinuation of treatment was also low (9 patients, 1.8%). However, the frequency of missing data was higher than others for some outcomes. Issues with the generalizability of these data are the same as for the parent double-blind studies. The findings from the week 96 OLE interim analysis were retrieved from a poster presentation at the North American Cystic Fibrosis Conference and no further details were provided by the sponsor.

Observational Studies in Patients With Advanced Lung Disease

Two observational studies provided short-term data on the efficacy and safety of ELX-TEZ-IVA in patients with CF who had advanced pulmonary disease (ppFEV₁ < 40% or under evaluation for lung transplantation). All patients had at least 1 F508del-CFTR mutation.

Irish Cohort (Adults)

A retrospective chart review by O’Shea et al. (2021)¹⁷ reported data for 14 patients who were followed for a mean duration of 4.9 months after starting ELX-TEZ-IVA. The mean age of patients was 34.4 years (range = 19 to 46). Statistically significant improvements were reported for mean ppFEV₁, which increased from 27% (standard deviation [SD] = 7.3) at baseline to 36% (SD = 16.5) after a mean follow-up of 26 days; mean BMI, which increased from 20.7 kg/m² (SD = 3.6) to 22.1 kg/m² (SD = 3.4); and mean sweat chloride, which decreased from 105 mmol/L (SD = 15) to 54 mmol/L (SD = 23) after an average of 62 days of follow-up. The rate of infective pulmonary exacerbations requiring hospitalization was 0.28 events per month (SD = 0.17) in the 12 months before ELX-TEZ-IVA, and 0.04 events per month (SD = 0.07) during the 4.9-month follow-up period (P < 0.001).

French Cohort (Adolescents and Adults)

A prospective cohort study by Burgel et al. (2021)¹⁸ reported data for 245 patients who were followed for a median of 84 days after initiating treatment with ELX-TEZ-IVA. The median age of patients treated was 31 years (interquartile range [IQR] = 24 to 38), of which 17 (7%) were adolescents. The mean change from baseline in ppFEV₁ was 15.1% (95% CI, 13.8 to 16.4) and the change from baseline in weight was 4.2 kg (95% CI, 3.9 to 4.6), based on pooled data from 1- and 3-month assessments. The authors reported statistically significant reductions in the percentage of patients receiving long-term oxygen (43% at baseline versus 23% at 3 months), noninvasive ventilation (28% at baseline versus 20% at 3 months); and enteral tube feeding (18% at baseline versus 10% at 3 months). Data were missing for 31% of patients at the 3-month visits, with no imputation in the analyses. Prior to the initiation of ELX-TEZ-IVA, 16 patients were waiting for a lung transplant and 37 were under consideration for inclusion as transplant candidates in the next 3 months (a total of 53 patients; 22%). At the end of follow-up, 5 patients (2%) were on the transplant list or being considered for transplant, 2 patients (0.8%) had received a transplant, and 1 patient had died while waiting for a transplant (0.4%).

Critical Appraisal

The 2 observational studies provided descriptive data on the effects of ELX-TEZ-IVA in patients with CF with advanced lung disease. The short-term results showed acute increases in ppFEV₁ and weight that were comparable to those observed in the clinical trials; but these should be interpreted with caution given the limitations of the open-label, uncontrolled, observational study designs, and the small sample size (N = 14) for the Irish cohort. Both studies had a limited follow-up duration, and the monitoring and reporting of patient outcomes were affected by the COVID-19 pandemic and lockdown measures. The large amount of missing data for some outcomes makes it challenging to interpret and generalize the results of these studies.

Observational Studies in Patients With Normal Lung Function

Interim Analysis From HELIO Study

HELIO is an ongoing multi-centre, prospective, observational study conducted in the US to evaluate the clinical effectiveness of ELX-TEZ-IVA in a real-world setting (N = approximately 200). The study will compare data from a 12-month period before initiating treatment with ELX-TEZ-IVA with data after 16 months of treatment with ELX-TEZ-IVA. At the time of the interim analysis, data were available from ||||||||| patients with a ppFEV₁ of greater than 90% at the time of enrolment. The sponsor reported that this subgroup of patients had a mean baseline ppFEV₁ of ||||||||| before starting treatment and a mean ppFEV₁ of ||||||||| after an average of ||||||||| months of treatment. No interim data were reported for change from baseline in BMI and BMI z scores, pulmonary exacerbations, pulmonary exacerbations requiring IV antibiotics, or pulmonary exacerbations requiring hospitalization, although these were pre-specified end points in the HELIO study.

US Cystic Fibrosis Foundation Patient Registry

The sponsor provided an unpublished analysis from the US Cystic Fibrosis Foundation Patient Registry (CFFPR). Individuals who met the following criteria were included in the analysis: a CFFPR record of initiating treatment with ELX-TEZ-IVA between October 21, 2019, and December 31, 2019; at least 12 years of age on the date of initiating treatment with ELX-TEZ-IVA; an F/MF or F/F genotype; a ppFEV₁ assessment available both within 90 days before and any time after ELX-TEZ-IVA initiation through March 15, 2020 (cut-off date); and a final ppFEV₁ measurement before ELX-TEZ-IVA initiation (baseline) of greater than 90%. There were |||||| patients with the F/MF genotype and |||||| patients with the F/F genotype who met the inclusion criteria. The mean ages of patients in the F/MF and F/F subgroups were |||||| and |||||| years, respectively. Among patients with the F/F genotype |||||| patients (||||||) had been exposed to a CFTR modulator prior to initiation of ELX-TEZ-IVA. Among patients with the F/MF genotype |||||| (||||||) had been exposed to a CFTR modulator prior to ELX-TEZ-IVA initiation. The mean baseline ppFEV₁ values for patients in the F/MF and F/F subgroups were |||||| and ||||||, respectively. The mean changes in ppFEV₁ from baseline in the F/MF and F/F subgroup of patients with a baseline ppFEV₁ of greater than 90% were |||||| and ||||||, respectively. Similar to the HELIO study, no statistical analyses were reported and no other end points were specified.

PROMISE Study

The PROMISE study is an ongoing, prospective, observational study to understand the effects of ELX-TEZ-IVA in clinical use in the US. The study is sponsored by the Cystic Fibrosis Foundation, and programmatic funding was provided by the National Institutes of Health. Patients were included if they met the following criteria: participants were 12 years of age or older, they had at least 1 copy of the F508del mutation, and they had the intent to initiate ELX-TEZ-IVA by the participant’s physician. Due to restrictions during the pandemic, the time frame to complete the pre-planned 6-month assessment was extended, and results were reported. Additional 18- and 30-month study visits are planned. The average age of patients in the interim dataset meeting the inclusion and exclusion criteria (N = 487) was 25.1 years. Almost half the patients were F508del homozygous (48.5%), and 26.7% (n = 130) of patients had a baseline ppFEV₁ of less than 65%, and 40.2% (n = 196) had a baseline ppFEV₁ of 90% or greater. For patients who completed the 6-month visit (n = 356) and for the subgroup of patients with a ppFEV₁ of less than 90% (n = 148), the mean changes in ppFEV₁ from baseline were 9.8 points and 6.5 points, respectively. The mean changes in sweat chloride concentration from baseline for patients who completed the 6-month visit (n = 383) and for the subgroup of patients with a ppFEV1 of greater than 90% (n = 158), were −41.7 mmol/L and −39.7 mmol/L, respectively. The mean changes in CFQ-R respiratory domain scores for patients who completed the 6-month visit (n = 302) and for the subgroup of patients with a ppFEV1 of greater than 90% (n = 120), were 20.4 points and 15.7 points, respectively. The mean changes in BMI for adult patients who completed the 6-month visit (n = 326) and for the subgroup of patients with a ppFEV1 of greater than 90% (n = 76), were 1.2 kg/m² and 0.8 kg/m², respectively. The mean changes in BMI z scores for pediatric patients who completed the 6-month visit (n = 139) and for the subgroup of patients with a ppFEV1 of greater than 90% (n = 93), were 0.3 and 0.3, respectively.

Simulation Study for Morbidity and Mortality

Stanojevic et al. (2020)¹⁹ used a microsimulation model to estimate the impact of treatment with ELX-TEZ-IVA in eligible patients in Canada. The model forecast an increase in median survival and a reduction in pulmonary exacerbations with the introduction of ELX-TEZ-IVA. The outcomes from these simulations are contingent on the validity of several assumptions that were required to build the model and extrapolate the impacts out to 10 years. There is uncertainty in the extrapolation of short-term effects of ELX-TEZ-IVA in a subset of patients with CF to the broader population in the longer term, and in the generalizability of observational data for IVA on the rate of decline in ppFEV₁ to patients treated with ELX-TEZ-IVA. Moreover, the model likely overestimates the proportion of patients with CF who may receive ELX-TEZ-IVA and the impact of treatment on pulmonary exacerbations.

Conclusions

For patients 6 to 11 years of age, a 24-week, double-blind, placebo-controlled RCT (Study 116; N = 121) and a pivotal, single-arm, open-label trial (Study 106B; N = 66) demonstrated that treatment with ELX-TEZ-IVA resulted in clinically meaningful improvements in lung function (increase in ppFEV₁), nutritional status (increase in BMI z scores), and HRQoL (increase in CFQ-R respiratory domain scores) and CF biomarkers (reduction in sweat chloride). In addition, AE data suggested that ELX-TEZ-IVA reduced the occurrence of pulmonary exacerbations in pediatric patients. The clinical studies for ELX-TEZ-IVA were limited to patients with an F/MF (Study 116 and Study 106B) or F/F genotype. As Study 106B was a single-arm trial, the sponsor conducted an indirect comparison to derive estimates for the comparative efficacy of ELX-TEZ-IVA versus placebo, LUM-IVA, and TEZ-IVA. No clinical studies were conducted on 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 all patients with at least 1 F508del mutation are likely to benefit from treatment with ELX-TEZ-IVA.

For patients 12 years and older, a 24-week, placebo-controlled RCT (Study 102; N = 403) conducted in patients with an F/MF genotype demonstrated that, compared with placebo, 24 weeks of treatment with ELX-TEZ-IVA was associated with statistically significant and clinically meaningful improvements in lung function (increase in ppFEV₁), nutritional status (increase in BMI), HRQoL (increase in CFQ-R respiratory domain scores), CF biomarkers (reduction in sweat chloride), and a reduced rate of pulmonary exacerbations, including events that required IV antibiotics and/or hospitalization to manage. Three additional double-blind, active-controlled RCTs compared switching to ELX-TEZ-IVA after 4 weeks of treatment with either TEZ-IVA or IVA with remaining on those other CFTR modulators. Study 103 (N = 107; 4 weeks) and Study 109 (N = 175; 24 weeks), which were conducted in patients with an F/F genotype, demonstrated that treatment with ELX-TEZ-IVA was associated with statistically significant and clinically meaningful improvements in ppFEV₁ and CFQ-R compared with remaining on TEZ-IVA. Study 104 (N = 258; 8 weeks) demonstrated that switching to ELX-TEZ-IVA was associated with statistically significant and clinically meaningful improvements in ppFEV₁ compared with remaining on IVA in patients with an F/G genotype and a modest improvement compared with remaining on TEZ-IVA for patients with an F/RF genotype. Patients with advanced lung disease were largely excluded from the phase III RCTs; however, post hoc subgroup analyses and data from 2 short-term observational studies suggest that treatment with ELX-TEZ-IVA resulted in clinically meaningful improvements in lung function in these patients.

Patients with normal lung function (i.e., ppFEV₁ > 90%) were considered an important subgroup for the current review of ELX-TEZ-IVA. Approximately half of the pediatric patients in Study 106B and Study 116 had a baseline ppFEV₁ of greater than 90%. For those 12 years and older, in addition to the previously reviewed HELIO and CFFPR data, the current review included subgroup data for patients with a baseline ppFEV1 of greater than 90% from a new observational study in adolescent and adults (PROMISE). Although limited by open-label administration and the lack of a control group, the data from PROMISE suggest that patients aged 12 and older with a ppFEV₁ of greater 90% at the time of initiating treatment with ELX-TEZ-IVA experienced meaningful improvements in ppFEV₁, BMI, and CFQ-R scores.

ELX-TEZ-IVA was well tolerated in the target patient populations (i.e., 6 years of age or older with at least 1 F508del mutation). Serious AEs and WDAEs were rare in the included studies. 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 before 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 ELX-TEZ-IVA treatment were not anticipated to result in a substantial increase in the number of the clinic visits for patients with CF (particularly after the first year of initiating the treatment).

Introduction

Disease Background

Cystic fibrosis, 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 the CFTR protein is dysfunctional, secretions become tenacious and sticky, resulting in pathology in multiple organs, including the lungs, large and small intestines, pancreatic and bile ducts, and the vas deferens. The F508del mutation is the most common mutation that results in CF.¹ The Canadian Cystic Fibrosis Registry reported that 4,344 Canadians were living with CF in 2019. Of these, 87.8% of patients carried at least 1 F508del mutation (47.1% were homozygous and 40.7% were heterozygous).¹

More than 2,090 variants of CFTR proteins have been identified among patients with CF.¹ The 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).²⁰ Variants within classes I to III are associated with severe CF as they are considered non-functional, while CFTR variants in classes IV to VI may retain CFTR function.^20,21 The F508del mutation is typically associated with 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 misfolding and most of the protein is removed before it can reach the cell membrane. In addition, F508del-CFTR proteins present a defect in channel gating, are unstable, and experience rapid turnover at the cell membrane.^22,23 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

Cystic fibrosis results in airway obstruction, chronic endobronchial infection, and inflammation, which ultimately lead to destruction of lung tissue through development of bronchiectasis and loss of lung function.²⁴ 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.²⁵ Chronic endobronchial infection of the airways with bacterial pathogens, such as Pseudomonas aeruginosa (reported in 38% of Canadian patients with CF in 2019)¹ is associated with a more rapid loss of lung function.²⁶ Acute or chronic endobronchial infections result in further destruction of lung tissue and is associated with respiratory morbidity. Lung disease accounts for the vast majority (> 80%) of death in patients with CF.^1,27

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 1 or more pulmonary exacerbations per year requiring IV antibiotics.²⁸

Maintenance of pulmonary function (FEV₁) and fewer respiratory exacerbations are associated with increased survival.²⁹ 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 outcome and longevity for patients with CF.³⁰ Virtually all of these people will be pancreatic insufficient and need to take life-long pancreatic enzyme replacements 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 in Canada with CF (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 in 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.^1,31,32 There is a clear unmet need for better CF therapies, as discussed in the Patient Group Input and Clinician Input sections.

Standards of Therapy

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 as either therapies used to manage symptoms, complications, and comorbidities of CF or therapies to correct underlying defects in 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).³³ Nutritional treatments consist of high-calorie and high-fat diets and pancreatic enzyme replacement for those with pancreatic insufficiency.^27,33 Pulmonary exacerbations are treated with oral or IV antibiotics.³⁴ 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 that are currently marketed in Canada or other jurisdictions are classified as potentiators and correctors. Potentiators function by increasing the channel-open probability of the CFTR protein at the cell surface. Ivacaftor is a CFTR potentiator. Correctors function by improving the conformational stability of F508del-CFTR protein, resulting in an increased expression of the F508del-CFTR protein at the cell surface. Lumacaftor, TEZ, and ELX are CFTR correctors.

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 been approved by Health Canada, and the 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 those who are homozygous for F508del mutations (Orkambi and Symdeko), heterozygous for the 508del mutation, and who also have 1 of the following mutations: residual function mutation (Symdeko) or a gating mutation (Kalydeco). A subset of individuals who are heterozygous for the F508del mutation will therefore 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, leaving an unmet medical need for treatments with the potential to offer greater treatment effects and benefits.³⁵ In 2019, CF Canada reported that 658 individuals (216 children and 442 adults) were receiving treatment with CFTR modulators, with 146 receiving Kalydeco, 368 receiving Orkambi, and 186 receiving Symdeko.¹

Drug

Trikafta consists of a fixed-dose combination tablet available as ELX, TEZ, and IVA co-packaged with a tablet containing IVA (ELX-TEZ-IVA). It is available in 2 dosage strengths:

• ELX 50 mg, TEZ 25 mg, and IVA 37.5 mg co-packaged with a tablet containing IVA 75 mg

• ELX 100 mg, TEZ 50 mg, and IVA 75 mg co-packaged with a tablet containing IVA 150 mg.

ELX-TEZ-IVA is indicated for the treatment of CF in patients aged 6 years and older who have at least 1 F508del mutation in the CFTR gene. The sponsor has requested the following reimbursement criteria for ELX-TEZ-IVA:

• Initiation criteria: Patients and aged 6 years and older must have a confirmed diagnosis with CF with at least 1 F508del mutation in the CFTR gene.

• First renewal: In addition to the previously recommended criteria for the 12-and-older population whereby the physician must provide evidence of continued treatment benefit in 1 or more of the predefined criteria (i.e., lung function, pulmonary exacerbations, hospitalizations, BMI and CFQ-R) after 6 months of treatment with Trikafta, the sponsor recommends adding reduction in sweat chloride the to the renewal criteria.

• Subsequent renewals annually: The physician must provide evidence of continued treatment benefit with Trikafta for subsequent renewal of reimbursement.

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 a CFTR protein 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^35-37:

• ELX and TEZ improve the conformational stability of F508del-CFTR protein, resulting in an increased expression of the F508del-CFTR protein at the cell surface.

• IVA increases the channel-open probability of the CFTR protein at the cell surface.

Recommended Dosage

The recommended dosage of ELX-TEZ-IVA for patients aged 6 to less than 12 years who weigh less than 30 kg is a combination of 2 tablets in the morning (each containing ELX 50 mg, TEZ 25 mg, and IVA 37.5 mg) and 1 standalone tablet (containing IVA 75 mg) taken in the evening. For those aged 6 to less than 12 years who weigh 30 kg or more and those 12 years and older, the recommended dosage is 2 combination tablets in the morning (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg) and 1 standalone tablet (containing IVA 150 mg) taken in the evening (Table 4). Both tablets are administered orally (swallowed whole) 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, and clarithromycin).

Table 4: Recommended Dosage

Source: Product monograph.³⁶

Table 5: Recommended Dosage Adjustments

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

^aTreatment of patients with moderate hepatic impairment 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 dosage, as follows: 2 ELX-TEZ-IVA tablets alternating with 1 elexacaftor-tezacaftor-ivacaftor tablet taken in the morning, on alternating days. The evening dose of the ivacaftor tablet should not be taken.

Previous CADTH Reviews

This is the second submission to CADTH for ELX-TEZ-IVA. CADTH previously reviewed ELX-TEZ-IVA for the treatment of CF in patients aged 12 years and older who have at least 1 F508del mutation in the CFTR gene; CDEC recommended that ELX-TEZ-IVA be reimbursed with conditions.²

CADTH has previously reviewed IVA alone for the following indications: patients 6 years of age 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 18 years of age and older who have an R117H mutation in the CFTR gene.^38-40 For each of these indications, CDEC 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 received do-not-reimburse recommendations in 2016 and 2018.^41,42 CADTH was unable to recommend reimbursement for TEZ-IVA as the manufacturer did not file a submission.⁴³

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Three patient groups, CF Canada, the Canadian Cystic Fibrosis Treatment Society, and CF Get Loud, responded to CADTH’s call for patient input for both the initial CADTH review of ELX-TEZ-IVA (i.e., for patients 12 years and older) and for the current review of ELX-TEZ-IVA, which is focused on patients 6 years and older.

Information from CF Canada was based on a survey of patients and caregivers that was conducted for the previous CADTH review of ELX-TEZ-IVA, Cystic Fibrosis Registry Annual Data Reports, press releases, news stories, and government submissions, as well as information gathered through social media campaigns, posts from individuals, and traditional media sources. In addition, CF Canada cites information that was presented at the 2021 North American Cystic Fibrosis Conference. For its initial submission to CADTH, CF Get Loud gathered information from a letter campaign that received 11,364 letters from Canadians, a town hall with CF experts and leaders, and from 20 Canadians who are currently receiving treatment ELX-TEZ-IVA. For the current submission, CF Get Loud gathered information from interviews with parents of children living with CF. Canadian CF Treatment Society gathered information through discussions with parents and caregivers of young patients with CF, advocates and physicians located in Canada.

The patient groups emphasized that CF has tremendous impact on those living with the condition, their loved ones, and on 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. Patients may suffer from pulmonary exacerbations requiring weeks of hospitalization and IV antibiotics. Malnutrition is another consequence of CF, and those living with the condition are often underweight and may require a feeding tube for supplemental nutrition. Patients may also suffer from CF-related comorbidities, such as CF-related diabetes and CF-related liver disease. In addition to the decline of the physical health of patients with CF, many suffer from the unseen effects of CF. These include, but are not limited to, depression, anxiety, and hopelessness. The mental anguish caused by the ever-present awareness of 1’s mortality cannot be expressed in words and can be difficult to quantify. Parents and caregivers often have an overwhelming desire to do something to help their loved ones.

Managing CF requires a demanding treatment routine with regular visits to specialized CF clinics. As the disease progresses, even more time and effort are needed to manage the progressive and debilitating symptoms. The condition has a significant impact on day-to-day quality of life, affecting life decisions that include education, careers, travel, relationships, and family planning.

Patients with CF and their loved ones are seeking treatments that can change the trajectory of the disease and improve both life expectancy and quality of life. Improved outcomes include retaining or increasing lung function, improving digestive health and energy levels, and minimizing symptoms of CF. Patients want to avoid hospital admissions, reduce the need for invasive medical procedures, and minimize the treatment burden of daily therapies. They also wish to avoid the adverse effects of therapies, such as osteoporosis, antimicrobial resistance, and CF-related diabetes or liver dysfunction.

Patient groups emphasized the importance of early and aggressive treatment of CF with a focus on maintaining health and slowing or preventing disease progression. They noted that even those children with CF who appear healthy (e.g., a ppFEV₁ of 100%) are subjected to an aggressive therapeutic regimen of physiotherapy and antibiotic treatments in addition to special diets and frequent clinic visits. All patient groups stressed that it is important to start treatment with ELX-TEZ-IVA as soon as possible to prevent the irreversible damage caused by CF. The patient groups referenced the initial CADTH recommendation for ELX-TEZ-IVA, noting that they believe the reimbursement policies are too restrictive, particularly the requirement that patients demonstrate a ppFEV₁ of less than 90% to be eligible. The patient groups stated that they believe all patients with at least 1 F508del mutation can benefit from treatment with ELX-TEZ-IVA.

Complete patient 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 review if ELX-TEZ-IVA is available on the CADTH website and discussed in the Patient Input section).

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 ELX-TEZ-IVA review, CADTH convened panels of clinical experts from across Canada 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 a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions).

Unmet Needs

Patients living with CF have significant unmet therapeutic needs. None of the treatments currently available can effectively achieve the most important goals of therapy: prolong survival, prevent the need for lung transplantation, prevent an accelerated decline in lung function over time, or 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

As a CFTR modulator, ELX-TEZ-IVA 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 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 (e.g., Orkambi and Symdeko) that are significantly less effective, 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).

Patient Population

The diagnosis of CF is not challenging in routine clinical practice. As all provinces and territories have instituted CF screening for newborns, most people with CF are now identified as newborns and have a confirmed diagnosis by 1 month of age (on average). Sweat chloride 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 little variability in expert opinion. Misdiagnosis and underdiagnosis of CF is exceedingly rare in Canadian clinical practice.

Every patient who meets the Health Canada–approved indication could be eligible for ELX-TEZ-IVA, regardless of their current or past treatment regimens. From a medical perspective, there is no rationale for a patient to demonstrate an inadequate 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; however, there is no practical method that could be used to predict who will be most likely to respond to ELX-TEZ-IVA.

Applicability of Existing Reimbursement Criteria to Pediatrics

The CADTH recommendation for patients 12 years of age and older includes an initiation criterion that patients are required to have a ppFEV₁ of less than or equal to 90% to be eligible for reimbursement. The included trials demonstrated that pediatric patients with a ppFEV₁ of greater than 90% experienced clinically meaningful improvements in lung function. Input from patient groups, clinician groups, and the clinical experts consulted by CADTH noted that patients should be eligible for treatment with ELX-TEZ-IVA irrespective of their baseline lung function. There was consensus that those with normal lung function should not be excluded from reimbursement.

Regarding the baseline measurements that must be completed before initiating treatment with ELX-TEZ-IVA, the clinical experts noted the frequency of pulmonary exacerbations can be quite low in pediatric patients and that 12 months would be a more appropriate time frame for evaluation. The nutritional end points (i.e., weight, height, and BMI) are typically measured using z scores and/or BMI percentiles for pediatric patients. The clinical experts noted that CFQ-R scores are typically only collected when conducting research, and not in clinical practice for pediatric patients. As such, this criterion could be challenging to implement in pediatric clinical practice. It would require additional resources for CF clinics to administer the CFQ-R instrument, document the responses, and track changes in scores over time. Differences in record-keeping across Canada (e.g., paper and/or electronic health record systems) were noted as an additional challenge when including CFQ-R assessments in the reimbursement criteria for ELX-TEZ-IVA in pediatric patients.

Table 7: CADTH-Recommended Reimbursement Conditions for ELX-TEZ-IVA in Patients at Least 12 Years of Age

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 1 second; ppFEV₁ = percent predicted forced expiratory volume in 1 second; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Assessing Response to Treatment

The magnitude of improvement in CF outcomes that would be considered clinically significant depends on the baseline status of the patient. The following end points are routinely assessed in Canadian clinical practice: FEV₁, nutrition and growth (e.g., BMI, BMI z score, or BMI percentile), hospital admissions and outpatient treatments for pulmonary exacerbations, and pulmonary exacerbation frequency per year. The initial review of ELX-TEZ-IVA noted that CF-related quality-of-life scales can be applied in clinical practice; however, these are not routinely applied in the pediatric setting. Each of these end points are discussed below with reflections on the applicability of the existing CADTH criteria to the expanded patient population.

Spirometry

The CADTH recommendation for patients 12 years or age and older included a criterion that those who demonstrate an improvement of 5% or greater in ppFEV₁ relative to baseline should be eligible for initial renewal of reimbursement. The clinical experts noted that there would be a ceiling effect for those with normal lung function, and demonstrating an improvement of 5% or greater in ppFEV₁ would be more challenging for these patients. It was noted that the stabilization of lung function (e.g., absence of a decline) or slowing the decline in ppFEV₁ is also clinically important and could be considered as evidence that the patient is benefiting from ELX-TEZ-IVA.

BMI and BMI Z Scores

The CADTH recommendation for patients ages 12 years and older included the following as a potential renewal criterion for ELX-TEZ-IVA: no decline in BMI at 6 months compared with the baseline BMI assessment. The pediatric clinical experts noted that BMI z scores and/or BMI percentiles are typically used in clinical practice for pediatric patients with CF and that the existing criterion could be applicable if modified accordingly. However, the pediatric experts suggested that the criterion could be adjusted to provide flexibility within the standard error (SE) of the BMI z score measurement and that 6 months may not be sufficient time to accurately assess the response to treatment. The clinical experts noted that 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 such patients would not be clinically appropriate.

Pulmonary Exacerbations

The CADTH recommendation for patients aged 12 years and older included the following as a potential renewal criterion 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 before initiating treatment or a decrease in the total number of pulmonary exacerbations requiring oral and/or IV antibiotics compared with the 6-month period before initiating treatment. Pulmonary exacerbations were less frequent in the studies that enrolled patients 6 to 11 years of age (e.g., 0.12 events per year in Study 106B) compared with the trials in adults and adolescents (e.g., 0.98 and 0.37 events per year in the placebo and ELX-TEZ-IVA groups, respectively, in Study 102). 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 this renewal criterion would be reasonable for the use of ELX-TEZ-IVA in some pediatric patients, but that patients who have not experienced a pulmonary exacerbation or those with a very low annual rate of pulmonary exacerbations would also benefit from treatment. In particular, the experts noted that a large subset of pediatric patients have not required antibiotic treatment in the year preceding the CADTH review, which is usual and likely due to the exceptional isolation and infection control that patients with CF and their families have adopted in response to the ongoing COVID-19 pandemic. Similar to the criterion for BMI, it was noted that 12 months would be a more appropriate time frame for evaluating changes in pulmonary exacerbations.

Quality of Life

The CADTH recommendation for patients ages 12 years and older included the following as a potential renewal criterion for ELX-TEZ-IVA: improvement by 4 points or more in the CFQ-R respiratory domain scale. As noted previously, implementation of the CFQ-R instrument in pediatric clinical practice would require additional resources for the CF clinics to administer the CFQ-R instrument, document the responses, and track changes in scores over time.

Sweat Chloride

The previous CADTH recommendation did not include sweat chloride testing as an initiation or renewal condition 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. The pediatric clinical experts agreed with the prior input from the review of ELX-TEZ-IVA in patients aged 12 years and older, noting that sweat chloride 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 such as ELX-TEZ-IVA. It was noted that poor adherence to the treatment regimen over a short period of time could influence sweat chloride results. In its comments on the draft CADTH report, the sponsor noted that sweat chloride testing has been included in the CF Canada Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients with Cystic Fibrosis, which recommend monitoring the reduction in sweat chloride for patients 6 years and older at baseline, the 3-month visit, and the 12-month visit after initiating treatment with a CFTR modulator (Appendix 1).

Discontinuing Treatment

The CADTH recommendation for patients 12 years of age and older stated that reimbursement should be discontinued in patients who have undergone lung transplantation. It was noted that, unlike the adolescent and adult CF population, lung transplants rare in those 6 to 11 years of age. Given the expected benefit of ELX-TEZ-IVA on nutrition and growth end points in the younger age group, it was anticipated that clinicians would consider ELX-TEZ-IVA for patients in this age group even post–lung transplant if it were not contraindicated due to medication interactions.

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 non-specialty setting or physician prescribe and monitor treatment with ELX-TEZ-IVA.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Three groups of clinicians provided input for the initial CADTH review of ELX-TEZ-IVA (the Canadian Cystic Fibrosis Clinic Directors, CF Canada’s Accelerating Clinical Trials Network, and The Toronto Adult CF Clinic) and 2 groups provided input for the current review (Cystic Fibrosis Canada’s Accelerating Clinical Trials Network and the Canadian Cystic Fibrosis Clinic Directors/CF Canada Health Care Advisory Council). Complete clinician input received for the current review of ELX-TEZ-IVA is reported in an appendix to this report. The complete input and feedback received for the previous CADTH review if ELX-TEZ-IVA is available on the CADTH website in the Clinician Input and Stakeholder Feedback sections). The input from the clinician groups identified the same unmet medical needs for patients with CF and potential place in therapy for ELX-TEZ-IVA as the clinical experts consulted by CADTH. Similar to the clinical experts consulted by CADTH, the clinician groups noted that the impact of ELX-TEZ-IVA has been dramatic and life-altering for the patients who have received the treatment. The groups emphasized that patients should be eligible for treatment with ELX-TEZ-IVA irrespective of their baseline lung function. There was consensus that those with normal lung function should not be excluded from reimbursement.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect 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

BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; FEV₁ = forced expiratory volume in 1 second; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

Clinical Evidence

The clinical evidence included in the review of ELX-TEZ-IVA is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of ELX 100 mg, TEZ 50 mg, and IVA 75 mg taken each morning and 150 mg of IVA taken each evening for the treatment of patients aged 6 years and older with CF who have at least 1 F508del mutation in the CFTR gene.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 9. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 9: Inclusion Criteria for the Systematic Review

CF = cystic fibrosis; ELX = elexacaftor; FEV₁ = forced expiratory volume in 1 second; 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; IVA = ivacaftor; LUM-IVA = lumacaftor-ivacaftor; TEZ = tezacaftor; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

^aOutcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and the drug programs.

Source: Clinical Study Reports.^3-8

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist (https://www.cadth.ca/resources/finding-evidence/press).⁴⁵ Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Trikafta (elexacaftor-tezacaftor-ivacaftor). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides detailed search strategies.

The initial search was completed on February 22, 2021. Regular alerts updated the search until the CDEC meeting on June 16, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist (https://www.cadth.ca/grey-matters).⁴⁶ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency [EMA]). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 6 studies were identified for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 10 and Table 11. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 10: Details of Included Studies for Pediatric Patients

ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX = elexacaftor; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutations in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; GFR = glomerular filtration rate; GGT = gamma-glutamyl transferase; IVA = ivacaftor; LCI = lung clearance index; OLE = open-label extension; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride; TEZ = tezacaftor; ULN = upper limit of normal.

Note: Seven additional reports were included: Clinical Study Reports,^3,4 European Public Assessment Report,⁵⁰ Common Technical Document,⁵¹ the Sponsor’s Clinical Summary,⁵² and clinicaltrials.gov.⁴⁸⁴⁹

Source: Clinical Study Reports.^3,4

Table 11: Details of Included Studies for Adolescent and Adult Patients

ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX = elexacaftor; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutations in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/G = 1 F508del mutation and 1 gating mutation in the CFTR gene; GFR = glomerular filtration rate; GGT = gamma-glutamyl transferase; IVA = ivacaftor; OLE = open-label extension; PEx = pulmonary exacerbation; ppFEV₁ = percent predicted forced expiratory volume in 1 second; RCT = randomized controlled trial; RD = respiratory domain; RF = residual function mutation in the CFTR gene; SwCl = sweat chloride; TEZ = tezacaftor; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor; TSQM = Treatment Satisfaction Questionnaire for Medication; ULN = upper limit of normal.

Note: Eight additional reports were included: Clinical Study Reports,^5,6,10,11 FDA Multi-Discipline Review,³⁵ European Public Assessment Report,⁵⁹ Common Technical Document,⁵¹ and the Sponsor’s Clinical Summary.⁶⁰

Source: Clinical Study Reports.^5,6,10,11

Description of Studies

Table 12 provides an overview of the studies that were summarized and appraised by CADTH for the current review of ELX-TEZ-IVA. Four double-blind, phase III, RCTs were included in the CADTH systematic review: 1 placebo-controlled trial conducted in patients who were heterozygous for the F508del mutation and who had 1 minimal function mutation (Study 102); 2 active-controlled trials in patients who were homozygous for the F508del mutation (Study 103 and Study 109); and 1 active-controlled trial in patients who were heterozygous for the F508del mutation and a residual function mutation or a gating mutation (Study 104).

CADTH also reviewed additional studies that did not meet the eligibility criteria of the systematic review but may address important gaps in the evidence from the pivotal and supportive RCTs. These included 1 long-term extension-phase study (Study 105),¹⁵ 1 indirect comparison filed by the sponsor,⁵² 2 observational studies that evaluated the use of ELX-TEZ-IVA in patients with advanced lung disease,^17,18 and 1 study that modelled the potential impact of ELX-TEZ-IVA on morbidity and mortality.¹⁹

Table 12: Summary of Studies

DB = double-blind; F/F = homozygous for F508del mutations 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/other = 1 F508del mutation and 1 other mutation; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; F/uncharacterized = 1 F508del mutation and 1 uncharacterized mutation; NA = not applicable; NR = not reported; RCT = randomized controlled trial.

^aGenotypes for patients who were heterozygous for the F508del mutation were not reported by Burgel et al. (2020).

^bThe microsimulation was conducted based on patients with at least 1 F508del mutation with no separate analyses based on the genotype of patients.

Patients Aged 6 to 11 Years

Placebo-Controlled Trial (Study 116; F/MF Genotype)

Study 116 was a phase III, multinational, parallel-group, placebo-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are heterozygous for the F508del mutation and who have a minimal function mutation (F/MF). Study 116 was conducted at 34 sites in Australia, Canada, Israel, Switzerland, the UK, Denmark, France, Germany, the Netherlands, and Spain. There were 3 sites in Canada ||||||. As shown in Figure 2, Study 116 consisted of a 28-day screening period, a 24-week double-blind treatment period, and a 28-day follow-up period. Patients who completed the 24-week treatment period could enrol in the OLE study (VX20 to 445 to 119) or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA or a matching placebo. Those weighing less than 30 kg received ELX 100 mg, TEZ 50 mg, and IVA 75 mg every morning plus IVA 75 mg every evening and those weighing 30 kg or more received ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening. Randomization was conducted using an IWRS and stratified by the screening visit values for LCI_2.5 (< 10 versus ≥ 10) and body weight (< 30 kg versus ≥ 30 kg).⁴

Figure 2: Schematic of the Design of Study 116

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

Source: Clinical Study Report.⁴

Single-Arm Trial (Study 106; F/F or F/MF Genotype)

Study 106 was a phase III, 2-part, multi-centre study evaluating the pharmacokinetics, safety, and tolerability of ELX-TEZ-IVA patients 6 to 11 years of age with an F/F or an F/MF genotype. Study 106 was conducted at 21 sites in the US, Australia, Canada, the UK, and Ireland. There were 2 sites in Canada ||||||||||||. As shown in Figure 3 and Figure 4, Study 106 included 2 parts (A and B). Part A consisted of a 28-day screening period, a 15-day, single-arm, open-label treatment period, and a 28-day safety follow-up period. Part B was initiated after completion of the internal review of the data in Part A that were used to confirm or adjust the doses to be evaluated in Part B. Similar to Part A, Part B of Study 106 included a 28-day screening period, which was followed by a 24-week single-arm, open-label treatment period. Those who completed the Part B treatment period and were not permanently discontinued were offered the opportunity to enrol in an optional OLE study (VX19 to 445 to 107).

Figure 3: Schematic of the Design of Study 106 Part A

IVA = ivacaftor; VX-445/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; TEZ = tezacaftor.

Source: Clinical Study Report.³

Figure 4: Schematic of the Design of Study 106 Part B

VX-445/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor.

Source: Clinical Study Report.³

Patients Aged 12 Years and Older

Patients With F/MF Genotype

Study 102 was a pivotal, phase III, multinational, parallel-group, placebo-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are heterozygous for the F508del mutation and who have a minimal function mutation. Study 102 was conducted at 110 sites in 13 countries, including 6 sites in Canada (n = 24). As shown in Figure 5, Study 102 consisted of a 28-day screening period, a 24-week double-blind treatment period, and a 28-day follow-up period. Patients who completed the 24-week treatment period could enrol in the OLE (Study 105) or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA (ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening) or a matching placebo. Randomization was conducted using an IWRS and stratified by ppFEV₁ at screening (< 70% or ≥ 70%), age at screening (less than 18 years or ≥ 18 years of age), and sex (male or female).

An interim efficacy analysis was planned after 140 or more patients completed the week 4 visit and 100 or more patients completed the week 12 visit. The interim analysis was performed by an external independent biostatistician who was not involved in the conduct of Study 102. The results of the interim analysis were reviewed by the independent data monitoring committee. If the committee declared that Study 102 had crossed the pre-specified efficacy boundary, then the study could be unblinded by a limited team from the sponsor for the purposes of preparing a regulatory submission. Those who were unblinded were not to be involved in or influence the conduct of the remaining part of Study 102. All patients (and their parents, caregivers, or companions), site personnel (including the investigator, the site monitor, and the study team), and members of the sponsor’s study team remained blinded until the final database lock.

Figure 5: Schematic of the Design of Study 102

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

Source: Common Technical Document, section 2.7.3.⁶⁴

Patients With F/F Genotype

Study 103 was a pivotal, phase III, multinational, parallel-group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are homozygous for the F508del mutation (F/F). The trial was conducted at 44 sites in 4 countries (Belgium, the Netherlands, the UK, and the US). As shown in Figure 6, Study 103 consisted of a 28-day screening period, a 28-day open-label run-in period during which all patients received TEZ 100 mg and IVA 150 mg once daily in the morning and IVA 150 mg once daily in the evening, a 4-week double-blind treatment period, and a 28-day follow-up period. Patients who completed the 4-week treatment period could enrol in the OLE (Study 105) or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA (ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening) or to continue with TEZ 100 mg once daily and IVA 150 mg every 12 hours. As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the TEZ-IVA group also received a matching placebo tablet for the morning dosage to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening). Randomization was conducted using an IWRS and stratified by ppFEV₁ at screening (< 70% or ≥ 70%) and age at screening (less than 18 years or ≥ 18 years of age).

Figure 6: Schematic of the Design of Study 103

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

Source: Common Technical Document section 2.7.3.⁶⁴

Study 109 was a phase IIIb, multinational, parallel-group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are homozygous for the F508del mutation (F/F). The trial was conducted at 35 sites in 4 countries (the UK, Germany, Belgium, and Australia).¹⁰ As shown in Figure 7, Study 109 consisted of a 28-day screening period, a 28-day open-label run-in period during which all patients received TEZ 100 mg once daily and IVA 150 mg every 12 hours (TEZ-IVA), a 24-week double-blind treatment period, and a 28-day follow-up period.¹⁰ Patients who completed the 24-week treatment period could enrol in the OLE study (NCT04362761)⁶⁵ or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA (ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening) or to continue with TEZ-IVA.¹⁰ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the TEZ-IVA group also received a matching placebo tablet for the morning dose to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening).¹⁰ Randomization was stratified by ppFEV₁ and ppFEV₁ category (i.e., < 70 versus ≥ 70) at day −14 of the TEZ-IVA run-in period; age at screening (< 18 versus ≥ 18 years of age), and whether the patient was receiving CFTR-modulator treatment at screening (yes versus no).¹⁰

Figure 7: Schematic of the Design of Study 109

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

Source: Sponsor’s Clinical Summary.⁶⁰

Patients With F/RF or F/G Genotype

Study 104 was a phase III, multinational, parallel-group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are heterozygous for the F508del mutation and a gating mutation (F/G) or a residual function mutation (F/RF).¹¹ This study was conducted at 96 sites in 11 countries (Australia, Belgium, Canada, France, Germany, Ireland, Italy, Spain, the Netherlands, the UK, and the US).¹¹ As shown in Figure 8, Study 104 consisted of a 28-day screening period, a 28-day open-label run-in period during which all patients with an F/RF genotype received TEZ 100 mg once daily and IVA 150 mg every 12 hours (TEZ-IVA) and those with an F/G genotype received IVA 150 mg every 12 hours, with a 4-week double-blind treatment period, and a 28-day follow-up period.¹¹ Patients who completed the 4-week treatment period could enrol in the OLE study (VX18 to 445 to 110)⁶⁶ or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA (ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening) or to the control group, whose members would continue with TEZ-IVA or IVA as per their genotype.¹¹ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the control group (TEZ-IVA or IVA) also received a matching placebo tablet for the morning dose to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening). Randomization was conducted using an IWRS and stratified by comparator group (IVA versus TEZ-IVA), ppFEV₁ at the day −14 visit, and sweat chloride at the day −14 visit.¹¹

Figure 8: Schematic of the Design of Study 104

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

Source: Common Technical Document, section 2.7.3.⁶⁴

Populations

Inclusion and Exclusion Criteria

Patients Aged 6 to 11 Years

Placebo-Controlled Trial (Study 116; F/MF Genotype): Patients aged 6 through 11 years (inclusive) were eligible for inclusion in Study 116 if they were heterozygous for F508del and a minimal function mutation in the CFTR gene and had a confirmed diagnosis of CF (determined by the investigator). Details regarding classification of minimal function mutations are described in the section for Study 102. Patients were required to weigh 15 kg or more, have stable CF disease in the opinion of the investigator, a ppFEV₁ of 70% or greater, and an LCI_2.5 result of 7.5 or greater at the time of screening. The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus. Patients were also considered ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before their first dose of TEZ-IVA in the run-in period. Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.⁴

Single-Arm Trial (Study 106; F/F or F/MF Genotype): Patients aged 6 through 11 years (inclusive) were eligible for inclusion in Study 106 if they were homozygous for the F508del mutation (F/F) or heterozygous for F508del and an minimal function mutation in the CFTR gene and had a confirmed diagnosis of CF (determined by the investigator). Details regarding classification of minimal function mutations are described in the following section for Study 102. Patients were required to weigh 15 kg or more, have stable CF disease in the opinion of the investigator, and a ppFEV₁ of 40 or greater at the time of screening. 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, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before first dose of TEZ-IVA in the run-in period. Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.³

Patients Aged 12 Years and Older

Patients With F/MF Genotype (Study 102): Patients aged 12 years and older were eligible for inclusion in Study 102 if they were heterozygous for F508del with a minimal function mutation in the CFTR gene and a confirmed diagnosis of CF (determined by the investigator).³⁴ To be considered minimal function, the mutation was required to meet at least 1 of the following criteria:

• biologic plausibility of no translated CFTR protein (i.e., the genetic sequence predicts the complete absence of CFTR protein)

• in vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ-IVA, and evidence of clinical severity on a population basis.⁵

The mutations that were classified as minimal function based on in vitro testing met the following criteria in the sponsor’s in vitro experiments: baseline chloride transport of less than 10% of wild-type CFTR and an increase in chloride transport of less than 10% over baseline following the addition of TEZ, IVA, or TEZ-IVA in the assay. Clinical severity on a population basis was determining using The Clinical and Functional Translation of CFTR (CFTR2)⁶⁷ patient registry. Patients with these mutations on 1 allele and F508del on the other allele exhibited evidence of clinical severity as defined as an average sweat chloride level of greater than 86 mmol/L and the prevalence of pancreatic insufficiency greater than 50%.⁵ A complete list of minimal function mutations is provided in Table 13.

Patients were also required to have stable CF disease in the opinion of the investigator and a ppFEV₁ of between 40% and 90% at the time of screening.⁵ The trials excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus. Patients were also considered ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before their first dose of the study drug.³⁴ Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.³⁴

Table 13: Minimal Function Mutations in Study 102

IVA = ivacaftor; PI = pancreatic insufficiency; SwCl = sweat chloride; TEZ = tezacaftor; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Clinical Study Report.⁵

Patients With F/F Genotype: Patients aged 12 years and older were eligible for inclusion in Study 103 and Study 109 if they were homozygous for the F508del mutation in the CFTR gene and had a confirmed diagnosis of CF (determined by the investigator). Patients were also required to have stable CF disease in the opinion of the investigator and a ppFEV₁ of between 40% and 90% at the time of screening.^6,10 The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus.^6,10 Patients were also considered ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before their first dose of TEZ-IVA in the run-in period.^6,10 Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.^6,10

Patients With F/G and F/RF Genotypes: Patients aged 12 years and older were eligible for inclusion in Study 104 if they were heterozygous for the F508del mutation and either a gating mutation (F/G) or a residual function mutation (F/RF) in a jurisdiction where regulatory authorities had approved treatment with IVA and/or TEZ-IVA for their genotype and age group.¹¹ Table 14 provides a summary of the gating mutations and residual function mutations.

Patients must have a confirmed diagnosis of CF with have stable disease (both determined based on the opinion of the investigator) and a ppFEV₁ of between 40% and 90% at the time of screening.¹¹ The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus.¹¹ Patients were also considered ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before their first dose of TEZ-IVA in the run-in period.¹¹ Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.¹¹

Table 14: Gating and Residual Function Mutations in Study 104

Source: Clinical Study Report.¹¹

Baseline and Demographic Characteristics

Patients Aged 6 to 11 Years

Placebo-Controlled Trial (Study 116; F/MF Genotype): The baseline and demographic characteristics in Study 116 were generally similar across the ELX-TEZ-IVA and placebo groups. Compared with the placebo group, a higher percentage of patients in the ELX-TEZ-IVA group had a baseline ppFEV₁ > 90% |||||||||||||||||||||||| and lower proportion had baseline ppFEV₁ < 70% ||||||||||||||||||||||||. A greater proportion of patients in the ELX-TEX-IVA group reporting prior usage of inhaled antibiotics compared with the placebo group |||||||||||||||||||||||| and a higher percentage of those in the placebo group reported prior use of a bronchodilator ||||||||||||||||||||||||||||||.⁴

Single-Arm Trial (Study 106; F/F or F/MF Genotype): The baseline and demographic characteristics in Study 106 are similar to those in Study 116, with the exception of the CFTR genotype. Study 106 enrolled patients with F/F or F/MF genotypes and Study 116 was limited to those with an F/MF genotype.³

Table 15: Summary of Baseline and Demographic Characteristics in Pediatric Studies

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; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI = lung clearance index; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation.

^aIncluded medications administered during the 56 days before the first dose of study drug in the treatment period.

Source: Clinical Study Report.^3,4

Patients Aged 12 Years and Older

Patients With F/MF Genotype: The baseline and demographic characteristics in Study 102 were similar across the ELX-TEZ-IVA and placebo groups, with the exception of a higher percentage of patients in the ELX-TEZ-IVA group reporting prior use of inhaled hypertonic saline compared with the placebo group (73.5% versus 62.6%, respectively) and a higher percentage of those in the ELX-TEZ-IVA group reported to have an infection with Pseudomonas aeruginosa within 2 years of screening (75.0% versus 70.0%, respectively).⁵ Body mass index z scores were calculated for patients less than 20 years of age at screening (mean = −0.40 [SD = 0.98] and −0.37 [SD = 0.79] in the placebo and ELX-TEZ-IVA groups, respectively).⁵

Patients With F/F Genotype: The baseline and demographic characteristics in Study 103 were generally similar across the ELX-TEZ-IVA and TEZ-IVA groups except for the prior use of CF medications and recent infection with Pseudomonas aeruginosa. A greater percentage of patients in the ELX-TEZ-IVA group of Study 103 reported prior use of azithromycin compared with the TEZ-IVA group (60.0% versus 48.1%, respectively), inhaled antibiotics (63.6% versus 53.8), bronchodilator (98.2% versus 90.4%), and inhaled corticosteroids (65.5% versus 53.8%).⁶ Conversely, prior use of inhaled hypertonic saline was greater in the TEZ-IVA group compared with the ELX-TEZ-IVA group (78.8% versus 69.1%, respectively).⁶ A greater percentage of patients in ELX-TEZ-IVA group were reported to have an infection with P. aeruginosa within 2 years of screening (70.9% versus 59.6%, respectively).⁶

The baseline and demographic characteristics in Study 109 were similar across the ELX-TEZ-IVA and TEZ-IVA groups with the exception that a greater percentage of patients in the TEZ-IVA group reported prior use of dornase alfa compared with the ELX-TEX-IVA group (81.8% versus 71.3%, respectively) and inhaled hypertonic saline (64.8% versus 58.6%).

Patients With F/G and F/RF Genotypes: Study 104 enrolled patients with either an F/G or an F/RF genotype. The percentages of patients with an F/RF genotype were 64.3% and 62.1% in the placebo and ELX-TEZ-IVA groups, respectively, and the percentages with an F/G genotype were 35.7% and 37.9% in the placebo and ELX-TEZ-IVA groups, respectively.¹¹ As shown in Table 16, data for TEZ-IVA and IVA groups are pooled into a single “control” group. The ELX-TEZ-IVA and control groups were well balanced for all baseline and demographic characteristics, with the exception of a greater percentage of patients with prior usage of inhaled antibiotics in the placebo group compared with the ELX-TEZ-IVA group (44.4% versus 37.1%, respectively.)¹¹

Interventions

Study Drugs

Patients Aged 6 to 11 Years

Placebo-Controlled Trial (Study 116; F/MF Genotype): Randomized patients received either ELX-TEZ-IVA or matching placebo tablets taken every morning and evening. Those weighing less than 30 kg received ELX 100 mg, TEZ 50 mg, and IVA 75 mg every morning plus IVA 75 mg every evening and those weighing 30 kg or more received ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening. The placebo tablets were identical in appearance to either the ELX-TEZ-IVA and IVA tablets.⁴

Single-Arm Trial (Study 106; F/F or F/MF Genotype): All patients in Part A received ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening. In Part B, those weighing less than 30 kg received ELX 100 mg, TEZ 50 mg, and IVA 75 mg every morning plus IVA 75 mg every evening and those weighing 30 kg or more received ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning plus IVA 150 mg every evening.³

Patients Aged 12 Years and Older

Patients With F/MF Genotype: Study 102 did not include a run-in period. Randomized patients received either ELX-TEZ-IVA (2 tablets for a total dose of ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning and 1 tablet of IVA 150 mg every evening) or matching placebo tablets taken every morning and evening. The placebo tablets were identical in appearance to either the ELX-TEZ-IVA and IVA tablets.

Patients With F/F Genotype: Patients in Study 103 and Study 109 underwent a 28-day open-label run-in period during which they received treatment with open-label TEZ 100 mg and IVA 150 mg once daily in the morning and IVA 150 mg once daily in the evening. Randomized patients received either ELX-TEZ-IVA (2 tablets for a total dose of ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning and 1 tablet of IVA 150 mg every evening) or continued with TEZ-IVA. As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the TEZ-IVA group also received 2 matching placebo tablets for the morning dose and those in the ELX-TEZ-IVA group received 1 matching placebo tablet to maintain blinding (i.e., both groups received 3 tablets in the morning and 1 in the evening). The placebo and active tablets were identical in appearance.

Patients With F/G and F/RF Genotypes: Patients in Study 104 underwent a 28-day open-label run-in period during which all patients with an F/RF genotype received TEZ 100 mg and IVA 150 mg once daily in the morning and IVA 150 mg once daily in the evening and those with an F/G genotype received IVA 150 mg every 12 hours. Randomized patients received either ELX-TEZ-IVA (2 tablets for a total dose of ELX 200 mg, TEZ 100 mg, and IVA 150 mg every morning and 1 tablet with IVA 150 mg every evening) or to the control group, whose members would continue with TEZ-IVA or IVA for those with F/RF and F/G genotypes, respectively.¹¹ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the control groups (TEZ-IVA or IVA) were also given 2 matching placebo tablets for the morning dose to maintain blinding and those in the ELX-TEZ-IVA group received 1 matching placebo tablet (i.e., both groups received 3 tablets in the morning and 1 in the evening). The placebo and active tablets were identical in appearance.

Table 17: Dosage Regimens for the Study Drugs

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; IVA = 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; NA = not applicable; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Clinical Study Reports.^3-6,10,11

Dose Modifications and Interruptions

The study protocols stated that no dose modifications for toxicity were permitted in the trials; however, dose interruptions were permitted for patients who met pre-specified criteria related to liver function tests and rash. For the liver function tests, administration of the study treatments was to be interrupted immediately if the patient met any of the following criteria: ALT or aspartate transaminase (AST) greater than 8 times the upper limit of normal (ULN); ALT or AST greater than 5 times the ULN for more than 2 weeks; and ALT or AST greater than 3 times the ULN, in association with total bilirubin greater than 2 times ULN and/or clinical jaundice. The potential causes of the elevated liver function tests were to be investigated and treatment was to be discontinued if subsequent ALT or AST values confirmed the initial elevations (i.e., exceeded the thresholds for treatment interruption) and no convincing alternative etiology was identified (e.g., acetaminophen use, viral hepatitis, or alcohol ingestion). If an alternative, reversible cause of elevated transaminases was identified, the study treatment could be resumed once the patient’s transaminase levels returned to baseline or to no greater than 2 times the ULN (whichever was greater). Treatment was also to be interrupted for patients who developed a generalized rash that was a grade 3 or higher AE or an SAE.

Concomitant Medications

Study participants were to remain on a stable CF treatment regimen from 28 days before the start of the run-in period through to completion of the study. Stable CF treatment regimen was defined as the current treatment regimen for CF that the patient had been receiving. Guidelines for stable treatment regimens for CF are as follows:

• Those using inhaled tobramycin or other chronically inhaled antibiotics should remain on the regimen throughout the study.

• Those who cycle onto and off of an inhaled antibiotic should continue on their prior schedule. The timing of the first dose of the study drug on the day 1 visit should be synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in the cycle onto the inhaled antibiotic.

• Those who alternate between 2 different inhaled antibiotics should remain on the same cycling schedule during the study. The timing of the first dose of study drug on the day 1 visit should be synchronized as closely as possible (e.g., not more than ± 3 days) to the first day in the cycle onto 1 of the inhaled antibiotics.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 18. These end points are further summarized in the following section. A detailed description and appraisal of the outcome measures is provided in Appendix 4.