CADTH Reimbursement Review

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

Sponsor: Vertex Pharmaceuticals (Canada) Incorporated

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

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

^aThis review focuses on patients aged 2 to 5 years.

Introduction

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

• Tablets for patients aged 6 years and older:

  • 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

• Granules for patients aged 2 to younger than 6 years:

  • ELX 100 mg, TEZ 50 mg, and IVA 75 mg (granules) and IVA 75 mg (granules)

  • ELX 80 mg, TEZ 40 mg, and IVA 60 mg (granules) and IVA 59.5 mg (granules), orally

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

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

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

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

Stakeholder Perspectives

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

Patient Input

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

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

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

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

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

Clinician Input

Input From Clinical Experts Consulted by CADTH

Unmet Needs

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

Place in Therapy

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

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

Patient Population

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

Applicability of Existing Reimbursement Criteria to Pediatric Patients

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

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

• Baseline measurements: Regarding the baseline measurements that must be completed before initiating treatment with ELX-TEZ-IVA, the clinical experts noted that the following baseline measurements that are currently recommended by CADTH would be problematic to implement, uninformative, and/or not relevant for patients aged 2 to 5 years: baseline forced expiratory volume in the first second (FEV₁) (spirometry is not performed in patients younger than 6 years); baseline frequency of pulmonary exacerbations (exacerbations can be infrequent, and it would be challenging establish a reliable baseline); and Cystic Fibrosis Questionnaire–Revised (CFQ-R) respiratory domain scores, which are not routinely obtained for patients in pediatric clinics (typically only when conducting research studies). The clinical experts noted that patients aged 2 to 5 years would have growth parameters monitored in routine clinical practice. However, it was noted that a majority of patients with CF aged 2 to 5 years do not show reductions in age-standardized BMI and that BMI percentile can fluctuate in younger patients, especially following periods of acute illness.

• Renewal criteria: Each of the end points are discussed subsequently, with reflection on the applicability of the existing CADTH criteria to the expanded patient population aged 2 to 5 years:

  • BMI and BMI z scores: The existing criterion is “no decline in BMI (BMI z score in children) at 6 months compared with the baseline BMI assessment.” The clinical experts noted that 6 months is not sufficient to accurately assess the response to treatment and that an assessment of BMI at 12 months would be more appropriate. The longer time was suggested to account for events that could temporarily reduce BMI (e.g., increased physical activity in summer months and growth spurts). It was strongly noted that discontinuation of ELX-TEZ-IVA in such patients would not be clinically appropriate.

  • Pulmonary exacerbations: The existing criterion is “a decrease in the total number of days for which the patient received treatment with oral and/or IV antibiotics for pulmonary exacerbations compared with the 6-month period prior to initiating treatment OR a decrease in the total number of pulmonary exacerbations requiring oral and/or IV antibiotics compared with the 6-month period prior to initiating treatment.” The clinical experts indicated that pulmonary exacerbations are less frequent in patients aged 2 to 5 years compared with adults and adolescents. The clinical experts suggested that the above renewal criterion would be problematic for patients aged 2 to 5 years. However, it was emphasized that patients who have not experienced a pulmonary exacerbation or those with a very low annual rate of pulmonary exacerbations would still benefit from the treatment. 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.

  • CF-related hospitalizations: The existing criterion is “decreased number of CF-related hospitalizations at 6 months compared with the 6-month period prior to initiating ELX-TEZ-IVA treatment.” The clinical experts consulted by CADTH noted that CF-related hospitalization is infrequent and highly variable in patients aged 2 to 5 years. As such, this would be very challenging to implement as a criterion for evaluate response to ELX-TEZ-IVA for the purposes of reimbursement.

• Sweat chloride (SwCl) testing: The previous CADTH recommendation did not include SwCl testing as one of the initiation or renewal conditions for ELX-TEZ-IVA. The sponsor has requested that “reduction in sweat chloride” be included as a reimbursement condition for ELX-TEZ-IVA in the current review. The pediatric clinical experts agreed with the prior input from the reviews of ELX-TEZ-IVA in patients aged 6 to 11 years and 12 years and older, noting that SwCl testing should not be used to evaluate the response to ELX-TEZ-IVA for the purposes of drug reimbursement because it is not clearly predictive of clinically important outcomes and only reflects the mechanism of action of CFTR modulators like ELX-TEZ-IVA. The clinical experts also noted that access to SwCl testing can be challenging in some jurisdictions; the timelines to receive the test results can fluctuate; and raised important concerns about the capacity of the health system to accommodate repeated SwCl testing for all patients with at least 1 F508del mutation.

Clinician Group Input

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

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

Drug Program Input

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

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

• Potential challenges with identifying objective reimbursement criteria for patients aged 2 to 5 years

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

Clinical Evidence

Systematic Review

Description of Study

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

• Part A (N = 18) consisted of a 15-day treatment period conducted to evaluate the pharmacokinetics and the safety and tolerability of ELX-TEZ-IVA.

• Part B (N = 75) consisted of a 24-week treatment period conducted to assess safety and tolerability (primary objective) and pharmacokinetics, pharmacodynamics, and efficacy (secondary objective).

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

Safety and tolerability were the primary end points in Study 111. The secondary end points were absolute change from baseline in SwCl through 24 weeks and absolute change from baseline in LCI_2.5. Changes from baseline in growth parameters (BMI, BMI z score, weight, weight z score, height, and height z score) were evaluated as additional efficacy end points, but no statistical analyses were conducted. Descriptive statistics were provided for pulmonary exacerbations and CF-related hospitalizations in Study 111. LCI_2.5 was only evaluated in patients aged at least 3 years at the time of screening (n = 50).

Efficacy Results

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

Among those patients who were assessed, treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in LCI_2.5 through 24 weeks. The within-group LS mean absolute change from baseline was –0.83 (95% CI, –1.01 to –0.66; nominal P < 0.0001). The reduction from baseline was observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). The results were similar in the F/F and F/MF genotype subgroups: the LS mean change was –0.89 (95% CI, –1.15 to –0.63) and –0.82 (95% CI, –1.06 to –0.57), respectively.

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

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

Harms Results

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

Critical Appraisal

Internal Validity

Study 111 was conducted in a manner similar to all other pivotal studies for the use of CFTR modulators in patients aged between 2 and 5 years (i.e., expansion of approval indications for Orkambi^4,5 and Kalydeco^6,7). Each of these studies was conducted in 2 parts, with Part A involving a small number of patients (n = 18 for Study 111), with a primary objective of evaluating pharmacokinetics, and Part B enrolling more patients (n = 75 for Study 111), with the primary objective of evaluating safety and tolerability. As with the other trials for CFTR modulators in patients aged 2 to 5 years, ELX-TEZ-IVA was administered in an open-label manner in Study 111, and there was no comparator group in either Part A or Part B. The limited number of secondary efficacy end points evaluated in the study were objective and unlikely to be influenced by the open-label administration of a CFTR modulator (i.e., change from baseline in SwCl concentration and change from baseline in LCI_2.5).

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

External Validity

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

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

Changes from baseline in lung function were evaluated as a secondary efficacy end point in Study 111 using LCI_2.5. This is reflective of regulatory guidance, which has noted that spirometry may not be sensitive enough to detect treatment differences in children with CF. In addition, spirometry is not typically performed in patients younger than 6 years in Canada, and FEV₁ has not been used as a clinical trial end point in any CFTR modulator studies for those younger than 6 years. LCI is used in CF clinical trials as it may be more sensitive in identifying early underlying structural deficiencies within the lungs of patients with CF that cannot be detected using spirometry.^8,9 Similar to spirometry assessments, the LCI test can be challenging to accurately perform with young children. In Study 111, the sponsor noted the LCI test was only performed on patients who were at least aged 3 years at the time of screening. Although LCI is used as an end point in clinical studies, as noted previously it is not routinely used in Canadian clinical practice, and the clinical relevance of differences in this end point have not been characterized.^9,10 The clinical experts consulted by CADTH indicated that LCI is not reliably correlated with FEV₁. A literature review conducted by CADTH found that variable correlation was observed between FEV₁ and LCI in children.

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

The 24-week study treatment periods were sufficient for observing change from baseline in SwCl and LCI_2.5 in Study 111; however, the clinical experts consulted by CADTH suggested that 24 weeks is unlikely to be enough time to observe meaningful changes in BMI for a younger patient population that is relatively healthy. In addition, the absence of a control group in Study 111 limits the ability to interpret the results of change from baseline in the growth parameters.

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

AE = adverse event; BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; LCI_2.5 = lung clearance index 2.5; NR = not reported; SAE = serious adverse event; SD = standard deviation; SwCl = sweat chloride.

Source: Sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

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

Indirect Comparisons

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

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

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

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

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

Studies Addressing Gaps in the Evidence From the Systematic Review

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

Conclusions

For patients aged 2 to 5 years, a 24-week, open-label, uncontrolled trial (Study 111 Part B; N = 75) suggested that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function (decrease in LCI_2.5 from baseline) and CF biomarkers (reduction in SwCl). Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA, as the regulatory submission is based on the extrapolation of efficacy data from the studies conducted in older patients with CF (i.e., those showing some measurable level of disease manifestations at baseline). The clinical experts consulted by CADTH noted that, given the mechanism of action and compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA would be expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. There is consensus across clinicians and patients that treatment with ELX-TEZ-IVA should be initiated as soon as possible given the clinically meaningful benefits observed in patients who can currently access the treatment. Uncertainty remains regarding the magnitude of the beneficial effect of ELX-TEZ-IVA in very young patients with CF, and future real-world evidence may help address this uncertainty.

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

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

Introduction

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

Disease Background

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

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

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

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

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

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

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

The median age of survival in Canada for a child born with CF in 2019 is estimated to be 53.4 years.¹ The Canadian Cystic Fibrosis Registry has reported an increase in the median age of death for patients with CF in Canada since the year 2000.¹ In 2019 the median age of death was 42.1 years, compared with 27.7 years in 2000, 35.1 years in 2013, and 38.9 years in 2016.^1,22,23 There is a clear unmet need for better CF therapies (refer to Patient Group Input and Clinician Input).

Standards of Therapy

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

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

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

Management of Symptoms, Complications, and Comorbidities

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

CFTR Modulators

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

• Potentiators, which function by increasing the channel-open probability of the CFTR protein at the cell surface. IVA is a CFTR potentiator.

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

Drug Under Review

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

• Tablets for patients aged 6 years and older:

  • ELX 50 mg–TEZ 25 mg–IVA 37.5 mg co-packaged with IVA 75 mg

  • ELX 100 mg–TEZ 50 mg–IVA 75 mg co-packaged with IVA 150 mg

• Granules for patients aged 2 to younger than 6 years:

  • ELX 100 mg–TEZ 50 mg–IVA 75 mg co-packaged with IVA 75 mg

  • ELX 80 mg–TEZ 40 mg–IVA 60 mg, co-packaged with IVA 59.5 mg

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

Table 3: Sponsor Requested Reimbursement Criteria

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

Source: Sponsor Summary of Clinical Evidence.

Mechanism of Action

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

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

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

Table 4: Recommended Dosage

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

Source: Product monograph.²⁹

Table 5: Recommended Dosage Adjustments

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

Source: Product monograph.²⁹

Previous CADTH Reviews

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

CADTH has previously reviewed IVA alone for the following indications: patients aged 6 years and older who have a G551D mutation in the CFTR gene; patients aged 6 years and older who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R; and patients aged 18 years and older who have an R117H mutation in the CFTR gene.^31-33 For each of these indications, the CADTH Canadian Drug Expert Committee recommended that IVA be reimbursed with conditions. LUM-IVA was previously reviewed for the treatment of CF in patients who are homozygous for the F508del mutation in the CFTR gene, and it received do not reimburse recommendations in 2016 and 2018.^34,35 CADTH was unable to recommend reimbursement for TEZ-IVA as a submission was not filed by the sponsor.³⁶

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

Table 6: Key Characteristics of CFTR Modulators

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

^aHealth Canada–approved indications.

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

Stakeholder Perspectives

Patient Group Input

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

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

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

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

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

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

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

Clinician Input

Input From Clinical Experts Consulted by CADTH

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

Unmet Needs

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

Place in Therapy

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

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

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

Patient Population

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

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

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

Applicability of Existing Reimbursement Criteria to Pediatric Patients

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

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

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

Baseline Measurements

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

• Baseline FEV₁: Spirometry is not performed in routine practice in Canada for patients younger than 6 years, and younger patients are unlikely to demonstrate any loss of lung function that can be measured using conventional pulmonary function testing.

• Baseline frequency of pulmonary exacerbations: The frequency of pulmonary exacerbations can be quite low in patients aged 2 to 5 years, and it would be challenging to establish a reliable baseline. This would be particularly challenging in situations where a young patient may reach important milestones, such as entering daycare, preschool, or school. In these cases, it could be possible to see an increase in the rate of pulmonary exacerbations, even after initiating treatment with a CFTR modulator, due to increased exposure to bacterial and/or viral infections in these settings.

• Baseline nutritional end points (i.e., weight, height, and BMI): As with the older patients, the clinical experts noted that patients aged 2 to 5 years would have growth parameters monitored in routine clinical practice. The clinical experts consulted by CADTH noted that a majority of patients with CF aged 2 to 5 years do not show reductions in age-standardized BMI. According to the CF Canada data registry online, 10.2% of all children with CF aged 2 to 17 years were underweight based on BMI percentile. The experts further noted that BMI percentile can fluctuate in younger patients, especially following periods of acute illness.

• CFQ-R: In the previous CADTH reviews of ELX-TEZ-IVA, it was noted that CFQ-R respiratory domain scores are not routinely obtained for patients in pediatric clinics (typically only when conducting research studies). The clinical experts consulted by CADTH confirmed that this remains the case in most Canadian clinics. In addition, the pediatric and caregiver versions of the CFQ-R were designed for use in those aged 6 to 13 years. Although some studies have been conducted to examine the utility of the caregiver version of the CFQ-R for evaluating health-related quality of life in children younger than 6 years, the CFQ-R remains largely a research tool for young patients and has not been applied in Canada or other international jurisdictions for evaluating response to treatment for the purposes of publicly funded drug reimbursement for CFTR modulators. Overall, the clinical experts suggested that the CFQ-R would not be appropriate as a renewal criterion for patients aged 2 to 5 and would be challenging to implement in pediatric clinical practice. No alternative health-related quality of life measure that could be readily implemented in Canadian practice was identified. As noted in the previous review of ELZ-TEZ-IVA for patients aged 6 to 11 years, CF clinics would require additional resources to administer the CFQ-R, 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 with including CFQ-R assessment in the reimbursement criteria for ELX-TEZ-IVA in pediatric patients.

Assessing Response to Treatment

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

BMI and BMI Z Scores

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

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

Pulmonary Exacerbations

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

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

CF-Related Hospitalizations

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

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

Sweat Chloride

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

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

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

Discontinuing Treatment

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

Prescribing Conditions

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

Continuation and Subsequent Renewals

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

Clinician Group Input

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

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

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

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

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

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

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

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

Drug Program Input

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

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

BMI = body mass index; CDEC = CADTH Canadian Drug Expert Committee; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; FEV₁ = forced expiratory volume in the first second; LCI_2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in the first second.

Clinical Evidence

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

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

Included Studies

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

• 1 pivotal study or RCT identified in the systematic review

• 1 ITC.

Systematic Review

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

Description of Study

Characteristics of the included study are summarized in Table 9.

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

AE = adverse event; BMI = body mass index; CF = cystic fibrosis; ELX = elexacaftor; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; IVA = ivacaftor; LCI_2.5 = lung clearance index; PK = pharmacokinetic; q.d. = every day; q.12.h = every 12 hours; TEZ = tezacaftor.

Source: Sponsor’s Summary of Clinical Evidence.

Study Design

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

Part A

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

Figure 1: Design of Part A of Study 111

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

Source: Clinical Study Report.⁴²

Part B

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

Figure 2: Design of Part B of Study 111

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

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

Source: Clinical Study Report.⁴²

Populations

Inclusion and Exclusion Criteria

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

Interventions

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

• Part A: Patients received ELX 100 mg, TEZ 50 mg, and IVA 75 mg in combination, and IVA 75 mg.

• Part B: Patients weighing least 10 kg and less than 14 kg received ELX 80 mg, TEZ 40 mg, and IVA 60 mg in combination, and IVA 59.5 mg; patients weighing at least 14 kg received the same dose as patients in Part A.

Outcomes

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

Sweat Chloride

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

Lung Clearance Index

The LCI is a multiple breath washout test that estimates the number of lung volume turnovers required to clear the lung of an inert gas.⁴⁴ The test is sensitive to changes in the small airways and may be able to detect pulmonary disease in patients with normal FEV₁.^8,45 LCI_2.5 represents the number of lung turnovers required to reduce the end tidal nitrogen concentration to 2.5% of the starting value. The LCI assessments were derived from multiple breath washout testing using nitrogen. Absolute change from baseline in LCI_2.5 was a secondary end point of Study 111.⁴²

Pulmonary Exacerbations

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

Table 10: Outcomes Summarized From Study 111

BMI = body mass index; CF = cystic fibrosis; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI_2.5 = lung clearance index; MMRM = mixed-effects model for repeated measures.

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

Source: Clinical Study Report.⁴²

Table 11: Pulmonary Exacerbation Criteria

FEV₁ = forced expiratory volume in the first second.

Source: Clinical Study Report.⁴²

CF-Related Hospitalizations

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

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

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

Adverse Events

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

Statistical Analysis

Sample Size and Power Calculation

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

Statistical Testing

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

The same MMRM structure was then applied to assess mean absolute change in LCI_2.5 from baseline through week 24 and to analyze the absolute change from baseline in weight, height, BMI, and associated z scores at week 24 (full analysis set [FAS], Part B).⁴⁶ Given that efficacy was a secondary objective of Study 111, no adjustments were made for multiplicity and all P values were considered nominal.⁴⁶

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

Multiple Testing Procedure

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

Subgroup Analyses

The absolute change in SwCl and LCI_2.5 from baseline through week 24 was analyzed in each genotype subgroup (i.e., F/F and F/MF). Similar MMRMs as specified in the Statistical Testing section were conducted for each subgroup, with genotype removed from the covariates.⁴⁶

Analysis Populations

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

Table 12: Analysis Populations of Study 111

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

Source: Sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

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

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

FAS = full analysis set; NR = not reported.

Source: Clinical Study Report.⁴²

Baseline Characteristics

The baseline characteristics outlined in Table 14 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. The mean age of the patients was 4.1 years, and over half (54.7%) of patients were female. Twenty-three (30.7%) patients had an F/F genotype, and 52 (69.3%) had an F/MF genotype. The baseline values for mean SwCl and mean LCI_2.5 were 100.7 mmol/L and 8.41, respectively.

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

BMI = body mass index; CF = cystic fibrosis; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI_2.5= lung clearance index; SD = standard deviation.

Source: Clinical Study Report.⁴²

Exposure to Study Treatments

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

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

SD = standard deviation.

Source: Clinical Study Report.⁴²

Concomitant Medications and Co-Interventions

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

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

Source: Clinical Study Report.⁴²

Efficacy

Key efficacy outcomes assessed in Study 111 included SwCl concentration, LCI_2.5, number of pulmonary exacerbations, number of CF-related hospitalizations, as well as body weight, height, BMI, and their respective z scores (Table 17). Specific outcomes are discussed in further detail in the following subsections.

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

BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; LCI_2.5 = lung clearance index; NR = not reported; SD = standard deviation.

Source: Sponsor’s Summary of Clinical Evidence.

Sweat Chloride Concentration

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

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

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

^aBaseline was taken across 71 patients.

Source: Clinical Study Report.⁴²

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

CI = confidence interval; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; LCI_2.5 = lung clearance index; NR = not reported; SD = standard deviation.

^aBaseline was taken across 51 patients.

Source: Clinical Study Report.⁴²

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

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

Source: Clinical Study Report.⁴²

Lung Clearance Index

Results for within-group change from baseline in LCI_2.5 are summarized in Table 19. LCI_2.5 was only evaluated in patients aged 3 years or older at the time of screening (n = 50). Among those patients, treatment with ELX-TEZ-IVA resulted in an improvement (reduction) in LCI_2.5 by 24 weeks: the within-group LS mean absolute change from baseline was –0.83 (95% CI, –1.01 to –0.66; nominal P < 0.0001). As shown in Figure 4, the reduction from baseline was observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). The results were similar in the F/F and F/MF genotype subgroups: LS mean change of –0.89 (95% CI, –1.15 to –0.63) and LS mean change of –0.82 (95% CI, –1.06 to –0.57), respectively.

Pulmonary Exacerbations

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

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

NR = not reported; PEx = pulmonary exacerbation.

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

Source: Clinical Study Report.⁴²

Body Weight

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

Height

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

Body Mass Index

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

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

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; LCI_2.5 = lung clearance index; LS = least squares; SE = standard error.

Source: Clinical Study Report.⁴²

CF-Related Hospitalizations

There were no CF-related hospitalizations in Study 111.

Harms

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

Adverse Events

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

Serious Adverse Events

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

Withdrawals Due to Adverse Events

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

Adverse Events of Special Interest

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

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

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

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

Source: Sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study 111 was conducted in a manner similar to all other pivotal studies for the use of CFTR modulators in patients aged between 2 and 5 years (i.e., expansion of approval indications for Orkambi^4,5 and Kalydeco^6,7). Each of these studies was conducted in 2 parts, with Part A involving a small number of patients (n = 18 for Study 111), with a primary objective of evaluating pharmacokinetics, and Part B enrolling more patients (n = 75 for Study 111), with the primary objective of evaluating safety and tolerability.

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

As with the other trials for CFTR modulators in patients aged 2 to 5 years, ELX-TEZ-IVA was administered in an open-label manner in Study 111, and there was no comparator group for either Part A or Part B. The limited number of secondary efficacy end points evaluated in the study were objective and unlikely to be influenced by the open-label administration of a CFTR modulator (i.e., change from baseline in SwCl concentration and change from baseline in LCI_2.5).

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

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

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

External Validity

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

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

Changes from baseline in lung function were evaluated as a secondary efficacy end point in Study 111 using LCI_2.5. This is reflective of regulatory guidance, which has noted that spirometry may not be sensitive enough to detect treatment differences in children with CF. In addition, spirometry is not typically performed in patients younger than 6 years in Canada, and FEV₁ has not been used as a clinical trial end point in any CFTR modulator studies for patients younger than 6 years. LCI is used in CF clinical trials as it may be more sensitive in identifying early underlying structural deficiencies within the lungs of patients with CF that cannot be detected using spirometry.^8,9 Similar to spirometry assessments, the LCI test can be challenging to accurately perform with young children. In Study 111, the sponsor noted that the LCI test was only performed on patients aged 3 years or older at the time of screening. Although LCI is used as an end point in clinical studies, it is not routinely used in Canadian clinical practice, and the clinical relevance of differences in this end point have not been characterized.^9,10 The clinical experts consulted by CADTH indicated that LCI is not reliably correlated with FEV₁. A literature review conducted by CADTH found that variable correlation was observed between FEV₁ and LCI in children.

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

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

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

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

The 24-week study treatment periods were sufficient for observing change from baseline in SwCl and LCI_2.5 in Study 111; however, the clinical experts consulted by CADTH suggested that 24 weeks is unlikely to be enough time to observe meaningful changes in BMI for a younger patient population that is relatively healthy. In addition, the absence of a control group in Study 111 limits the ability to interpret the results of change from baseline in the growth parameters.

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

Long-Term Extension Studies

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

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

Indirect Evidence

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

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

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

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

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

Description of Indirect Comparison

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

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

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

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

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

Study Selection Methods

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

• study design is a phase III trial

• population includes patients aged 6 to 11 years with F/F genotype

• interventions include ELX-TEZ-IVA, TEZ-IVA, or LUM-IVA

• comparators include TEZ-IVA, LUM-IVA, or placebo

• study duration of 24 weeks.

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

ITC Analysis Methods

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

• Study 106 was a single-arm trial, which precluded anchored comparisons using Bucher or network meta-analysis methods.

• The sponsor (Vertex Pharmaceuticals) has access to the individual patient-level data for each of the relevant comparator groups.

• The baseline characteristics were similar across all included studies.

• MMRM allows flexibility to account for missing data and aligns more closely with the original study analyses for each of the end points.

• The MMRM meta-analysis approach is consistent with the methodology used in the cross-trial comparison requested by the European Medicines Agency Paediatric Committee as part of the European Paediatric Investigation Plan (MAA Module 2.5, Section 4.7.2).

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

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

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

^aAnalyses for TEZ-IVA were conducted at 8 weeks.

Source: Sponsor’s indirect treatment comparison.⁵⁰

Results for ITC Analysis

Included Studies

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

Study Characteristics

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵⁰

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

DB = double blind; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; GLI = Global Lung Function Initiative; ITC = indirect treatment comparison; IVA = ivacaftor; LCI_2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; NA = not applicable; OL = open label; ppFEV₁ = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

^aSensitivity analysis only.

Source: Sponsor’s indirect treatment comparison.⁵⁰

Baseline Characteristics

As shown in Table 26, the baseline and demographic characteristics were generally similar across the studies included in the indirect comparisons for patients aged 6 to 11 years with an F/F genotype. For the comparisons of interest for this review (i.e., ELX-TEZ-IVA versus LUM-IVA or placebo), the baseline ppFEV₁, LCI_2.5, weight-for-age z score, and BMI-for-age z score were similar across the treatment groups, with the exception of the BMI-for-age z score, which was greater in Study 661-113B (TEZ-IVA), at 0.39 (SD = 0.90) than in the other trials (range, –0.09 [0.86] in the pooled LUM-IVA studies to 0.09 [0.96] in the pooled TEZ-IVA studies). The baseline CFQ-R respiratory domain scores were lower for the placebo (77.1) and LUM-IVA groups (78.5) than for the ELX-TEZ-IVA and TEZ-IVA groups (81.8 and 83.2, respectively).

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

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; LCI_2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; NA = not applicable; ppFEV₁ = percent predicted forced expiratory volume in the first second; SD = standard deviation; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

Source: Sponsor’s indirect treatment comparison.⁵⁰

Indirect Comparison Results

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵⁰

Critical Appraisal

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

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

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor and ivacaftor; F/F = homozygous for F508del mutation in the CFTR gene; F/MF = 1 F508del mutation and 1 minimal function mutation in the CFTR gene; F/RF = 1 F508del mutation and 1 residual function mutation in the CFTR gene; ITC = indirect treatment comparison; LCI_2.5 = lung clearance index; LUM-IVA = lumacaftor-ivacaftor; MMRM = mixed-effects model for repeated measures; ppFEV₁ = percent predicted forced expiratory volume in the first second; RCT = randomized controlled trial; SwCl = sweat chloride; TEZ-IVA = tezacaftor-ivacaftor and ivacaftor.

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

Study Selection Methods

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

• Study design is a phase III RCT.

• Population includes patients aged 12 years and older with an F/G (including 1 F508del mutation and 1 R117H mutation in the CFTR gene [F/R117H]) genotype.

• Interventions include ELX-TEZ-IVA or IVA.

• Comparators include IVA or placebo.

• Study duration is 8 weeks.

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

ITC Analysis Methods

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

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

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

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Results for ITC Analysis

Included Studies

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Study Characteristics

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

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

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Baseline Characteristics

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Indirect Comparison Results

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Critical Appraisal

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

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

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

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

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

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

Study Selection Methods

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

• Study design is a phase III RCT.

• Population includes patients aged 12 years and older with an F/RF genotype.

• Interventions include ELX-TEZ-IVA or TEZ-IVA.

• Comparators include TEZ-IVA or placebo.

• Study duration is at least 8 weeks.

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

ITC Analysis Methods

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Results for ITC Analysis

Included Studies

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Study Characteristics

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Baseline Characteristics

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Indirect Comparison Results

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

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

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

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

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

Source: Sponsor’s indirect treatment comparison.⁵¹

Critical Appraisal

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

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

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

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

Summary of ITCs

Patients Aged 6 to 11 Years

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

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

Patients Aged 12 Years and Older

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

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

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

Studies Addressing Gaps in the Systematic Review Evidence

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

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

Discussion

Summary of Available Evidence

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

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

• The disease process in patients with CF of all age groups stems from a common etiology of dysfunctional CFTR protein that is targeted by ELX-TEZ-IVA.

• The indication is the same.

• The outcome of therapy in younger age groups is likely to be comparable to that in older age groups.

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

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

Interpretation of Results

Efficacy

As previously reported in CADTH reviews of ELX-TEZ-IVA, LCI is not currently used in Canadian clinical practice to evaluate lung function in patients with CF, but it has been recommended as an end point in clinical trials conducted in younger patients.⁸ This is because spirometry may not be sensitive enough to detect treatment differences in patients who have relatively normal lung function but may still have underlying structural abnormalities in the lungs. In Study 111, ELX-TEZ-IVA demonstrated an improvement from baseline in LCI_2.5 through 24 weeks of treatment (absolute reduction = –0.83; 95% CI, –1.01 to –0.66).⁵⁶ The mean improvements from baseline were observed at all postbaseline assessments (i.e., weeks 4, 12, and 24). In previous CADTH reviews of CFTR modulators in pediatric patients (including ELX-TEZ-IVA for patients aged 6 to 11 years), the sponsor indicated that LCI is correlated with FEV₁ (which has been validated as an end point) in its ability to measure airway disease. CADTH’s review of the literature found that the correlation between LCI and FEV₁ was variable across studies, an observation supported by the clinical experts consulted by CADTH. Overall, the clinical experts consulted by CADTH indicated that LCI is not currently used in Canadian practice and that there is no consensus in the Canadian clinical community regarding the magnitude of improvement in LCI_2.5 that would be considered clinically relevant.

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

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

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

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

Harms

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

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

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

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

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

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

Other Considerations

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

Conclusion

For patients aged 2 to 5 years, a 24-week, open-label, uncontrolled trial (Study 111 Part B; N = 75) suggested that treatment with ELX-TEZ-IVA resulted in improvements from baseline in lung function (decrease in LCI_2.5 from baseline) and in CF biomarkers (reduction in SwCl). Study 111 was primarily designed to evaluate the safety, tolerability, and pharmacokinetics of ELX-TEZ-IVA, as the regulatory submission is based on the extrapolation of efficacy data from the studies conducted in older patients with CF (i.e., those showing some measurable level of disease manifestations at baseline). The clinical experts consulted by CADTH noted that, given its mechanism of action and the compelling efficacy data in patients aged 6 years and older, ELX-TEZ-IVA would be expected to benefit patients aged 2 to 5 years who have at least 1 508del mutation in the CFTR gene. There is consensus across clinicians and patients that treatment with ELX-TEZ-IVA should be initiated as soon as possible, given the clinically meaningful benefits observed in patients who can currently access the treatment. Uncertainty remains regarding the magnitude of the beneficial effect of ELX-TEZ-IVA in very young patients with CF, and future real-world evidence may help address this uncertainty.

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

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

References

1.The Canadian Cystic Fibrosis registry: 2019 annual data report. Toronto (ON): Cystic Fibrosis Canada; 2020: https://www.cysticfibrosis.ca/registry/2019AnnualDataReport.pdf. Accessed 2023 Nov 15.

2.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: elexacaftor / tezacaftor / ivacaftor and ivacaftor (Trikafta - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2021 Sept 16: https://cadth.ca/sites/default/files/DRR/2021/SR0673%20Trikafta%20-%20CADTH%20Final%20Rec%20Revised.pdf. Accessed 2023 Nov 15.

3.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: elexacaftor / tezacaftor / ivacaftor and ivacaftor (Trikafta - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2022 July 6: https://www.cadth.ca/sites/default/files/DRR/2022/SR0710%20Trikafta%20-%20CADTH%20Final%20Rec-meta.pdf. Accessed 2023 May 16.

4.Vertex Pharmaceuticals Incorporated. NCT02797132: Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2018: https://clinicaltrials.gov/ct2/show/NCT02797132. Accessed 2023 May 19.

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

6.Vertex Pharmaceuticals Incorporated. NCT01705145: Study of Ivacaftor in Cystic Fibrosis Subjects 2 Through 5 Years of Age With a CFTR Gating Mutation. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2016: https://clinicaltrials.gov/ct2/show/study/NCT01705145. Accessed 2023 May 19.

7.Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4(2):107-115. PubMed

8.Report of the workshop on endpoints for cystic fibrosis clinical trials. Amsterdam (NL): European Medicines Agency; 2012: https://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/12/WC500136159.pdf. Accessed 2023 Nov 15.

9.Committee for Medicinal Products for Human Use. Assessment report variation: Orkambi (ivacaftor/lumacaftor). (European public assessment report). Amsterdam (NL): European Medicines Agency; 2017: https://www.ema.europa.eu/en/documents/variation-report/orkambi-epar-assessment-report-variation_en.pdf. Accessed 2023 Nov 15.

10.CADTH Common Drug Review Clinical Review Report: lumacaftor/ivacaftor (Orkambi - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2018 Oct: https://www.cadth.ca/sites/default/files/cdr/clinical/SR0559_Orkambi_CL_Report.pdf. Accessed 2023 Nov 15.

11.Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001. PubMed

12.Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016;27(3):424-433. PubMed

13.Lukacs GL, Verkman AS. CFTR: folding, misfolding and correcting the DeltaF508 conformational defect. Trends Mol Med. 2012;18(2):81-91. PubMed

14.Okiyoneda T, Barriere H, Bagdany M, et al. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science. 2010;329(5993):805-810. PubMed

15.Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-969. PubMed

16.Cogen J, Emerson J, Sanders DB, et al. Risk factors for lung function decline in a large cohort of young cystic fibrosis patients. Pediatr Pulmonol. 2015;50(8):763-770. PubMed

17.Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91-100. PubMed

18.Canadian consensus statement on aerosolized antibiotic use in cystic fibrosis. Toronto (ON): Cystic Fibrosis Canada; 2020: https://www.cysticfibrosis.ca/uploads/About%20Us/CFC005%20AEROSOLIZED%20ANTIBIOTIC%20_englishFinal.pdf. Accessed 2023 Nov 15.

19.Cystic Fibrosis Foundation patient registry 2019 annual data report. Bethesda (MD): Cystic Fibrosis Foundation; 2020.

20.Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. 2001;153(4):345-352. PubMed

21.Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol. 1988;41(6):583-591. PubMed

22.The Canadian Cystic Fibrosis registry: 2013 annual report. Toronto (ON): Cystic Fibrosis Canada; 2015: https://www.cysticfibrosis.ca/uploads/cf%20care/Canadian-CF-Registry-2013-FINAL.pdf. Accessed 2023 Nov 15.

23.The Canadian Cystic Fibrosis registry: 2016 annual data report. Toronto (ON): Cystic Fibrosis Canada; 2017: https://www.cysticfibrosis.ca/registry/2016AnnualDataReport.pdf. Accessed 2023 Nov 15.

24.Mogayzel PJ, Jr., Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689. PubMed

25.Flume PA, Mogayzel PJ, Jr., Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802-808. PubMed

26.Center for Drug Evaluation and Research. Multi-Disciplinary Review. Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor tablets). Company: Vertex Pharmaceuticals Incorporated. Application No.: 212273. Approval date: 10/21/2019 (FDA approval package). Rockville (MD): U.S. Food and Drug Administration (FDA); 2019: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212273Orig1s000MultidisciplineR.pdf. Accessed 2023 Nov 15.

27.INESSS. Trikafta - Reimbursement Recommendation. 2022 Aug 5. https://www.inesss.qc.ca/en/themes/medicaments/drug-products-undergoing-evaluation-and-evaluated/extract-notice-to-the-minister/trikafta-fibrose-kystique-6104.html Accessed 2023 Nov 15.

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

29.Trikafta®: elexacaftor tezacaftor/ivacaftor tablets and ivacaftor tablets, oral 100 mg/50 mg/75 mg and 150 mg [product monograph]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2020 Nov 11.

30.Center for Drug Evaluation and Research. Label. Trikafta (elexacaftor, tezacaftor and ivacaftor tablets; ivacaftor tablets). Company: Vertex Pharmaceuticals Incorporated. Application No.: 212273. Approval date: 10/21/2019 (FDA approval package). Rockville (MD): U.S. Food and Drug Administration (FDA); 2020: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212273s000lbl.pdf. Accessed 2023 Nov 15.

31.CADTH Canadian Drug Expert Committee (CDEC) final recommendation: ivacaftor (Kalydeco - Vertex Pharmaceuticals [Canada] Incorporated). Ottawa (ON): CADTH; 2013 Mar 22: https://www.cadth.ca/sites/default/files/cdr/complete/cdr_complete_Kalydeco_March-25-13_e.pdf. Accessed 2023 Nov 15.

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

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

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

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

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

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

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

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

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

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

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

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

44.Subbarao P, Milla C, Aurora P, et al. Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report. Ann Am Thorac Soc. 2015;12(6):932-939. PubMed

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

64.Vertex response to March 10, 2021 request for additional information regarding Trikafta CADTH review [internal additional sponsor's information]. Toronto (ON): Vertex Pharmaceuticals (Canada) Incorporated; 2021 Mar 22.

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

Note that this appendix has not been copy-edited.

Table 39: Summary of Key Results From Pediatric Studies

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

Source: Clinical Study Reports.^39,56

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

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