CADTH Reimbursement Review

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

Sponsor: Vertex Pharmaceuticals (Canada) Incorporated

Therapeutic area: Cystic fibrosis, F508del CFTR mutation

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

Trikafta consists of a fixed-dose combination tablet containing elexacaftor (ELX) 100 mg, tezacaftor (TEZ) 50 mg, and ivacaftor (IVA) 75 mg co-packaged with a tablet containing IVA 150 mg (ELX-TEZ-IVA). ELX-TEZ-IVA is indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A deletion of phenylalanine 508 in the first nucleotide binding domain (NBD1) (F508del) is the most common mutation in the CFTR gene that results in CF.¹ The Canadian Cystic Fibrosis Registry (CCFR) reported that there were 4,344 Canadians living with CF in 2019. Of these, 87.8% of patients carried at least 1 F508del mutation (47.1% were homozygous and 40.7% were heterozygous).¹ The sponsor has requested that ELX-TEZ-IVA receive a recommendation to reimburse in accordance with the Health Canada–approved indication. ELX-TEZ-IVA was accepted as a priority review by Health Canada.

The objective of this review was to perform a systematic review of the beneficial and harmful effects of ELX-TEZ-IVA for the treatment of patients aged 12 years and older with CF who have at least 1 F508del mutation in the CFTR gene.

CADTH also reviewed additional studies that did not meet the eligibility criteria of the systematic review but may address important gaps in the evidence from the pivotal and supportive randomized controlled trials (RCTs). These included 1 long-term extension phase study (Study 105),² 1 indirect comparison submitted by the sponsor,³ 2 observational studies that evaluated the use of ELX-TEZ-IVA in patients with advanced lung disease,^4,5 and 1 study that modelled the potential impact of ELX-TEZ-IVA on CF-related morbidity and mortality.⁶

Following the issuance of the draft CADTH Canadian Drug Expert Committee (CDEC) recommendation for ELX-TEZ-IVA in July 2021, the following additional information was provided to CADTH.

• Cystic Fibrosis Canada (CF Canada) provided their Health care Advisory Council’s guidelines for the prescribing of CFTR modulators. These guidelines provide recommendations regarding the following aspects of CFTR modulators, including ELX-TEZ-IVA: treatment initiation, assessing the response to treatment, safety monitoring, and discontinuation of therapy. The guidelines have been summarized as an addendum to the CADTH report in Appendix 1.

• The sponsor provided additional unpublished data for the use of ELX-TEZ-IVA in patients who initiated treatment with a baseline percent predicted forced expiratory volume in 1 second (ppFEV₁) of 90% or greater. These data were not included in the submission to CADTH (the sponsor reported that the data only became available after the CADTH recommendation was issued). As a result of their exclusion from the pivotal trials for ELX-TEZ-IVA, this patient population has been identified as an important gap in the evidence and the information from the sponsor has been summarized as an addendum to the CADTH report in Appendix 2.

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.

Patient Input

Three patient groups, CF Canada, the Canadian Cystic Fibrosis Treatment Society and CF Get Loud, responded to CADTH’s call for patient input. Information for the CF Canada submission was based on a cross-Canada survey of patients and caregivers that was circulated through CF clinics, email, and social media (1,455 respondents). The Canadian Cystic Fibrosis Treatment Society gathered information through 1-on-one and group discussions with individuals with CF, parents, caregivers, and treating physicians. CF Get Loud gathered information from a letter campaign that received 11,364 letters from Canadians, a town hall with CF experts and leaders, and from 20 Canadians who are currently receiving treatment with ELX-TEZ-IVA.

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

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

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

Clinician Input

Input From Clinical Experts Consulted By CADTH

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

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

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

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

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

The clinical experts noted that ELX-TEZ-IVA should be prescribed and treatment monitored in an adult or pediatric CF clinic.

Clinician Group Input

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

Drug Program Input

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

• Potential need for objective criteria that can be used to evaluate response to treatment

• Potential time points that should be used when evaluating the response to treatment

• Advice on the use of ELX-TEZ-IVA in key patient populations that were excluded from the phase III studies

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

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

There were 4 double-blind, phase III, RCTs included in the CADTH systematic review: 1 placebo-controlled trial conducted in patients who were heterozygous for the F508del mutation and who had 1 minimal function mutation (F/MF) (Study 102, N = 405); 2 active-controlled trials in patients who were homozygous for the F508del mutation (F/F) (Study 103, N = 107 and Study 109, N = 107); and 1 active-controlled trial in patients who were heterozygous for the F508del mutation and a residual function mutation (F/RF) or a gating mutation (F/G) (Study 104, N = 259).

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

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

Efficacy Results

Patients With F/MF Genotype (Study 102)

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

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

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

Treatment with ELX-TEZ-IVA was associated with a statistically significant and clinically meaningful improvement in Cystic Fibrosis Questionnaire–Revised (Respiratory Domain) (CFQ-R [RD]) score from baseline compared with placebo through 24 weeks (LSMD = 20.2; 95% CI, 17.5 to 23.0).

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

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

Patients With F/F Genotype (Study 103 and Study 109)

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

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

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

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

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

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

Patients With F/G and F/RF Genotypes (Study 104)

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

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

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

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

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

Harms Results

Patients With F/MF Genotype (Study 102)

The overall percentage of patients who experienced at least 1 AE was 96.0% in the placebo group and 93.1% in the ELX-TEZ-IVA group. The percentage of patients who experienced at least 1 serious AE (SAE) was 20.9% in the placebo group and 17.3% with ELX-TEZ-IVA. Pulmonary exacerbations were the most reported SAE and were more frequent in the placebo group compared with the ELX-TEZ-IVA group (17.9% versus 6.4%). There were few other SAEs that were reported for more than 1 patient in each treatment group. There were 2 withdrawal due to AEs (WDAEs) reported in the ELX-TEZ-IVA group (1.0%) and none in the placebo group. The reasons for discontinuation from the ELX-TEZ-IVA group included portal hypertension (0.5.%) and rash (0.5%).

Patients With F/F Genotype (Study 103 and 109)

The overall percentage of patients who experienced at least 1 AE in Study 103 and Study 109 was 63.5% and 88.5% in the TEZ-IVA groups, respectively, compared with 58.2% and 92.0% in the ELX-TEZ-IVA groups, respectively. The percentage of patients who experienced at least 1 SAE was 15.9% in the TEZ-IVA group compared with 5.7% in the ELX-TEZ-IVA group of Study 109. The difference between the groups was due to a greater percentage of patients in the TEZ-IVA group who experienced a pulmonary exacerbation compared with the ELX-TEZ-IVA group (11.4% versus 1.1%). SAEs were rare in the 4-week Study 103 and only reported for 1 patient in the TEZ-IVA group (pulmonary exacerbation) and 2 patients in the ELX-TEZ-IVA group (pulmonary exacerbation and rash) (1.9% versus 3.6%). There were no WDAEs reported in either the TEZ-IVA or ELX-TEZ-IVA groups in Study 103. In Study 109, WDAEs were reported for 2 patients (2.3%) in the TEZ-IVA group (compulsive disorder and psychotic disorder) and 1 patient (1.1%) in the ELX-TEZ-IVA group (anxiety and depression).

Patients With F/G and F/RF Genotypes (Study 104)

The overall percentage of patients who experienced at least 1 AE was 66.7% in the ELX-TEZ-IVA group and 65.9% in the control group. The percentage of patients who experienced at least 1 SAE was 8.7% in the control group compared with 3.8% in the ELX-TEZ-IVA group. The difference between the groups was due to a greater percentage of patients in the control group who experienced a pulmonary exacerbation that was classified as an SAE compared with the ELX-TEZ-IVA group (5.6% versus 1.5%). There were 2 WDAEs from the control group (1.6%; pulmonary exacerbation and anxiety and depression) and 1 in the ELX-TEZ-IVA group (0.8%; elevated alanine transaminase [ALT] and aspartate transaminase [AST] levels).

Critical Appraisal

Randomization was stratified based on relevant prognostic factors (i.e., age, sex, baseline ppFEV₁, and prior CFTR modulator usage [in Study 104]).^7-10 Baseline and demographic characteristics were generally well-balanced across the treatment groups in each of the included studies. Study treatments were administered in a double-blind manner with all groups issued the same number of tablets each day. The AE profile of ELX-TEZ-IVA and the comparators was unlikely to compromise blinding in any of the included trials. There were few patients who discontinued the trials (completion rate ranged from 96.8% to 100%), although the studies were relatively short in duration which may in part explain the high percentage of patients who completed.^7-10 Adherence with the study treatments was reported to be greater than 99% across all treatment groups in the included trials.^7-10 In accordance with the study protocols, the use of concomitant medications remained stable throughout the treatment period for all treatment groups. The only exception was the lower usage of some antibiotics for pulmonary exacerbations in the ELX-TEZ-IVA group relative to the placebo group in Study 102. This difference was attributable to the efficacy of ELX-TEZ-IVA for reducing pulmonary exacerbations relative to placebo. The primary and key secondary end points were analyzed with statistical testing procedures that controlled the type I error rate and all end points within the statistical testing hierarchies were statistically significant.

The diagnostic criteria used in Study 103 and Study 109 were consistent with Canadian clinical practice for identifying patients with CF who are homozygous for the F508del-CFTR mutation. The gating and residual function (RF) mutations that were used to select patients for inclusion in Study 104 were consistent with the approved indications for TEZ-IVA and IVA in Canada.^9,12,13 There were no widely accepted criteria for defining minimal function (MF) mutations in the CFTR gene; therefore, the identification of patients with MF mutations in Study 102 relied on a novel approach designed by the sponsor (i.e., in vitro response to TEZ, IVA, or TEZ-IVA).⁷ The clinical experts consulted by CADTH noted that terms “residual function” and “minimal function” are not currently used in Canadian clinical practice. Patients with CF with more severe lung disease (e.g., ppFEV₁ < 40% at screening) or a normal ppFEV₁ at screening (≥ 90%) were excluded from the studies^7-10; therefore, the results of the included studies are primarily applicable to patients with moderate (i.e., FEV₁ = 40% to 69%) to mild (i.e., FEV₁ = 70% to 89%) lung disease. As patients with advanced lung disease are an important subgroup with a high level of unmet medical need, CADTH supplemented this review with additional evidence from observational studies to address this important gap in the RCT evidence.

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

Indirect Comparisons

Description of Studies

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

All the sponsor’s indirect comparisons were conducted using the Bucher method for continuous end points. The sponsor stated that the Bucher method was considered the most appropriate approach for these indirect comparisons because of the 4-week active treatment run-in periods in the ELX-TEZ-IVA trials. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Efficacy Results

For patients with an F/F genotype

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For patients with an F/G genotype

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For patients with an F/RF genotype

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Harms Results

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

Critical Appraisal

The primary limitation of the indirect comparisons was the difference in study design across the included studies. The ELX-TEZ-IVA studies (i.e., Study 104 and Study 109) included the open-label, 4-week, active treatment period with TEZ-IVA or IVA before randomization. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Other Relevant Evidence

Long-Term Extension Study

Study 105 is an ongoing, open-label uncontrolled trial that enrolled patients who had completed Study 102 or 103 (i.e., patients with either an F/MF or an F/F genotype). Interim results were reported for 24 weeks of follow-up for Study 102 patients and 36 weeks for Study 103 patients (data cut-off October 2019).² A total of || patients were enrolled in the extension study (n = || from Study 102 and n = || from Study 103).

Efficacy Results

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

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

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

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

Harms Results

Most patients |||||| reported at least 1 AE during the extension study. The most reported AEs were infective pulmonary exacerbation of CF ||||||, cough ||||||, oropharyngeal pain |||||| and nasopharyngitis ||||||. |||| patients |||||| stopped treatment due to AEs and 　|　 patients |||||| experienced at least 1 SAE.

Critical Appraisal

Study 105 is an ongoing, uncontrolled, open-label trial that enrolled patients who had completed Study 102 or Study 103. As this was an unblinded study, patient’s expectations of treatment could potentially have biased the reporting of subjective outcomes, such as respiratory symptoms (as measured by the CFQ-R), or harms. Extension studies are often limited by selection bias, as only patients who are tolerant to treatment and complete the parent studies are eligible to enrol. For Study 105, the risk of selection bias may be low given that only 　|　 patients |||||| out of the || randomized in the parent studies, were not enrolled or treated in the extension study. During the first 24 weeks of follow-up, discontinuation of treatment was also low (　|　 patients, ||); however, the frequency of missing data was higher for some outcomes relative to others. Issues with the generalizability of these data are the same as for the parent double-blind studies.

Observational Studies in Patients With Advanced Lung Disease

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

Irish Cohort

The retrospective chart review by O’Shea et al⁴ reported data for 14 patients who were followed for a mean duration of 4.9 months after starting ELX-TEZ-IVA. Statistically significant improvements were reported for: mean ppFEV₁ (increased from 27% [standard deviation {SD} = 7.3] at baseline to 36% [SD = 16.5] after a mean follow-up of 26 days); mean BMI (increased from 20.7 kg/m² [SD = 3.6] to 22.1 kg/m² [SD = 3.4]) and mean sweat chloride (reduced from 105 mmol/L [SD = 15] to 54 mmol/L [SD = 23]) after an average of 62 days of follow-up. The rate of infective pulmonary exacerbations requiring hospitalization was 0.28 events per month (SD = 0.17) in the 12 months before ELX-TEZ-IVA, and 0.04 events per month (SD = 0.07) during the 4.9-month follow-up period (P < 0.001).

French Cohort

The prospective cohort study by Burgel et al⁵ reported data for 245 patients who were followed for a median of 84 days after initiating treatment with ELX-TEZ-IVA. The mean change from baseline in the ppFEV₁ was 15.1% (95% CI, 13.8 to 16.4) and the change from baseline in weight was 4.2 kg (95% CI, 3.9 to 4.6), based on pooled data from 1- and 3-month assessments. The authors reported statistically significant reductions in the percentage of patients receiving long-term oxygen (43% at baseline versus 23% at 3 months), non-invasive ventilation (28% at baseline versus 20% at 3 months), and enteral tube feeding (18% at baseline versus 10% at 3 months). Data were missing for 31% of patients at the 3-month visits with no imputation in the analyses. Prior to the initiation of ELX-TEZ-IVA, 16 patients were waiting for a lung transplant and 37 were under consideration for inclusion as transplant candidates in the next 3 months (total of 53 patients; 22%). At the end of follow-up, 5 patients (2%) were on the transplant list or being considered for transplant, 2 patients had received a transplant (0.8%), and 1 patient died while waiting for transplant (0.4%).

Critical Appraisal

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

Simulation Study for Morbidity and Mortality

Stanojevic et al⁶ used a microsimulation model to estimate the impact of treatment with ELX-TEZ-IVA in eligible patients in Canada. The model forecasted an increase in median survival and a reduction in pulmonary exacerbations with the introduction of ELX-TEZ-IVA. The outcomes from these simulations are contingent on the validity of several assumptions that were required to build the model and extrapolate the impacts out to 10 years. There is uncertainty in the extrapolation of short-term effects of ELX-TEZ-IVA in a subset of patients with CF, to the broader population in the longer-term, and in the generalizability of observational data with IVA on the rate of decline in ppFEV₁ to patients treated with ELX-TEZ-IVA. Moreover, the model likely overestimates the proportion of CF patients who may receive ELX-TEZ-IVA and impact of treatment on pulmonary exacerbations.

Conclusions

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

ELX-TEZ-IVA was well tolerated in the target patient populations (i.e., at least 12 years of age with at least 1 F508del mutation). SAEs and WDAEs were rare in the included studies. The product monograph notes that elevated transaminases have been observed in patients treated with ELX-TEZ-IVA and recommends that ALT and AST be assessed before initiating treatment with ELX-TEZ-IVA, every 3 months during the first year of treatment, and annually thereafter. The clinical experts consulted by CADTH noted that the recommendations for monitoring with ELX-TEZ-IVA was not anticipated to result in a substantial increase in the number of the clinic visits for CF patients (particularly after the first year of initiating the treatment).

Introduction

Disease Background

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, large and small intestines, pancreatic and bile ducts, and the vas deferens. A deletion of phenylalanine 508 in the first nucleotide binding domain (NBD1) (F508del) is the most common mutation that results in CF.¹ The CCFR reported that there were 4,344 Canadians living with CF in 2019. Of these, 87.8% of patients carried at least 1 F508del mutation (47.1% were homozygous and 40.7% were heterozygous).¹

More than 2,090 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).¹⁴ CFTR variants within classes I to III are associated with severe CF as they are considered non-functional, while CFTR variants in classes IV to VI may retain CFTR function.^14,15 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. 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 CFTR presents a defect in channel gating, as well as being unstable and having more rapid turnover at the cell membrane.^16,17 Genotyping for mutations in the CFTR gene is routinely performed 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 development of bronchiectasis and loss of lung function.¹⁸ 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.¹⁹ Chronic endobronchial infection of the airways with bacterial pathogens, such as Pseudomonas aeruginosa (reported in 38% of Canadian CF patients in 2019)¹ is associated with a more rapid loss of lung function.²⁰ 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 death in CF patients (> 80%).^1,21

Pulmonary exacerbations are associated with lung function decline, mortality, and may require treatment with IV antibiotics and hospitalization. The Cystic Fibrosis Foundation has reported that approximately 1-third of CF patients will have at least 1 pulmonary exacerbation per year requiring IV antibiotics.²¹

Maintenance of pulmonary function (higher FEV₁) and fewer respiratory exacerbations are associated with increased survival.²² Pulmonary management of CF therefore aims to clear the airways of secretions and treat lung pathogens to minimize inflammation.

Patients who are homozygous or heterozygous for the F508del mutation typically have pancreatic, gastrointestinal, and nutritional disease as well as progressive pulmonary damage. Gastrointestinal and pancreatic involvement results in pancreatic exocrine insufficiency in most individuals with CF, causing malabsorption of fats and fat-soluble vitamins, which leads to malnutrition. Maintaining adequate nutrition is associated with improved clinical outcome and longevity for patients with CF.²³ Virtually all of these people will be pancreatic insufficient 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 Canadian CF patients (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 CCFR has reported in increase in the median age of death for patients with CF in Canada since the year 2000.¹ In 2019 the median age of death was 42.1 years compare with 27.7 years in 2000, 35.1 years in 2013, and 38.9 years in 2016.^1,24,25 There is a clear unmet need for better CF therapies (see Patient Group Input and Clinician Input).

Standards of Therapy

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

Treatments that are approved and/or available can be broadly classified as therapies used to manage symptoms, complications, and comorbidities of CF, and 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, and colistin), anti-inflammatory agents, or mucolytics (e.g., hypertonic saline and/or dornase alfa).²⁶ Nutritional treatments consist of high calorie and high fat diets and pancreatic enzyme replacement for those with pancreatic insufficiency.^26,27 Pulmonary exacerbations are treated with oral or IV antibiotics.²⁸ These treatments do not halt, but only slow, the decline in lung function and the progression of disease.

CFTR Modulators

CFTR modulators are a class of medications that aim to correct the underlying defects of the CFTR protein. The CFTR modulators that are currently marketed in Canada or other jurisdictions are classified as 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 F508del-CFTR protein, resulting in an increased expression of the F508del-CFTR protein at the cell surface. LUM, TEZ, and ELX are CFTR correctors.

Table 4 provides a summary of the CFTR modulators currently marketed or under review in Canada, the CFTR mutations and age ranges for which they been approved by Health Canada, and the reimbursement status within the public drug programs. The currently available CFTR modulators are not approved for use in all patients with at least 1 F508del mutation. The approved indications currently cover those who are homozygous for F508del mutations (Orkambi and Symdeko), heterozygous for the 508del mutation and who also have 1 of the following mutations: RF mutation (Symdeko) or a gating mutation (Kalydeco). Hence, there are 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.²⁹ In 2019, CF Canada reported that 658 individuals were receiving treatment with CFTR modulators (216 children and 442 adults). The number of patients receiving each treatment were: 146 receiving Kalydeco, 368 receiving Orkambi, and 186 receiving Symdeko.¹

Drug

Trikafta consists of a fixed-dose combination tablet containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg co-packaged with a tablet containing IVA 150 mg (ELX-TEZ-IVA). ELX-TEZ-IVA is indicated for the treatment of CF in patients aged 12 years and older who have at least 1 F508del mutation in the CFTR gene. The sponsor has requested that ELX-TEZ-IVA receive a recommendation to reimburse in accordance with the Health Canada–approved indication. ELX-TEZ-IVA was accepted as a priority review by Health Canada.

Mechanism of Action

ELX-TEZ-IVA is the third treatment specifically indicated for the treatment of CF patients who have F508del mutation(s) in the CFTR gene. This mutation is believed to be associated with misfolding of the CFTR protein, which results to 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^29-31:

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

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

Recommended Dosage

The recommended dose of ELX-TEZ-IVA is 2 combination tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg) in the morning and 1 stand-alone tablet (containing IVA 150 mg) taken in the evening. Both tablets are administered orally (swallowed whole) and should be taken approximately 12 hours apart with fat-containing food. Table 3 provides a summary of the recommended dosage adjustments for patients with hepatic insufficiency or those receiving concomitant treatment with moderate CYP3A inhibitors (e.g., fluconazole or erythromycin) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin).

Previous CADTH Reviews

This is first submission to CADTH for ELX-TEZ-IVA. CADTH has previously reviewed IVA alone for the following indications: patients 6 years of age 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.^32-34 For each of these indications, CDEC recommended that IVA be reimbursed with conditions. LUM-IVA was previously reviewed for the treatment of CF in patients who are homozygous for the F508del mutation in the CFTR gene and received do not reimburse recommendations in 2016 and 2018.^35,36 CADTH was unable to recommend reimbursement for TEZ-IVA as a submission was not filed by the sponsor.³⁷

Stakeholder Perspectives

Patient Group Input

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

Three patient groups, CF Canada, the Canadian Cystic Fibrosis Treatment Society and CF Get Loud, responded to CADTH’s call for patient input.

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. CF Canada funds basic, discovery science, and clinical research, as well as multi-disciplinary CF clinics in Canada, manages the CCFR, and maintains a network of CF advocates. Information for this submission was based on a cross-Canada survey of patients and caregivers that was circulated through CF clinics, email, and social media in January 2021. Of the 1,455 respondents, 31% were adults living with CF, 17% were a spouse or caregiver of an adult living with CF, 12% were parents of 1 or more children with CF between the ages of 12 to 17 years, and 20% were parents of 1 or more children with CF aged 11 years or younger (other respondents were excluded from the data submitted). Of the 422 adults with CF who responded, 12% were currently taking ELX-TEZ-IVA through SAP, 7% received it through a clinical trial, and all but 1 adult was still accessing it. Six percent of respondents had tried to access ELX-TEZ-IVA through SAP but were unsuccessful and 63% have not tried to access ELX-TEZ-IVA but had an indication for it. All respondents were residents of Canada. The patient input submission also includes information from the medical literature and the CCFR.

The Canadian Cystic Fibrosis Treatment Society is a not-for-profit organization whose mandate is to advocate for individuals with CF that require access to medications and medical procedures that save and improve lives. The Canadian Cystic Fibrosis Treatment Society gathered information through 1-on-one and group discussions with individuals with CF, parents, caregivers, and treating physicians.

CF Get Loud is a Canadian grassroots movement that represents a community of greater than 4,000 patients, families, and allies across Canada. Its goal is to bring hope, in the form of new life-saving medicines, to the community. CF Get Loud gathered information for this submission from a letter campaign in July 2020 that received 11,364 letters from Canadians, a town hall with CF experts and leaders in May 2020, and from 20 Canadians who are currently receiving ELX-TEZ-IVA.

Disease Experience

CF is the most common fatal genetic disease affecting children and young adults in Canada. There is no cure.

CF causes various effects on the body, but mainly affects the digestive system and lungs. The clinical progression of CF can vary greatly from person to person, even among those with the same genetic mutations. The most significant clinical impact is in the lungs, where patients have difficulty in clearing secretions, which in combination with aberrant inflammation, leads to persistent infections with cycles of inflammation that are ineffective in clearing infections. This leads to progressive scarring of the airways and a progressive and sometimes rapid decline in lung function. Patients may suffer frequent pulmonary exacerbations requiring weeks of hospitalization and IV antibiotics. Exacerbations cause rapid decline of lung function and more rapid disease progression and are associated with a greater risk of death. Other consequences of having CF include malnutrition and very low BMI, and CF-related comorbidities such as CF-related diabetes and CF-related liver disease. People living with CF are often unable to build enough body mass and may require a feeding tube for supplemental nutrition.

CF has a tremendous impact on the people who live with it, their loved ones, and on society. As the disease advances, even more time and effort are needed to manage the progressive and debilitating symptoms. Children with CF may need to quit school or go part-time and adults with CF may need to leave the work force or undertake part-time work, as may caregivers of children and adults with CF.

In addition to the decline of CF patients’ physical health, many suffer from the unseen effects of CF. These include, but are not limited to depression, anxiety, and hopelessness. The mental anguish caused by the ever-present awareness of 1’s mortality cannot be expressed in words and are often not quantified. Parents and caregivers have an overwhelming desire to do something to help their loved ones. CF Canada reported that significantly more caregivers for adults with CF (44%) said caregiving had a negative impact on their physical health than said it had a positive impact (17%). More than 2-thirds (72%) of reporting caregivers said that caregiving had a negative impact on their mental health while 11% felt that it had a positive effect.

I lost 3 friends in 3 months, while they waited for a lung transplant. It’s not right to bury your friends all under the age of 25. I’ve been to more funerals than weddings in my life. – Adult with CF

I struggled to keep up with work and university and had to spend up to 2 hours a day on exhausting, never ending, treatments. For 20 years I had about 3 hospital admissions a year. This meant I had over 60 hospital admissions, equalling more than 3 years of my life in hospital. – Adult with CF

My 11-year-old daughter spends in excess of 26 hours a week trying to stay healthy. The fight against CF is all encompassing for the family. It requires giving up 2 to 7 hours every day for her therapies. The physical therapies take a toll on my and my wife’s bodies. We both have repetitive strain injuries and arthritis in our hands, wrists, and shoulder. This commitment requires scheduling all meals and everyone’s activities around her therapies. We restrict our social activities to prevent passing on colds and flus. Each day that a control for CF is not available to her is a day that her lungs are deteriorating. All the treatments that she has access to only try to mitigate her existing health problems, none address the root cause. Without the availability of drugs that fix the basic defect in CF, our daughter and others like her will lose their valiant fight as they pass away while gasping for air. – CF parent

Experiences With Currently Available Treatments

Currently available treatments now include 4 CFTR modulator therapies that are indicated for specific CFTR mutations. IVA (Kalydeco) is the only CFTR modulator that is broadly available in Canada and treats approximately 4% of people living with CF. LUM-IVA (Orkambi) and TEZ-IVA (Symdeko) are both second generation CFTR modulators that could benefit as many as 50% of Canadians with CF, but neither is available through public payers in Canada, with the exception of Quebec, which provides access only to those who meet the strict eligibility requirements of the “patient d’exception” program. ELX-TEZ-IVA is the third generation of CFTR modulators.

The patient groups stated that individual responses to currently available CFTR modulators are highly variable and some patients report having benefited greatly from 1 or another of the earlier modulators. The Canadian Cystic Fibrosis Treatment Society reported that its founder has experienced a life-changing benefit from IVA and reported normal weight gain, improved lung function and energy levels, and reduced cough. CF Canada stated that the clinical benefits gained from IVA, LUM-IVA, or TEZ-IVA are more modest than those from ELX-TEZ-IVA. Some patients reported intolerable adverse effects with LUM-IVA in particular.

There are hundreds of therapies that aid in symptom management in the categories of antibiotics, supplemental vitamins, aerosol bronchodilators, mucolytics and pancreatic enzymes, anti-inflammatories, and steroids. Most CF patients take pancreatic enzymes, multi-vitamins, and nutritional supplements to maintain normal growth. Every day, patients with CF perform airway clearance techniques at least twice a day for about 30 to 60 minutes per session to improve the clearance of secretions from their lungs. Inhaled medications are used to open the airways while inhaled antibiotic treatments are used to control infections. The total time spent on maintaining lung health for many patients is 2 to 4 hours each day. People with CF may take more than a hundred different pills a day.

Patients frequently have periods of infection and acute inflammation called exacerbations that require a hospital stay that may be 2 to 4 weeks in duration. Patients may require IV antibiotics administered in the hospital or at home. Eventually the ongoing cycles of infection and inflammation destroy the lungs. Lung transplantation is the last recourse for people with end-stage CF.

Many of the drugs that patients need to take on a regular basis have negative adverse effects. The steroids that are used to reduce the inflammation and help patients recover from the exacerbation ultimately damage organs in the long run, contributing to the development of CF-related diabetes in 35.2% of all Canadian adults with CF. Antibiotics can cause kidney damage and total lifetime dose must be controlled; others permanently stain the teeth. Chronic use of antibiotics leads to resistance and as patients age, a need to try multiple antibiotics to find 1 that works. Because patients are on so many drugs, drug-drug interactions become difficult to manage and can interfere with optimum therapy.

A summary of the day in the life of 1 CF patient with advanced disease, during the evaluation period pre-transplant:

A typical day at home: 6:00 to 7:30 AM: IV (IV) antibiotics (2x40 minutes). They connect with my picc-line. It's rather tedious because of the many steps of the procedure: disinfect, flush with saline, connect the antibiotic, wait 40 minutes, flush with saline again, connect the next antibiotic, wait 40 minutes... etc. Very often, my Mum, Dad or sister will do this for me while I sleep in, so I can catch a bit more sleep. 8:00 to 9:00 AM: wake-up routine; asthma meds, inhaled antibiotics and enzymes, pep-mask physiotherapy, wash all the nebulizers, prep any meds that need to be reconstituted. 9:00 to 10:00 AM: breakfast; meal routine: check blood sugar, take insulin, have breakfast, morning pills (the usuals + check calendar for the ones on a variable schedule), Scandishake, after-breakfast meds, if any (check calendar). 1:00 to 2:00 PM: lunch; repeat meal routine; 2:00 to 4:00 PM: IV antibiotics (3x40 minutes), (concurrent) 3:00 to 3:10 PM: inhaled antibiotics. 4:00 to 5:00 PM: exercise. 6:00 to 7:00 PM: supper; repeat meal routine. 8:00 to 9:00 PM: clapping physiotherapy. 9:00 to 9:30 PM: bedtime routine; asthma meds, inhaled antibiotic, bedtime meds (check calendar). 10:00 to 11:30 PM: IV medications (2x40 minutes) Fairly often, my Mum, Dad or sister will do this 1 for me too so I can go to bed a bit earlier. Juggling the timing of everything is a bit of a headache, mostly because I need to space out eating with physiotherapy (doing physio or exercise tends to give me coughing fits, which makes me throw up if I've eaten too recently). On most days I've also got a limited amount of energy, so I've got to manage my activities to make sure I don't crash before the end of the day. Other regular tasks include: keeping medical appointments (1/week or more); preparing pills in advance (it saves time at meals); speaking with my pharmacist 2 to 3 × a week to order meds, arrange delivery...and…staying on top of insurance reimbursements (3 to 4 hours/month or so).

In addition to the time spent administering daily treatments, the hospitalizations and outpatient CF clinic visits interfere with school and work for both adult patients and the parents of children with CF. Many patients must travel significant distances to specialized CF clinics to receive routine care. CF Canada’s survey findings indicate that the burden for caregivers of individuals with CF to provide standard treatments is significant. Of the caregivers of adults, 40% spend 10 hours or less per week on caregiving activities, but 33% spend between 11 to 20 hours per week, and another 27% spend more than 20 hours per week on caregiving activities. Of the caregivers of children, only 17% spend less than 10 hours per week, 53% spend 11 to 20 hours, 17% spend 21 to 30 hours, and another 12% spend more than 30 hours weekly on disease management. Among caregivers of patients with CF, 60% had to take time off work, 6% to 12% had to leave full-time work for part-time work, 6% to 13% had to quit work altogether, and 2% to 4% had to take time off school or leave school altogether.

Improved Outcomes

Patients with CF are seeking treatments that can change the trajectory of the disease and improve both life expectancy and quality of life. Improved outcomes include retaining or increasing lung function, improved digestive health, better energy levels, and minimizing symptoms of CF. Patients want to avoid hospital admissions and reduce the needs for invasive medical procedures and the treatment burden of daily therapies. They also wish to avoid the adverse effects of therapies, such as osteoporosis, antimicrobial resistance, and CF-related diabetes or liver dysfunction. Patients are seeking a feeling of wellness and well-being that is not provided by the currently available treatments. Patients want treatments that will allow them to attend school and work, be physically and socially active, participate in everyday household activities, have a family, and live a “normal” life.

When asked about what their child or spouse taking ELX-TEZ-IVA could mean for them personally, caregivers said:

She would be totally independent, free to plan her life without all the physical, and medical regime restrictions she has to endure at present, because her health status would improve greatly on the drug. She would finally be able to breathe easy, to be happy and hopeful for a long enriching life. – CF parent

My son would be able to pursue his studies as an Engineer without the health decline that comes with CF. He could work, chase his dreams like anyone else. – CF parent

I wouldn’t have to think about becoming a widow before age 40.– CF spouse

It would have a positive impact all around not only for them, but also on the rest of the family- especially their mental health. – CF parent

Companion Diagnostic

Medical diagnostic laboratories typically conduct panel screens for the most common mutations in Canada. Such tests detect the mutations in approximately 98% of the Canadian CF population. If medically indicated, complete exome sequencing will identify virtually all CF mutations, and in fact, the falling costs of such tests make it even more economical to sequence than to screen panels of mutations. Both the coverage and the availability of genetic testing vary across Canada.

According to the Canadian CF Registry, genetic mutations have been identified in 99% of all patients who were seen in a CF clinic in 2019. Most individuals for whom ELX-TEZ-IVA is indicated are known by their clinic or can be queried by their clinic using the registry.

ELX-TEZ-IVA is the first CFTR modulator therapy available to treat patients with at least 1 copy of the most common CF mutation, F508del.

Experience With Drug Under Review

Two executive team members from CF Get Loud who received ELX-TEZ-IVA through SAP were able to postpone lung transplant, had normal sweat chloride levels, and felt revitalized because of treatment. Another patient with end-stage disease reported an improvement in lung function, weight gain, better sleep, and energy levels after receiving ELX-TEZ-IVA. She experienced such a marked improvement in her physical health that she was able to go running. In addition, her spouse was able to work full time, and her family’s fears for her well-being have been abated. Another adult with severe CF stated that ELX-TEZ-IVA reduced the thick, sticky mucous in her lungs, and made daily airway cleaning treatments easier and more effective. During treatment with ELX-TEZ-IVA, she has had no CF exacerbations, need for IV antibiotics or supplemental oxygen, and has shown a nearly 10% increase in lung function. Plans for a lung transplant have been put on hold. She reported that she is living life like a 38-year-old mother should be.

CF Canada provided input from 53 patients who have experience with the drug under review (28% through clinical trials and 72% through SAP). Forty-six (87%) found their experience with ELX-TEZ-IVA to be very positive, 6 (11%) found it to be positive, and 1 respondent (2%) indicated a neutral experience. There were no negative or very negative experiences reported. In terms of health outcomes, adults reported that ELX-TEZ-IVA has resulted in positive changes to their health. Specifically, it helped them gain weight (87%), increased their lung function (85%), slowed or stopped progression of symptoms (83%), resulted in fewer hospitalizations (83%), improved their energy (83%), improved mucus clearance (81%), and improved mental health (64%) among others. Compared with other treatments, 84% found that ELX-TEZ-IVA is better at improving lung function, 80% noted that it results in fewer pulmonary exacerbations, and 68% found that it is better at improving nutritional status.

My life post Trikafta is not even comparable to before. I haven’t been hospitalized or on antibiotics in over 2 years. I can work and contribute to society like a normal human. – Adult with CF

I have more energy and I am not so fatigued all the time. I barely cough or spit up mucous. I am able to do more activities and not run out of breath so quickly. My appetite has gone up and weight gain has been way easier. – Adult with CF

I did lung transplant work up. I got Trikafta under compassionate care. My lung function increased by 13%. I no longer cough, have gained 25 pounds and have a new quality of life. Put it this way I wasn’t able to walk up a flight of stairs pre-Trikafta I am now bike riding.” – Adult with CF

Seventy-nine percent of parents of children with CF who are 12 years of age or older said that their child’s experience with ELX-TEZ-IVA was very positive, and 21% said it was positive. When compared to other therapies, adult caregivers of children with CF noted that ELX-TEZ-IVA better manages improvements in lung function (93%), improvements in nutritional status (64%), and reductions in rate of pulmonary exacerbations (57%).

My son has never enjoyed better health than he has since accessing this drug. His chronic intestinal issues have cleared up (within days) and he had the longest period in his life without antibiotics. He’s gained weight and height at a rapid rate. He looks healthy.” - Parent of a child with CF

In both the adult and child populations, a number of respondents noted improved sleep and better mental health.

Almost 80% of adults and 92% of caregivers of children with CF reported ELX-TEZ-IVA to be easier to take than other medications, as it was only 3 pills and is taken twice a day. Most respondents noted that the burden of care associated with CF lessens with ELX-TEZ-IVA. After taking ELX-TEZ-IVA, adults with CF spent a median of 10 hours a week on disease management, whereas their caregivers spent a median of 4 hours. Many caregivers of adults with CF reported that treatment with ELX-TEZ-IVA reduced the number of hours spent per week on caregiving activities. The change in burden on caregivers of children was less significant.

The survey also found that 60% of adult respondents who are taking ELX-TEZ-IVA noted the drug has helped them reduce the number of medications they take, including but not limited to inhaled antibiotics (63%), chest therapies (48%), anti-inflammatories (30%), antifungals (26%), and antivirals (22%). Twenty-five percent of respondents said that their child has reduced the number of medications they take since starting ELX-TEZ-IVA (e.g., inhaled antibiotics [67%], chest therapies [33%], and antivirals [33%]).

CF Canada reported that approximately 50% of adults had experienced adverse effects, including but not limited to headache (38%), abdominal pain (29%), rash (21%), diarrhea (17%) nasal congestion (17%), runny nose (17%), and elevated liver enzymes (13%). Almost 30% of children who are taking ELX-TEZ-IVA experienced adverse effects such as headache (25%), elevated liver enzymes (50%), and rash (25%). Adult respondents and adult caregivers of children with CF found all the adverse effects associated with ELX-TEZ-IVA to be acceptable. Cataracts were the least acceptable, with only 2% of adult respondents finding them to be acceptable.

Almost 80% of adult respondents with CF and caregivers of children with CF who were not on ELX-TEZ-IVA said that there is a gap or unmet need in current therapies that ELX-TEZ-IVA could alleviate. In particular, it would give some adult respondents a more efficacious option than other CFTR modulators (61% to 63%), it could be of benefit to those who fail treatment on another CFTR modulator (37%), it would provide a treatment option for patients with specific CFTR mutations that other CFTR modulators are not indicated to treat (35% to 46%), and it would give some choice among the different CFTR modulators (35% to 41%).

Additional Information

The patient groups who provided input for this review feel that Canada has fallen behind other countries in terms of access to CFTR modulators, including the drug under review. Three other CFTR modulators have received Notices of Compliance from Health Canada over the past 8 years, but they remain widely inaccessible for most Canadians with CF, except for 1 drug that most, but not all, who may benefit from it are able to access in several provinces.

One of the biggest complaints from the patient side is requiring us to be “sick enough” to qualify for a drug. Preventive medicine is important. – Adult with CF

Unmet needs include the fact that right now my child cannot access any modulators, and preventive therapies currently are not taking away the progression of her disease. Quality of life is hugely impacted and lessened, having no modulator to improve her overall health and help her body be protected from other illnesses. – CF parent

I worry constantly. Knowing medication may be available that could better her life but she may not be able to access it is very stressful. – CF spouse

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the ELX-TEZ-IVA review, a panel of 5 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 a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion is presented below.

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 transplantation, prevent an accelerated decline in lung function over time, or reverse the course of the disease. In addition, the current standard treatments are burdensome for patients and their caregivers. Patients may not respond or may stop responding over time to the currently available treatments.

Place In Therapy

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

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.

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). Sweat chloride testing is available and reliably used to confirm the screening test. The provinces and territories have slightly different testing algorithms and CFTR mutation screening panels; however, all provinces and territories have effective processes. Almost 100% of newly diagnosed infants would have both CFTR mutations identified. Infants who are not identified via newborn screening (i.e., false negatives), are usually diagnosed before 1 year of age after the development of clinical symptoms of CF. There are clear diagnostic guidelines and 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 to demonstrate an inadequate or loss of response to prior therapies. However, from an economic perspective, it might be useful for payers to insist that patients try other treatments (e.g., inhaled antibiotics, mucolytics, anti-inflammatories, and/or chest physiotherapy) before the initiation of ELX-TEZ-IVA. It would be reasonable to require patients to complete important standard CF therapies at the same time as receiving treatment with ELX-TEZ-IVA. In clinical practice, eligible patients would be identified based on their CFTR genotype; however, there is no practical method that could be used to predict who will be most likely to respond to ELX-TEZ-IVA.

The patients with CF who are most likely to respond to treatment with ELX-TEZ-IVA are those who are homozygous or heterozygous for the F508del mutation in the CFTR gene. The patients who are most in need of treatment with ELX-TEZ-IVA include: patients with moderate to severe lung disease (e.g., ppFEV₁ ≤ 60%), patients whose BMI is less than or equal to 20 kg/m², patients with frequent pulmonary exacerbations, and those experiencing a rapid decline in FEV₁. However, it could be argued that all patients, including those with mild lung disease, could benefit from treatment when considering the long-term outcomes and goal of prevention of severe outcomes. Given the mechanism of action of the drug under review, pre-symptomatic patients should be considered for treatment.

Assessing Response to Treatment

The following end points are routinely assessed in Canadian clinical practice: FEV₁, nutrition and growth (e.g., BMI or BMI z score), hospital admissions and outpatient treatments for pulmonary exacerbations, and pulmonary exacerbation frequency per year. In addition, CF-related quality of life scales can be applied in clinical practice.

The magnitude of improvement in CF outcomes that would be considered clinically significant depends on the baseline status of the patient. For ppFEV_1, an improvement in ppFEV₁ of greater than or equal to 5% would typically be considered clinically meaningful for most patients in Canadian clinical practice. Those with a high baseline FEV₁ (e.g., younger patients) may see much smaller improvements from baseline. Similarly, patients with advanced lung disease may see smaller improvements from baseline, but even stabilization in such patients can be clinically important. FEV₁ is routinely assessed in the target population and the experts noted that evaluations could be performed 3 to 4 times per year.

The experts noted that an increase in BMI should only be viewed as a goal of therapy if the patient is malnourished. Increasing the BMI of a patient who is in the normal range or overweight may pose challenges and should not be viewed as a desirable outcome for evaluating the response to a treatment such as ELX-TEZ-IVA. For those who are malnourished, the goal of treatment would be to bring BMI up into the target range and keep it there.

Pulmonary exacerbations are important clinical events for patients with CF and are associated with long-term declines in lung function. The experts noted that the following could be considered clinically relevant with respect to pulmonary exacerbations for typical patients: a decrease in exacerbation frequency by 20% or more; or a reduction of 1 hospital admission for a pulmonary exacerbation. For assessing changes in the frequency of pulmonary exacerbations, a yearly assessment would provide the most relevant data. The clinical experts noted that younger patients typically have fewer pulmonary exacerbations, and it may be possible to demonstrate improvements from baseline in these patients.

The clinical experts noted that sweat chloride testing should be not used to evaluate the response to ELX-TEZ-IVA for the purposes of drug reimbursement.

Discontinuing Treatment

Treatment with ELX-TEZ-IVA would most likely be interrupted or discontinued because of AEs or progression to lung transplant. The most likely known AE that would result in discontinuation would be development of persistent liver enzyme abnormalities. Generally, if liver enzymes are significantly elevated (ALT or AST > 5 × upper limit of normal [ULN]), a reasonable approach would be to stop the treatment and monitor and consider a re-trial of treatment once liver enzymes normalize. If liver enzymes become abnormal again, a decision to discontinue treatment may occur, if the risk of liver enzyme abnormalities outweighs benefit of treatment.

The progression of CF toward end-stage lung disease would not be an indication to discontinue treatment in most cases nor would the need to initiate additional CF therapies because of disease progression. The clinical experts noted that ELX-TEZ-IVA is unlikely to be initiated or continued in patients who have received a lung transplant.

Prescribing Conditions

The only appropriate setting for initiation and monitoring of treatment with ELX-TEZ-IVA is 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 multi-disciplinary 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 ELX-TEZ-IVA would be prescribed and monitored in a non-specialty setting or by a non-specialty physician.

Clinician Group Input

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

Three groups of clinicians responded to CADTH’s call for input: CCFCD, CF Canada’s Accelerating Clinical Trials Network, and the Toronto Adult CF Clinic.

The CCFCD noted that there are 42 CF clinics in Canada which deliver a multi-disciplinary specialty care to individuals living with CF. The input from CCFCD notes that each clinic has a physician who serves as the medical director of the clinic. These clinic directors have special training, expertise, and experience in delivering medical care and support to those living with CF. The CCFCD gathered information for their input through personal experience gained by working with and delivering medical services to people with CF, treating people with CF who received ELX-TEZ-IVA through either clinical trials or Health Canada’s SAP. The CCFCD also noted that they conducted a review of the medical and scientific literature and reviewed the CCFR, which is a collection of patient data and other information regarding CF care and outcomes.

CF Canada’s Accelerating Clinical Trials Network (also called CF CanACT) Executive Committee operates under the auspices of CF Canada. Its purposes are to conduct clinical trials in CF and to attract research for new therapies to Canada. The physicians contributing to the input are also clinic directors of 14 clinics serving 60% of the CF population in Canada. They gathered information through the Canadian CF Registry which contains individual patient information on people living with CF, through outcomes of patients who have participated in clinical trials within the network, scientific publications, and personal experience from treating individuals with CF.

The Toronto Adult CF Clinic provides care to adult patients with CF and consists of 5 academic CF respirologists working alongside a multi-disciplinary team including specialized CF pharmacies. Their input reflects a review of published literature on CFTR modulators, clinical guidelines, and their clinical expertise. They also reviewed the outcomes of the 50 patients in their clinic who are receiving ELX-TEZ-IVA through SAP or compassionate access. The group also gathered information from the CF Canada’s CCFR.

Unmet Needs

All 3 clinician groups noted that CF is the most common fatal, genetic disease in the Canadian population and that it affects approximately 4,300 Canadians with an incidence of approximately 1 in 3,600. The clinician groups also noted that CF is a lifelong, chronic, degenerative disease that affects multiple organ systems, most importantly the lungs and digestive system.

All 3 clinician groups noted that mutations in the CF gene cause abnormalities in the CFTR protein which is responsible for the hydration of mucus secretions in the body. As a result, mucus builds up and harbours bacteria leading to chronic infections. Treatments are lifelong and to date the clinicians note that there is no cure for CF. The Toronto Adult CF Clinic noted that the available treatments are either those that treat the consequences of accumulation of the mucus or that aim to address the underlying defects of the CFTR protein. The therapies that treat the downstream consequences of CF in the lungs include chest physiotherapy and exercise to promote clearance of mucus from the airways, inhaled mucolytics, inhaled antibiotics, anti-inflammatory agents (inhaled and oral), inhaled bronchodilators, and in patients with severe lung disease, supplemental oxygen, and non-invasive ventilation. The CCFCD notes that there is a disparity in the availability of CFTR modulators which has Canadian clinicians concerned.

CF CanACT noted that as survival improves, the main cause of morbidity and mortality is lung damage due to a cycle of infection, inflammation, and lung destruction. The daily chest physiotherapy, inhaled mucolytics (e.g., hypertonic saline or dornase alfa) and chronic suppressive inhaled antibiotic therapy (e.g., tobramycin or aztreonam) were noted to improve survival as this strategy aims to slow the evolving lung damage and the resultant decline in lung function that ultimately leads to respiratory failure and death.

The groups noted that CF treatment also focuses on optimizing growth and nutrition and patients require additional pancreatic enzyme supplementation with fat-soluble vitamin supplementation which promote good nutrition and is critically linked to survival. Those living with CF are prescribed treatments which include high calorie, high fat, and high protein diets, medications, and airway clearance treatments. These treatments are initiated at the time of diagnosis and then continued throughout the patient’s life.

In addition, CCFCD noted that there are several classes of medications required for comprehensive treatment, including acute and chronic antibiotic therapies, mucolytics, bronchodilators, pancreatic enzymes, fat-soluble vitamin supplementation, insulin for people with CF-related diabetes, ursodiol for liver disease, and others. CCFCD added that physiotherapy (airway clearance) treatments are prescribed once to several times a day. They noted that most people with CF spend at least 1 or 2 hours a day on treatments and this time increases as the severity of the disease increases. Routine medical visits to the CF clinic every 3 months are recommended and the clinicians note that additional visits may be required due to illness or closer monitoring of progressing symptoms, severe disease, or pre- and post-transplant care. Hospitalizations and home IV treatments may be required for these patients as well. CCFCD added that the indirect costs to patients include lost days of work and school, travel costs, risk of employment insecurity, and decreased lifetime earning potential, non-insured personal medical expenses, and reduced participation in creative and leisure activities.

All 3 clinician inputs noted that lung transplant is required for end-stage respiratory failure and is a treatment for end-stage pulmonary disease. However, CCFCD noted that lung transplant comes with risk factors and additional treatment burden and does not address CF disease in other organ systems. The median length of survival after lung transplant was noted as 10.6 years as reported in the 2019 Registry report, indicating that it is not a cure and comes with considerable medical costs. CCFCD added that lung transplantation is only offered at 4 centres in Canada and relocating to these is required during the transplant process. These are Toronto, Montreal, Edmonton, or Vancouver.

CCFCD added that most of the current CF treatments treat the symptoms, attempt to slow down the progression of the disease, and treat acute exacerbations such as acute pulmonary infections. All 3 clinician inputs noted that CFTR modulators are medications that work on the various defects of the CFTR protein. Although not a cure, CF CanACT adds that these treatments aim to restore the function of the CFTR protein at the cell surface. The first modulator available was IVA and was effective in patients who have “gating” mutations (approximately 4% of the Canadian population). Additionally, CF CanACT noted that IVA is an extremely effective medication, restoring CFTR function with clinical benefits of increasing lung function, reducing hospitalizations, improving nutritional status, decreasing need for lung transplant, and improving survival. The Toronto Adult CF Clinic added that IVA is a potentiator and that correctors such as TEZ and LUM fix the folding defect in the CFTR protein and in combination with IVA are used to correct the protein defect seen in patients with F508del mutation. CF CanACT noted that the F508del mutation is seen in approximately 50% of Canadian patients with CF and for patients with 2 copies of the most common CF mutation, LUM-IVA and TEZ-IVA have been developed; however, these medications are not available provincially and consequently only 12% of Canadian patients with CF receive these through participation in clinical trials or third-party payers. CCFCD agreed with CF CanACT that IVA was recommended for provincial reimbursement and is generally available for qualifying patients, but access to the other mildly effective CFTR modifier medications is limited to participation in clinical trials, private insurance coverage, or very limited special provincial programs.

All 3 clinician groups noted that the most important treatment goals are to cure CF and prevent multisystem, progressive disease manifestations. However, treatments that address the basic defect and restore normal chloride transport are still a decade away. CFTR modulators are noted to provide a therapy that is as close to a cure as the CF realm has seen. The clinicians note that CFTR modulators do not correct the genetic defect but are able to correct defects in the protein structure. The most important goals of therapy are noted by the clinicians groups as follows: increasing life expectancy, preventing development of lung disease, delaying disease progression for people with established disease, improving lung function for people with established disease, reducing frequency of pulmonary exacerbations and avoiding need for admission to hospital, reducing need for lung transplantation, improving quality of life, improving nutrition and growth, reducing psychosocial issues, allowing attendance at school, university, and work, reducing burden of care and number of therapies to maintain care, and altering the disease trajectory.

All 3 clinician inputs agreed that CFTR modulator therapy is the only available treatment that treats the basic defect in CF. These treatments only treat the symptoms and complications of CF and attempt to slow down the progression of the disease. Treatments such as inhaled antibiotics and mucus-thinning agents target downstream consequences of CF lung disease and do not treat the underlying cause of the disease. CF CanACT noted that most patients eventually become refractory to inhaled antibiotics due to the development of antibiotic resistance which leads to more frequent infectious pulmonary exacerbations and eventually lung transplantation.

All 3 clinician groups noted that patients with 2 copies of F508del have a substantial unmet need as only a small minority have been able to access the LUM-IVA or TEZ-IVA combinations. In addition, response is variable and side effects can be considerable. CF CanACT notes that the drug under review will add improvements beyond the effects of LUM-IVA or TEZ-IVA combinations. CF CanACT also notes that patients with very mild or early disease have a great unmet need as current treatments do not reverse the course of disease or prevent end organ damage. The initiation of CFTR modulator therapy before irreversible damage occurs to the lungs, pancreas, and other affected organs should be a primary goal to prevent sequelae and reduce the need of other lifelong treatments such as inhaled antibiotics, inhaled mucolytics, pancreatic enzymes, and insulin which add significant treatment burden and impact quality of life.

CCFCD adds that the development of a highly effective CFTR modifier such as ELX-TEZ-IVA fills a niche in CF care where patients do not have access to another effective treatment. The group also adds that the current review is for patients aged 12 and older. If the clinical trials under way are positive, the group is hopeful that this population will be reviewed. CCFCD added that it is unclear if patients with CF with lung transplant will have non-pulmonary benefits from this medication.

The Toronto Adult CF Clinic added that triple combination therapy with 2 correctors offers a significant response in patients who have at least 1 F508del mutation, thereby providing significant clinical benefit to 90% of Canadians with CF.

All 3 clinician groups noted that patients with a single copy of the F508del paired with another CF mutation (F508del heterozygous) that is not a gating or RF mutation have the greatest unmet need as there are currently no approved CFTR modulator therapies for this population. In patients with single copy F508del and an MF mutation, clinical manifestations are severe and the drug under review is considered a breakthrough as it leads to substantial improvements in lung function and respiratory-related quality of life and markedly reduces exacerbations and hospitalization. The clinicians added that patients with 2 copies of the F508del also have substantial unmet need as only a small minority (< 12%) have been able to access the LUM-IVA or TEZ-IVA treatments; the response to these treatments is variable and often with considerable side effects. Patients with mild or early disease are noted by the clinicians as a group with an unmet need as currently available treatments do not reverse the course of the disease. Initiation of the CFTR modulator therapy before irreversible damage occurs to the organs should be a primary goal.

Place in Therapy

All 3 clinician groups note that ELX-TEZ-IVA addresses the underlying disease process and would be added to the current standard of care for CF as a first-line therapy for those patients with the appropriate CF mutations (i.e., at least 1 F508del mutation in the CFTR gene). ELX-TEZ-IVA should be added to the standard of care regardless of treatment response as it is the only therapy that targets the defect in the CFTR protein. CF CanACT noted that it would be beneficial for eligible patients who are receiving treatment with IVA, TEZ-IVA, or LUM-IVA to switch to ELX-TEZ-IVA. The Toronto Adult CF Clinic noted that there are trials under way to test which downstream therapies may be discontinued in patients on ELX-TEZ-IVA but at this point, all standard of care treatments should be continued.

The clinician groups who provided input to CADTH agreed that ELX-TEZ-IVA is not the first therapy that addresses the underlying defect of CF, rather it is an improvement on the existing CFTR modulators and is indicated for a broader CF population. CF CanACT added that the addition of ELX-TEZ-IVA would hopefully delay disease progression and thus delay the need for other therapies including lung transplant. This improvement in clinical status may lead to other standard or care treatments no longer being required.

Patient Population

All 3 clinician groups agreed that patients with CF who have at least 1 copy of the F508del mutation and are aged 12 years or older would be best suited for treatment with ELX-TEZ-IVA. The groups added that younger patients generally have less severe lung disease but can benefit from a reduction in pulmonary exacerbations which will impact the rate of lung function decline. The Toronto Adult CF Clinic added that clinical trials were conducted in adolescents and adults as well as those with mild and more severe lung disease and all subgroups responded to ELX-TEZ-IVA. The group added that patients with severe lung disease (ppFEV₁ < 40%) who received ELX-TEZ-IVA through SAP or compassionate access seem to have a meaningful clinical response. The CCFCD input added that in patients with FEV₁ greater than 90%, there are often early signs of CF lung disease present, such as bronchiectasis, mucus plugging, or early mild declines in FEV₁% which could benefit from treatment with ELX-TEZ-IVA. CF CanACT noted that all subgroups responded to ELX-TEZ-IVA in the phase III trials.

All 3 clinician groups added that eligible patients would be identified by their CF physician. Newborn screening for CF is now available across Canada and allows for early referral to CF clinics as well as confirmation of the diagnosis of CF and initiation of therapy often before the development of symptoms. The clinicians noted that genetic testing is done at the time of diagnosis and this would determine eligibility for CFTR modulator therapy. CF CanACT also added that there should be no lower limit of lung function to be eligible for treatment with ELX-TEZ-IVA. They cited that many patients with lung function less than 40% who were waiting for lung transplantation improved with ELX-TEZ-IVA to the point where they are no longer required transplantation.

All 3 clinician groups noted that any patient who does not have a CFTR mutation genotype that would respond to the medication or persons with a known allergy or other adverse reaction to this or a similar medication would not be suitable for this medication. The Toronto Adult CF Clinic added that patients with severe liver disease (Child-Pugh Class C) should not be started on ELX-TEZ-IVA. The groups also noted that it is not yet clear if ELX-TEZ-IVA would benefit patients with CF who have had a lung transplant.

The clinician groups also noted that patients who are most likely to exhibit a response to treatment with ELX-TEZ-IVA would be identified by their CF clinic care provider based on having an eligible CFTR genotype and no contraindications to this therapy. The CF CanACT added that the clinical trials have demonstrated that those patients with at least 1 F508del mutation, regardless of the second mutation, respond to this therapy, as noted by improvements in lung function, weight, and reduced pulmonary exacerbations requiring antibiotics. The Toronto Adult CF Clinic added that there is no way to predict which patients would respond to ELX-TEZ-IVA without a trial of therapy.

Assessing Response to Treatment

All 3 clinician groups noted that the outcomes used to determine whether a patient is responding to treatment in clinical practice are the same as those used in clinical trials. The outcomes are measured at every CF clinic visit and documented in the CCFR. The outcomes include FEV₁, weight, frequency of pulmonary exacerbations, hospitalizations, and lung transplantation. CF CanACT noted that at each clinic visit, patients have spirometry to measure lung function, have their weight and height measured, and provide a sputum sample for culture. They group added that the assessment by the CF physician would review their respiratory and other CF symptoms and determine the presence of pulmonary exacerbations at or between clinic visits; therefore, additional visits or testing are not required to assess response to therapy with CFTR modulators.

According to all the clinician groups, clinically meaningful response to treatment would be improvements in pulmonary function testing, weight and nutritional status, and quality of life. The groups noted that improvement in lung function, stabilization of lung function over time (i.e., prevention of the usual decline in lung function), reduction in the number of pulmonary exacerbations, reduction or stabilization of respiratory symptoms, improvement in nutritional status, and improvement in quality of life. The Toronto Adult CF Clinic added that in CF, the minimal important difference (MID) for these outcomes has not been determined; however, in this progressive disease, it is more important to demonstrate that therapies can prevent deterioration rather than just showing short-term improvements in lung function.

CCFCD noted that because of the routine clinic visits at 3-month intervals, treatment response is assessed frequently. For TEZ-IVA or LUM-IVA, a visit at 1 month after the start of therapy was also commonly used to assess for early response and potential side effects. The Toronto Adult CF Clinic noted that quarterly clinic visits are standard of care in CF and that is an appropriate frequency to assess response to CFTR modulator therapy. The clinicians from the Toronto Adult CF Clinic added that they would recommend blood work after 1 month on ELX-TEZ-IVA and every 3 months for the first year to ensure no derangements in liver function. CF CanACT added that treatment response time intervals depend on the outcome measure used. As such, they noted that improvement in lung function, stabilization of lung function over time, reduction or stabilization of respiratory symptoms, and improvement in nutritional status should be assessed in the first 3 months of therapy, every 3 to 6 months in the first year of treatment and on a yearly basis subsequently. Changes in quality of life scores should be assessed on a yearly basis.

Discontinuing Treatment

All 3 clinician groups noted that discontinuation of therapy should be considered in patients who have clinically significant adverse effects that persist and recur after stopping and re-initiating therapy. Additionally, the groups added that treatment should be discontinued if there are allergies or the development of signs of worsening liver disease. The treatment should also be discontinued if there are drug-drug interactions with medications such as rifampin or antiseizure medications.

Prescribing Conditions

Treatment of patients with CF with ELX-TEZ-IVA should be limited to CF specialists practising at CF clinics certified by CF Canada.

Additional Considerations

Clinician groups added that the impact of ELX-TEZ-IVA has been dramatic and life-altering for the patients who have received the treatment through SAP, compassionate access, or in clinical trials.

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 5.

Clinical Evidence

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

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of ELX-TEZ -IVA for the treatment of patients aged 12 years and older with CF and who have at least 1 F508del mutation in the CFTR gene.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist (https://www.cadth.ca/resources/finding-evidence/press).³⁹ Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Trikafta (ELX-TEZ-IVA). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

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

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

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist (https://www.cadth.ca/grey-matters).⁴⁰ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

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

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

Findings From the Literature

A total of 127 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Table 8 provides an overview of the studies that were summarized and appraised by CADTH for the current review of ELX-TEZ-IVA. There were 4 double-blind, phase III, RCTs included in the CADTH systematic review: 1 placebo-controlled trial conducted in patients who were heterozygous for the F508del mutation and who had 1 MF mutation (Study 102); 2 active-controlled trials in patients who were homozygous for the F508del mutation (Study 103 and Study 109); and 1 active-controlled trial in patients who were heterozygous for the F508del mutation and a RF mutation or a gating mutation (Study 104).

CADTH also reviewed additional studies that did not meet the eligibility criteria of the systematic review but may address important gaps in the evidence from the pivotal and supportive RCTs. These included 1 long-term extension phase study (Study 105),² 1 indirect comparison filed by the sponsor,³ 2 observational studies that evaluated the use of ELX-TEZ-IVA in patients with advanced lung disease,^4,5 and 1 study that modelled the potential impact of ELX-TEZ-IVA on morbidity and mortality.⁶

Patients With F/MF Genotype

Study 102 was a pivotal, phase III, multi-national, parallel group, placebo-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are heterozygous for the F508del mutation and who have a MF mutation. Study 102 was conducted at 110 sites in 13 countries, including 6 sites in Canada (n = 24). As shown in Figure 2, Study 102 consisted of a 28-day screening period, a 24-week double-blind treatment period, and a 28-day follow-up period. Patients who completed the 24-week treatment period could enrol the open-label extension study (Study 105) or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA or a matching placebo. Randomization was conducted using an interactive web response system (IWRS) and stratified by ppFEV₁ at screening (< 70% or ≥ 70%), age at screening (< 18 years or ≥ 18 years of age), and sex (male or female).

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

Figure 2: Schematic Showing the Design of Study 102

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

Source: Common Technical Document section 2.7.3.⁴⁹

Patients With F/F Genotype

Study 103 was a pivotal, phase III, multi-national, parallel group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are homozygous for the F508del mutation (F/F). The trial was conducted at 44 sites in 4 countries (Belgium, Netherlands, UK, and the US). As shown in Figure 3, Study 103 consisted of a 28-day screening period, a 28-day open-label run-in period where all patients received TEZ 100 mg and IVA 150 mg once daily in the morning and IVA 150 mg in the evening, a 4-week double-blind treatment period, and a 28-day follow-up period. Patients who completed the 4-week treatment period could enrol the open-label extension study (Study 105) or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA or to continue with TEZ 100 mg once daily and IVA every 12 hours. As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the TEZ-IVA group were also administered a matching placebo tablet for the morning dosage to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening). Randomization was conducted using an IWRS and stratified by ppFEV₁ at screening (< 70% or ≥ 70%) and age at screening (< 18 years or ≥ 18 years of age).

Figure 3: Schematic Showing the Design of Study 103

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

Source: Common Technical Document section 2.7.3.⁴⁹

Study 109 was a phase IIIb, multi-national, parallel group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are homozygous for the F508del mutation (F/F). The trial was conducted at 35 sites in 4 countries (UK, Germany, Belgium, and Australia).¹⁰ As shown in Figure 4, Study 109 consisted of a 28-day screening period, a 28-day open-label run-in period where all patients received TEZ 100 mg once daily and IVA 150 mg every 12 hours (TEZ-IVA), a 24-week double-blind treatment period, and a 28-day follow-up period.¹⁰ Patients who completed the 24-week treatment period could enrol the open-label extension study (NCT04362761)⁵¹ or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA or to continue with TEZ-IVA.¹⁰ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the TEZ-IVA group were also administered a matching placebo tablet for the morning dosage to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening).¹⁰ Randomization was stratified by ppFEV₁ and ppFEV₁ category (i.e., < 70% versus ≥ 70%) at day 14 of the TEZ-IVA run-in period; age at screening (< 18 versus ≥ 18 years of age), and whether the patient was receiving CFTR modulator treatment at screening (yes versus no).¹⁰

Figure 4: Schematic Showing the Design of Study 109

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

Source: Sponsor’s Clinical Summary.⁵⁰

Patients With F/RF or F/G Genotype

Study 104 was a phase III, multi-national, parallel group, active-controlled, randomized trial conducted to investigate the efficacy and safety of ELX-TEZ-IVA in patients with CF who are heterozygous for the F508del mutation and a gating mutation (F/G) or a residual function mutation (F/RF).⁹ This study was conducted at 96 sites in 11 countries (Australia, Belgium, Canada, France, Germany, Ireland, Italy, Spain, the Netherlands, UK, and US).⁹ As shown in Figure 5, Study 104 consisted of a 28-day screening period, a 28-day open-label run-in period where all patients with an F/RF genotype received TEZ 100 mg once daily and IVA 150 mg every 12 hours (TEZ-IVA) and those with an F/G genotype received IVA 150 mg every 12 hours; there was a 4-week double-blind treatment period, and a 28-day follow-up period.⁹ Patients who completed the 4-week treatment period could enrol the open-label extension study (VX18 to 445 to 110)⁵² or enter the 28-day safety follow-up period. Eligible patients were randomized (1:1) to receive ELX-TEZ-IVA or to the control group who would continue with TEZ-IVA or IVA as per their genotype.⁹ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the control group (TEZ-IVA or IVA) also received a matching placebo tablet for the morning dosage to maintain blinding (i.e., both groups administered 2 tablets in the morning and 1 in the evening). Randomization was conducted using an IWRS and stratified by comparator group (IVA versus TEZ-IVA), ppFEV₁ at day 14 visit, and sweat chloride at day 14 visit.⁹

Figure 5: Schematic Showing the Design of Study 104

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

Source: Common Technical Document section 2.7.3.⁴⁹

Populations

Inclusion and Exclusion Criteria

Patients With F/MF Genotype

Patients aged 12 years and older were eligible for inclusion in Study 102 if they were heterozygous for F508del and an MF mutation in the CFTR gene and had a confirmed diagnosis of CF (determined by the investigator).³⁴ To be considered “MF” the mutation was required to meet at least 1 of the following criteria:

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

• in vitro testing that supports lack of responsiveness to TEZ, IVA, or TEZ-IVA, and evidence of clinical severity on a population basis.⁷

The mutations that were classified as MF mutations based on in vitro testing met the following criteria in the sponsor’s in vitro experiments: baseline chloride transport that was less than 10% of wild-type CFTR, and an increase in chloride transport of less than 10% over baseline following the addition of TEZ, IVA, or TEZ-IVA in the assay. Clinical severity on a population basis was determining using The Clinical and Functional Translation of CFTR (CFTR2)⁵³ patient registry. Patients with these mutations on 1 allele and F508del on the other allele exhibited evidence of clinical severity as defined as: average sweat chloride greater than 86 mmol/L, and the prevalence of pancreatic insufficiency greater than 50%.⁷ The complete list of MF mutations are provided in Table 9.

Patients were also required to have stable CF disease in the opinion of the investigator and a ppFEV₁ of 40% or greater and 90% or less at the time of screening.⁷ The trials excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus. Patients were also considered to be ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before first dose of study drug.³⁴ Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.³⁴

Patients With F/F Genotype

Patients aged 12 years and older were eligible for inclusion in Study 103 and Study 109 if they were homozygous for the F508del mutation in the CFTR gene and had a confirmed diagnosis of CF (determined by the investigator). Patients were also required to have stable CF disease in the opinion of the investigator and a ppFEV₁ of 40% or greater and 90% or less at the time of screening.^8,10 The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus.^8,10 Patients were also considered to be ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before first dose of TEZ-IVA in the run-in period.^8,10 Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.^8,10

Patients With F/G and F/RF Genotypes

Patients aged 12 years and older were eligible for inclusion in Study 104 if they were heterozygous for the F508del mutation and either a gating mutation (F/G) or a residual function mutation (F/RF) and was in a region where their genotype and age group were approved by regulatory authorities for treatment with IVA and/or TEZ-IVA.⁹ Table 10 provides a summary of the gating mutations and RF mutations.

Patients must have a confirmed diagnosis of CF with have stable disease (both determined based on the opinion of the investigator) and a ppFEV₁ of 40% or greater and 90% or less at the time of screening.⁹ The trial excluded patients with a history of colonization with Burkholderia cenocepacia, Burkholderia dolosa, and/or Mycobacterium abscessus.⁹ Patients were also considered to be ineligible if they reported an acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before first dose of TEZ-IVA in the run-in period.⁹ Patients with a history of solid organ or hematological transplantation were excluded, as were patients with abnormal laboratory values (e.g., hemoglobin < 10 g/dL), abnormal liver function, or abnormal renal function.⁹

Baseline and Demographic Characteristics

Patients With F/MF Genotype

The baseline and demographic characteristics in Study 102 were similar across the ELX-TEZ-IVA and placebo groups, with the exception of a higher percentage of patients in the ELX-TEZ-IVA group reporting prior usage of inhaled hypertonic saline compared with the placebo group (73.5% versus 62.6%) and a higher percentage of those in the ELX-TEZ-IVA group reported to have infection with Pseudomonas aeruginosa within 2 years of screening (75.0% versus 70.0%).⁷ BMI z score were calculated for patients less than 20 years at screening (mean [SD] = –0.40 [0.98] and –0.37 [0.79] in the placebo and ELX-TEZ-IVA groups, respectively).⁷

Patients With F/F Genotype

The baseline and demographic characteristics in Study 103 were generally similar across the ELX-TEZ-IVA and TEZ-IVA groups except for the prior usage of CF medications and recent infection with Pseudomonas aeruginosa. A greater percentage of patients in the ELX-TEZ-IVA group of Study 103 reported prior use of azithromycin (60.0% versus 48.1%), inhaled antibiotics (63.6% versus 53.8), bronchodilator (98.2% versus 90.4%), and inhaled corticosteroids (65.5% versus 53.8%).⁸ Conversely, prior use of inhaled hypertonic saline was greater in the TEZ-IVA group compared with the ELX-TEZ-IVA group (78.8% versus 69.1%).⁸ A greater percentage of patients in ELX-TEZ-IVA group were reported to have infection with Pseudomonas aeruginosa within 2 years of screening (70.9% versus 59.6%).⁸

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

Patients With F/G and F/RF Genotypes

Study 104 enrolled patients with either an F/G or an F/RF genotype. The percentage of patients with an F/RF genotype were 64.3% and 62.1% in the placebo and ELX-TEZ-IVA groups (respectively) and the percentage with an F/G genotype were 35.7% and 37.9% in the placebo and ELX-TEZ-IVA groups (respectively).⁹ As shown in Table 11, data for TEZ-IVA and IVA groups are pooled into a single “control” group. The ELX-TEZ-IVA and control groups were well-balanced for all baseline and demographic characteristics, with the exception of a greater percentage of patients with prior usage of inhaled antibiotics in the placebo group compared with the ELX-TEZ-IVA group (44.4% versus 37.1%).⁹

Interventions

Study Drugs

Patients With F/MF Genotype

Study 102 did not include a run-in period and randomized patients received either ELX-TEZ-IVA or matching placebo tablets taken every morning and evening. The placebo tablets were identical in appearance to either the ELX-TEZ-IVA and IVA tablets.

Patients With F/F Genotype

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

Patients With F/G and F/RF Genotypes

Patients in Study 104 underwent a 28-day open-label run-in period where all patients with an F/RF genotype received TEZ 100 mg and IVA 150 once daily in the morning and IVA 150 mg once daily in the evening (TEZ-IVA) and those with an F/G genotype received IVA 150 mg every 12 hours. Randomized patients received either ELX-TEZ-IVA or, in the control group, continued with TEZ-IVA or IVA for those with F/RF and F/G genotypes, respectively.⁹ As the morning dose of ELX-TEZ-IVA is administered as 2 tablets (each containing ELX 100 mg, TEZ 50 mg, and IVA 75 mg), patients randomized to the control groups (TEZ-IVA or IVA) also administered 2 matching placebo tablets for the morning dosage to maintain blinding and those in the ELX-TEZ-IVA group administered 1 matching placebo tablet (i.e., both groups administered 3 tablets in the morning and 1 in the evening). The placebo and active tablets were identical in appearance.

Dose Modifications and Interruptions

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

Concomitant Medications

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

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

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

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

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 13. These end points are further summarized below. A detailed description and appraisal of the outcome measures is provided in Appendix 4.

Percent Predicted FEV₁

Percent predicted FEV₁ was calculated using the ratio of FEV₁ (L) to the predicted FEV₁ (L). The predicted FEV₁ was calculated using the equations of the Global Lung Function Initiative.^7,55 Absolute change from baseline was calculated as post-baseline value minus baseline value. Absolute change from baseline in ppFEV₁ was the primary end point of 3 of the included studies:

• Study 102 (versus placebo): evaluated at 4 weeks and through 24 weeks in the global European protocols (respectively)

• Study 103 (versus TEZ-IVA): evaluated at 4 weeks

• Study 104 (within-group change for ELX-TEZ-IVA); evaluated through 8 weeks^7-9

Due to the onset of the COVID-19 pandemic, patients in Study 104 could be provided with spirometry devices to perform in-home assessments of lung function (as clinic visits were not occurring). As noted in the Statistical Analysis section, sensitivity analyses were performed to investigate the impact of including and excluding the in-home spirometry measurements.

At the time of this review, a literature search did not identify an accepted MID for absolute change from baseline in ppFEV₁ for patients with CF. The clinical experts consulted by CADTH noted that an absolute improvement of 5% is typically considered to be meaningful for acute changes in ppFEV₁; however, it was noted that even stabilization of ppFEV₁ can be meaningful for patients, especially those who are at risk of rapid decline. Both the clinical experts consulted by CADTH and the clinician groups who provided input into this review noted that slowing the decline in lung function is considered to be more important than short-term increases.

Pulmonary Exacerbations

Pulmonary exacerbations were evaluated as an efficacy end point in Study 102. Pulmonary exacerbations were defined as a change in antibiotic therapy (IV, inhaled, or oral) for any 4 or more of the following signs or symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature greater than 38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in lung function by at least 10% (based on spirometry); or radiographic changes indicative of pulmonary infection. Changes in antibiotic therapy for sinopulmonary signs and/or symptoms were determined and documented by the study investigator at each study visit.⁷

Several of the criteria for sinopulmonary signs and symptoms were assessed by the investigator alone (including temperature greater than 38°C, anorexia or weight loss, sinus pain or tenderness, change in physical examination of chest, decrease in pulmonary function by 10% [based on spirometry], and radiographic changes indicative of pulmonary infection). Changes in sputum, new or increased hemoptysis, increase cough, increased dyspnea, malaise, fatigue, or lethargy, and change in sinus discharge were independently assessed by the investigator, or together with patient description, evaluated and reported by the investigator. There did not appear to have been an independent adjudication of pulmonary exacerbation events.

The following end points related to exacerbations were evaluated in Study 102:

• Rate of pulmonary exacerbations

• Rate of pulmonary exacerbations requiring hospitalization

• Rate of pulmonary exacerbations requiring IV antibiotics

• Rate of pulmonary exacerbations requiring IV antibiotics or hospitalization

• Time-to-first pulmonary exacerbation

• Time-to-first hospitalization for pulmonary exacerbation

• Time-to-first IV antibiotic therapy for pulmonary exacerbation

• Time-to-first pulmonary exacerbation requiring IV antibiotics or hospitalization

• Duration of pulmonary exacerbations

• Duration of hospitalization for pulmonary exacerbation

• Duration of IV antibiotic therapy for pulmonary exacerbation

• Duration of IV antibiotic therapy or hospitalization for pulmonary exacerbation

BMI and Body Weight

Three of the included studies evaluated changes from baseline in BMI (Studies 102, 103, and 104).^7-9 BMI was analyzed as BMI-for-age z score for patients aged 12 to 20 years in Study 102.⁷ Absolute change from baseline in BMI at 24 weeks was a key secondary end point of Study 102.⁷ Studies 103 and 104 included absolute change from baseline at 4 and 8 weeks, respectively, as an additional efficacy end point.^8,9

Cystic Fibrosis Questionnaire–Revised

The CFQ-R is a disease-specific, health-related quality of life instrument designed for patients with CF, comprised of age-appropriate versions for children aged 6 to 13 (CFQ-C), their parents (who serve as a proxy for their child; CFQ-P), and individuals aged 14 years or older (CFQ-14).⁵⁶ For children 6 to 11, the CFQ-C is interviewer-administered, and for children aged 12 and 13 year, it is self-administered.⁵⁷ The number of items and domains vary between versions with the child version including 35 items within 8 domains, parent version including 44 items and 11 domains, and the adolescent and adult version including 50 items within 12 domains (see Figure 18 on page 167).^56,57 The domains included in the adolescent and adult version are as follows: a health-related quality of life module including physical functioning, vitality, emotional functioning, social or school functioning, role functioning, body image, eating problems, treatment burden; a symptoms module that includes respiratory symptoms, digestive symptoms, and weight; and a health perception module. A 4-point Likert scale is used to measure frequency (always, often, sometimes, never), intensity (a great deal, somewhat, a little, not at all) and true-false scales (very true, somewhat true, somewhat false, very false). Items within domains are summed and standardized. Individual domain scores range from 0 to 100, with higher scores indicating better health-related quality of life.⁵⁶ The scales are designed to measure symptoms and functioning during the 2-week period before administration of the questionnaire.⁵⁸ A difference of at least 4 points in the RD score of the CFQ-R is commonly cited as the MID for patients with CF.⁵⁹

The absolute change from baseline in the CFQ-R (RD) score was the primary end point of Study 109 and a pre-specified key secondary end point in Study 102 (4 and 24 weeks) and Study 103 (4 weeks).^7-10 Absolute change from baseline in the non-respiratory domain scores were included as other efficacy end points in Study 102 (through 24 weeks), Study 103 (at 4 weeks), and Study 104 (through 8 weeks).^7-9 Due to the onset of the COVID-19 pandemic, some patients in Study 104 and Study 109 were provided with the CFQ-R to perform in-home assessments. As noted in the Statistical Analysis section, sensitivity analyses were performed to investigate the impact of including and excluding the in-home evaluation of the CFQ-R.

Treatment Satisfaction Questionnaire for Medication

The TSQM is an instrument used to assess a patient’s satisfaction with the study medication and includes 4 domains: effectiveness, side effects, convenience, and global satisfaction.^7,8 The TSQM consists of 14 items to form 4 domains: effectiveness (items 1, 2, 3), side effects (items 4, 5, 6, 7, 8), convenience (items 9, 10, 11), and global satisfaction (items 12, 13, 14).⁷ A 5- or 7-point Likert scale is used to score the domains and each domain score ranges from 0 (least satisfied) to 100 (most satisfied).^7,60 The TSQM was included as an additional efficacy end point in Study 102 (evaluated through 24 weeks) and Study 103 (evaluated at 4 weeks).^7,8 The sponsor reported that the TSQM was conducted for patients between the ages of 12 and 17 years of age to meet European regulatory commitments.^7,8

Sweat Chloride

Sweat chloride 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.⁷ All of the included studies evaluated absolute change from baseline in sweat chloride. Absolute change from baseline in sweat chloride was a key secondary end point in Study 102 (evaluated at 4 weeks and through 24 weeks), Study 103 (evaluated at 4 weeks), and Study 104 (evaluated as the within-group change for the ELX-TEZ-IVA group through 8 weeks).

Hospitalizations

Study 102 included the frequency and duration of planned CF hospitalizations and unplanned CF hospitalizations as additional end points.

• Planned hospitalizations for CF (i.e., antibiotic therapy) were assumed to be for pre-planned IV antibiotic therapy or for pre-planned treatment of CF-related clinical issues or events. Patients who received IV antibiotics for the treatment of an acute pulmonary exacerbation were not to be included in this category of planned hospitalization.

• Unplanned hospitalizations for CF were those due to reasons other than protocol-defined acute pulmonary exacerbations, including non-protocol-defined pulmonary exacerbations or other CF-related reasons (e.g., pancreatitis, distal intestinal obstruction syndrome, and so forth).

It is important to note that neither the planned nor the unplanned hospitalization end points included hospitalizations due to protocol-defined pulmonary exacerbations.⁵⁴ Pulmonary exacerbations requiring hospitalization were evaluated separately (as reported in the section on pulmonary exacerbations).

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., increased in its severity or frequency). An AE was considered serious if it met any of the following outcomes: fatal; life-threatening; 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 1 of the aforementioned outcomes.

Statistical Analysis

Power Calculations

Patients With F/MF Genotype

In Study 102, the power calculation was based on 180 patients and a 10% dropout rate in both the ELX-TEZ-IVA and placebo groups for the final analysis and 70 patients and a 5% dropout rate in both groups for the interim analysis. Assuming a within-group standard deviation of 7%, the trial was estimated to have 98% and 99% power at the interim and final analyses, respectively, to detect a treatment difference of 5% in the primary end point (absolute change from baseline in ppFEV₁ at 4 weeks) across the ELX-TEZ-IVA and placebo groups with a 2-sided alpha of 0.044 (interim analysis) and 0.01 (final analysis).

Patients With F/F Genotype

In Study 103, the power calculation was based on 100 patients and a 5% dropout rate at 4 weeks. For the primary end point of absolute change in ppFEV₁ from baseline at 4 weeks, assuming a within-group SD of 7%, this trial was estimated to have approximately 93% power to detect a difference of 5.0% for the primary end point, with a 2-sided alpha of 0.05.

In Study 109, the power calculation was based on 158 patients and a 10% dropout rate through 24 weeks. For the primary end point of absolute change in CFQ-R (RD) score from baseline through 24 weeks, assuming a dropout rate of 10% and within-group SD of 18 points, a sample size of 158 patients was estimated to have approximately 90% power to detect a difference of 10 points for the primary end point, with a 2-sided alpha of 0.05. For the key secondary end point of absolute change in ppFEV₁ from baseline through 24 weeks, assuming a dropout rate of 10% and within-group SD of 7%, a sample size of 158 patients was estimated to have approximately 98% power to detect a treatment difference of 5%, with a 2-sided alpha of 0.05.

Patients With F/G or F/RF Genotype

In Study 104, the power calculation was based on 125 patients in the ELX-TEZ-IVA group and a 10% dropout rate after 8 weeks. For the primary efficacy end point of absolute change in ppFEV₁ from baseline through 8 weeks for the ELX-TEZ-IVA group, assuming a within-group SD of 7.0%, the trial was estimated to have greater than 99% power to detect a within-group difference of 3.0% (1 sample t-test at a 2-sided significance level of 0.05).

Primary Outcomes

In Studies 102, 103, and 104, absolute changes from baseline in ppFEV₁ were calculated using a mixed-effects model for repeated measures (MMRM) approach. The models for Study 102 and Study 103 included treatment group, visit, and treatment-by-visit interaction as fixed effects, with continuous baseline ppFEV₁, age at screening (< 18 versus ≥ 18 years of age), and sex (male versus female) as covariates. The model for Study 104 included treatment group, visit, and treatment-by-visit interaction as fixed effects, with continuous baseline ppFEV₁, continuous baseline sweat chloride, and comparator group (i.e., IVA or TEZ-IVA) as covariates. Missing post-baseline values were not imputed for efficacy analyses conducted using the MMRM approach (assumed data were missing at random). Sensitivity analyses using multiple imputation were performed to assess the robustness of the primary analyses.

There were 2 statistical analysis protocols used in Study 102: the “global” protocol which specified absolute change in ppFEV₁ from baseline at 4 weeks as the primary end point; and a European protocol which specified absolute change in ppFEV₁ from baseline through week 24 as the primary end point.⁷ The analysis that was conducted “at 4 weeks” used the 4-week evaluation as the end point and the analysis that was conducted “through 24 weeks” used an average of week 4, week 8, week 12, week 16, and week 24. The sponsor noted that this was due to regulatory requirements in different jurisdictions (i.e., European regulators requested that the primary end point be evaluated through 24 weeks).⁷ As a result, the statistical testing order of the primary and first key secondary end points was reversed in the 2 protocols (i.e., the primary end point in the global protocol was the first key secondary end point in the European protocol and vice versa).⁷

Secondary and Other Efficacy End Points

The statistical evaluation of the continuous key and other secondary end points (e.g., ppFEV₁, BMI, CFQ-R, weight, and TSQM) were conducted using an MMRM model similar to the 1 used for the primary analysis, but with the additional of the baseline value for the end point of interest as a covariate. For number of pulmonary exacerbations in Study 102 (overall and those requiring IV antibiotics or hospitalization), the comparison between the ELX-TEZ-IVA and the comparator group (i.e., placebo) was conducted using regression analyses for a negative binomial distribution with sex, baseline age group (< 18 versus ≥ 18 years), and baseline ppFEV₁ severity at screening (< 70% versus ≥ 70%) as covariates. Time-to-first pulmonary exacerbation (any exacerbation and those requiring IV antibiotics or hospitalization) were analyzed using Cox regression. The sponsor’s model included a main effect for treatment, with covariates for sex, baseline age group (< 18 versus ≥ 18 years), and ppFEV₁ severity at screening (< 70% versus ≥ 70%).

Subgroup Analyses

The CADTH review protocol identified 4 subgroups of interest: severity of disease (based on baseline FEV₁), CFTR genotype (F/F, F/MF, F/G, and F/RF), prior therapy with CFTR modulator(s), and patient age. The different subgroups that were investigated in the included clinical studies are described in the section below.

Patients With F/MF Genotype

In Study 102, the following pre-planned subgroup analyses were conducted for the primary end point (i.e., absolute change in ppFEV₁): age at screening (< 18 years or ≥ 18 years); ppFEV₁ at baseline (< 70% or ≥ 70%); sex (male or female); geographic region (North America or Europe/Australia); prior use of inhaled antibiotic (yes or no); prior use of dornase alfa (yes or no); prior use of inhaled bronchodilator (yes or no); prior use of inhaled hypertonic saline (yes or no); prior use of inhaled corticosteroids (yes or no); prior use of azithromycin (yes or no); and infection with Pseudomonas aeruginosa within 2 years of the screening visit (positive or negative).⁷ An additional post hoc subgroup analysis was performed for the subset of patients with a ppFEV₁ less than 40% at baseline. The subgroup analyses were conducted using an MMRM model similar to that used in the primary analysis. There was no adjustment of multiplicity in the subgroup analyses.

Patients With F/F Genotype

In Study 103, the following pre-planned subgroup analyses were conducted for the primary end point (i.e., absolute change in ppFEV₁): age at screening (< 18 years or ≥ 18 years); ppFEV₁ at baseline (< 70% or ≥ 70%); sex (male or female); geographic region (North America or Europe); prior use of inhaled antibiotic (yes or no); prior use of dornase alfa (yes or no); prior use of inhaled bronchodilator (yes or no); prior use of inhaled hypertonic saline (yes or no); prior use of inhaled corticosteroids (yes or no); prior use of azithromycin (yes or no); and infection with Pseudomonas aeruginosa within 2 years of the screening visit (positive or negative).⁸ An additional post hoc subgroup analysis was performed based on prior exposure to CFTR modulators (treatment-naive or treatment-experienced). In Study 109, the following pre-planned subgroup analyses were conducted for the primary end point (i.e., absolute change in CFQ-R [RD]): age at screening (< 18 years or ≥ 18 years); ppFEV₁ at baseline (< 70% or ≥ 70%); sex (male or female); and CFTR modulator use at screening (yes or no).¹⁰ For both studies, the subgroup analyses were conducted using an MMRM model similar to that used in the primary analysis. There was no adjustment of multiplicity in the subgroup analyses.

Patients With F/G or F/RF Genotype

In Study 104, the following pre-planned subgroup analyses were conducted: age at screening (< 18 years or ≥ 18 years); ppFEV₁ at baseline (< 70% or ≥ 70%); sex (male or female); geographic region (North America and Europe/Australia); and comparator group (TEZ-IVA comparator or IVA comparator).⁹ The subgroup analyses were conducted using an MMRM model similar to that used in the primary analysis. There was no adjustment of multiplicity in the subgroup analyses.

Multiplicity Adjustment

Patients With F/MF Genotype

Study 102 included 2 study protocols: a global protocol and a European protocol. The timing and methods for evaluating the primary end point differed between the 2 protocols. In the global protocol, a Lan and DeMets alpha spending function was applied to control the overall type I error rate of 0.05 for the primary end point during the interim analysis and the final analysis such that an alpha of 0.01 would be preserved for the final analysis. The actual alpha at the interim analysis was determined based on the number of patients included in the analysis and since all patients had been on treatment for at least 4 weeks at the time of the analysis, the primary end point of absolute change in ppFEV₁ at 4 weeks was tested at an alpha of 0.05 during the interim analysis. Hence, the interim analysis was the primary analysis for Study 102. For the European protocol, the primary end point of absolute change in ppFEV₁ through 24 weeks was tested at an alpha of 0.05.

The key secondary end points in Study 102 were tested at an alpha of 0.05 only if the primary end point was statistically significant. A hierarchical testing procedure was used to control the type I error rate and for a test to be considered statistically significant all previous tests within the hierarchy must be statistically significant at the 0.05 level. The testing order for the key secondary end points was:

1. Absolute change in ppFEV₁ from baseline through 24 weeks (global protocol) or at 4 weeks (European protocol)

2. Number of pulmonary exacerbations through 24 weeks

3. Absolute change in sweat chloride from baseline through 24 weeks

4. Absolute change in CFQ-R (RD) from baseline through 24 weeks

5. Absolute change in BMI from baseline at 24 weeks

6. Absolute change in sweat chloride from baseline at 4 weeks

7. Absolute change in CFQ-R (RD) from baseline at 4 weeks⁷

Patients With F/F Genotype

In Study 103, the key secondary end points were formally tested at an alpha of 0.05 only if the primary end point was statistically significant. A hierarchical testing procedure was used to control the type I error rate for the multiple key secondary end points tested at an alpha of 0.05. For a test to be considered statistically significant, the previous test within the hierarchy must be statistically significant at the 0.05 level. The testing order of the key secondary end points is as follows:

1. Absolute change in sweat chloride from baseline at 4 weeks

2. Absolute change in CFQ-R RD score from baseline at 4 weeks⁸

In Study 109, a hierarchical fixed-sequence testing procedure was used to first test the primary end point and then the key secondary end point, to control the overall family-wise type I error at a 2-sided alpha of 0.05. The key secondary end point was tested only after the primary end point was determined to be statistically significant.¹⁰

Patients With F/G or F/RF Genotype

In Study 104, the key secondary end points were formally tested at an alpha of 0.05 only if the primary end point was statistically significant. A hierarchical testing procedure was used to control the overall type I error rate at an alpha of 0.05 for the primary and key secondary end points tested. For a test to be considered statistically significant within the testing hierarchy, all previous tests within the hierarchy must be statistically significant at the 0.05 level. The testing order of the key secondary end points was as follows:

1. Absolute change in sweat chloride from baseline through 8 weeks within the ELX-TEZ-IVA group

2. Absolute change in ppFEV₁ from baseline through 8 weeks for the ELX-TEZ-IVA group compared to the control group

3. Absolute change in sweat chloride from baseline through 8 weeks for the ELX-TEZ-IVA group compared to the control group⁹

Data Imputation Methods

The MMRM analyses performed in all the included studies assumed that data were missing at random, and no imputation of missing data was performed. As shown in Table 14, sensitivity analyses were performed using multiple imputation to assess the impact of missing data. Missing values were imputed starting from the first visit with missing values, for which all subsequent visits were also missing. Intermediate missing data (i.e., missing values that fell between 2 non-missing values) were assumed to be missing at random and therefore were not imputed.^7-10

Analysis Populations

The analysis sets that were used to evaluate the safety and efficacy end point in the included studies are summarized in Table 15.

Results

Patient Disposition

Patient disposition is summarized in Table 16 for Study 102 (i.e., the study that did not include a run-in period) and in Table 17 for Study 103, 104, and 109 (i.e., the studies with a run-in period).

Patients With F/MF Genotype

In Study 102, a total of 438 patients were screened for inclusion and 405 patients were randomized (7.5% failed to the meet the eligibility criteria).¹¹ Two hundred and 4 patients were randomized to the placebo group and 201 to the ELX-TEZ-IVA group. One patient in each group was randomized but never received the study drug; therefore, a total of 403 patients were included in the full analysis set for the interim and final analyses. All the patients in the placebo group and 98.5% of those in the ELX-TEZ-IVA group completed the study (overall completion rate of 99.3%). Reasons for discontinuation included AEs (n = 2) and pregnancy (n = 1). All of the patients who completed the study elected to continue in the open-label extension phase.⁷

Patients With F/F Genotype

In Study 103, a total of 118 patients were screened for inclusion and 113 were enrolled in the 28-day TEZ-IVA run-in period (4.2% failed to the meet the eligibility criteria). A total of 108 patients were randomized (56 in the ELX-TEZ-IVA group and 52 in the TEZ-IVA group). One patient in the ELX-TEZ-IVA group was randomized but never received the study drug; therefore, a total of 107 patients were included in the full analysis set. All of the patients in both the ELX-TEZ-IVA and TEZ-IVA groups completed the study (overall completion rate of 100%) and all of the patients elected to continue in the open-label extension phase.⁸

In Study 109, a total of 180 patients were screened for inclusion and 176 were enrolled in the 28-day TEZ-IVA run-in period (2.2% failed to the meet the eligibility criteria). One patient was excluded from the trial during the run-in period due to a pulmonary exacerbation. This patient was randomized to the ELX-TEZ-IVA group but discontinued before the first dose of the study treatments in the double-blind phase. Therefore, the total number of patients randomized was 176 (88 in the ELX-TEZ-IVA group and 88 in TEZ-IVA group), but only 175 patients were included in the full analysis set. The proportions of patient who completed the study were 98.9% and 97.7% in the ELX-TEZ-IVA and TEZ-IVA groups, respectively. Two patients withdrew due to AEs from TEZ-IVA group and 1 patient withdrew due to AEs from the ELX-TEZ-IVA group. All of the patients who completed the study elected to enroll in the open-label extension study.¹⁰

Patients With F/G or F/RF Genotypes

A total of 300 patients were screened for inclusion in Study 104 and 29 (9.7%) failed to the meet the eligibility criteria for the study. A total of 271 patients were enrolled in the 28-day run-in phase where they received treatment with TEZ-IVA or IVA for those with F/RF and F/G mutations, respectively. Ten patients (3.7%) withdrew during the run-in phase. The reasons for discontinuation included AEs (n = 2; 0.7%); refusal to undergo further dosing (n = 1; 0.4%); failure to meet the eligibility criteria for Study 104 (n = 1; 0.4%). The sponsor reported that of the 6 patients who discontinued for “other” reasons (as shown in Table 17), 5 patients withdrew due to the onset of the COVID-19 pandemic and 1 patient for reasons that were related to the eligibility of the study. A total of 259 patients were randomized (133 in the ELX-TEZ-IVA group and 126 in the TEZ-IVA or IVA group—referred to as the control group). One patient in the ELX-TEZ-IVA group discontinued before the first dose of the study treatments in the double-blind phase; therefore, the full analysis set included 258 patients. The proportions of patient who completed the study were 99.2% and 96.8% in the ELX-TEZ-IVA and control groups, respectively. Two patients from the control group withdrew due to AEs and 1 patient from the ELX-TEZ-IVA group withdrew due to AEs (WDAE). With the exception of 1 patient in each of the treatment groups, all the patients who completed the study elected to enroll in the open-label extension study.

Exposure to Study Treatments

Study Treatments

Patient exposure to the study drugs is summarized in Table 18.

The median treatment duration was 24 weeks in Study 102 and Study 109, 4 weeks in Study 103, and 8 weeks in Study 104.^7-10 Adherence with the study treatments was evaluated by counting the number of study drugs at each visit and was reported to be 99.2% in Study 102, 100% in Study 103, 99.8% in Study 109, and 99.6% in Study 104.^7-10

Concomitant Therapies

Prior and concomitant medications that were used by at least 20% of patients in the included studies are summarized in Table 19. The most commonly used concomitant medications included: mucolytics (inhaled sodium chloride and dornase alfa); bronchodilators (fluticasone propionate, salmeterol xinafoate, salbutamol); antibiotics (ciprofloxacin, sulfamethoxazole/trimethoprim, azithromycin, tobramycin, aztreonam lysine, colistimethate sodium); pancreatic enzymes (pancreatin and pancrelipase); vitamin supplementals (tocopherol and cholecalciferol); proton pump inhibitors (omeprazole); and bile acid (ursodeoxycholic acid).^7-10

Patients With F/MF Genotype

A larger percentage of patients in the ELX-TEZ-IVA group were using inhaled sodium chloride compared with the placebo group (81.5% versus 74.9%).⁷ Three antibiotics were more commonly used in the placebo group compared with the ELX-TEZ-IVA group: tobramycin (55.7% versus 39.0%), ciprofloxacin (35.0% versus 16.0%), and trimethoprim/sulfamethoxazole (26.1% versus 17.0%).⁷

Patients With F/F Genotype

Study 103 and Study 109 had the smallest sample sizes of the 4 included studies and showed the greatest number of imbalances in the use of concomitant medications across the treatment groups.^8,10 In Study 103, a greater percentage of patients in the ELX-TEZ-IVA group received treatment with salbutamol (65.5% versus 59.6%), azithromycin (58.2% versus 46.2%), ursodeoxycholic acid (27.3% versus 19.2%), and fluticasone propionate/salmeterol xinafoate (25.5% versus 17.3%) compared with the TEZ-IVA group.⁸ Compared with the ELX-TEZ-IVA group, a greater percentage of patients in the TEZ-IVA group received treatment with inhaled sodium chloride (82.7% versus 74.5%), fluticasone propionate (34.6% versus 29.1%), and omeprazole (28.8% versus 18.2%).⁸ In Study 109, a greater percentage of patients in the ELX-TEZ-IVA group received treatment with aztreonam lysine (25.3% versus 18.2%) and colistimethate sodium (41.4% versus 31.8%) compared with the TEZ-IVA group. Compared with the ELX-TEZ-IVA group, a greater percentage of patients in the TEZ-IVA group received treatment with dornase alfa (81.8% versus 71.3%), tobramycin (40.9% and 29.9%), cholecalciferol (31.8% versus 25.3%), and ciprofloxacin (33.0% versus 17.2%).¹⁰

Patients With F/G or F/RF Genotypes

The prior and concomitant medications used in Study 104 were well-balanced across the ELX-TEZ-IVA and the control group.⁹ As shown in Table 19, the percentage of patients using some concomitant medications was considerably lower in Study 104 compared with the other included trials. These included dornase alfa (52.7% in Study 104 versus 81.6% in Study 102, 92.5% in Study 103, and 76.6% in Study 109); inhaled sodium chloride (51.9% in Study 104 versus 78.2% in Study 102, 78.5% in Study 103, and 75.4% in Study 109); and pancreatin (51.9% in Study 104 versus 63.5% in Study 102, 65.4% in Study 103, and 93.7% in Study 109).^7-10

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below. See Appendix 3 for detailed efficacy data.

Forced Expiratory Volume in 1 Second

Patients With F/MF Genotype

Treatment with ELX-TEZ-IVA was associated with a statistically significant increase from baseline in ppFEV₁ compared with placebo at 4 weeks (13.8%; 95% CI, 12.1 to 15.4; P < 0.0001) and 24 weeks (14.3%; 95% CI, 12.7 to 15.8; P < 0.0001). As shown in Figure 6, improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were higher at all time points throughout the study. Results of the sensitivity analyses using MMRM with multiple imputation were consistent with the result of the primary analysis (Table 20).⁷

Results for change from baseline in ppFEV₁ were generally consistent across all subgroup analyses, including those based on age (12 to < 18 years or ≥ 18 years) and ppFEV₁ at screening (< 70% or ≥ 70%) (Table 75).⁷ The sponsor conducted an additional post hoc subgroup analysis for the subset of patients with a ppFEV₁ below 40% at baseline (16 out of 203 [7.9%] in the placebo group and 18 out of 200 [9.0%] in the ELX-TEZ-IVA group). Treatment with ELX-TEZ-IVA was associated with an improvement in absolute change in ppFEV₁ at 4 weeks (LSMD = 15.2%; 95% CI, 7.3 to 23.1) and through 24 weeks (LSMD = 18.4%; 95% CI, 11.5 to 25.3).⁷ Complete details regarding these subgroup analyses in patients with advanced lung disease are provided in Table 76.

Figure 6: Absolute Change from Baseline in ppFEV₁ in F/MF Genotype

F/MF = heterozygous for F508del mutation with 1 minimal function mutation; LS = least squares; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SE = standard error; ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor + ivacaftor.

Source: Product Monograph.³⁰

Patients With F/F Genotype

Absolute change from baseline in ppFEV₁ at 4 weeks was primary end point of Study 103. Treatment with ELX-TEZ-IVA was associated with a statistically significant increase from baseline in ppFEV₁ compared with TEZ-IVA at 4 weeks (10.0%; 95% CI, 7.4 to 12.6; P < 0.0001) (Table 21).⁷ As shown in Figure 7, improvements in ppFEV₁ with ELX-TEZ-IVA were observed at the time of the first post-baseline assessment (i.e., day 15) and were higher at all time points throughout the study.⁷ Results of the sensitivity analyses using MMRM with multiple imputation were consistent with the result of the primary analysis (LSMD = 9.3%; 95% CI, 6.8 to 11.7).⁷ The results for change from baseline in ppFEV₁ were generally consistent across all subgroup analyses; however, there the CIs for the analyses of subgroups with small sample sizes, such as ages 12 to 18 years, were wide (Table 77).⁷ The European Medical Association (EMA) reported the results of an additional post hoc subgroup analysis from Study 103 (CFTR modulator naive [n = 41] versus treatment-experienced [n = 66]). The observed treatment effect was 7.8% (95% CI, 4.8 to 10.8) for CFTR modulator-experienced patients and 13.2% (95% CI, 8.5 to 17.9) for CFTR modulator-naive patients.^48,61

Absolute change from baseline in ppFEV₁ through 24 weeks was a pre-specified key secondary end point of Study 109. Treatment with ELX-TEZ-IVA was associated with a statistically significant absolute increase from baseline in ppFEV₁ compared with TEZ-IVA through 24 weeks (LSMD = 10.2%; 95% CI, 8.2 to 12.1; P < 0.0001) (Table 21).¹⁰ Results of the sensitivity analyses using MMRM with multiple imputation were consistent with the result of the primary analysis (LSMD = 10.1%; 95% CI, 8.2 to 11.9).¹⁰ Subgroup analyses were not conducted for change from baseline in ppFEV₁ in Study 109.¹⁰

Figure 7: Absolute Change From Baseline in ppFEV₁ in F/F Genotype

ELX/TEZ/IVA = elexacaftor/tezacaftor/ivacaftor + ivacaftor; F/F = homozygous for F508del mutation; LS = least squares; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SE = standard error; TEZ/IVA = tezacaftor/ivacaftor + ivacaftor.

Source: Product Monograph³⁰ and Clinical Study Report.¹⁰

Patients With F/G and F/RF Genotypes

The primary end point of Study 104 was absolute change in baseline in ppFEV₁ through 8 weeks for the ELX-TEZ-IVA group (i.e., within-group change from baseline).⁹ Treatment with ELX-TEZ-IVA was associated with a statistically significant improvement in ppFEV₁ through 8 weeks (LS mean change = 3.7%; 95% CI, 2.8 to 4.6; P < 0.0001) (Table 22).⁹ Results of the sensitivity analyses using MMRM with multiple imputation were consistent with the result of the primary analysis. An additional pre-specified analysis was performed that included spirometry assessed independently by the patients at home (due to the COVID-19 pandemic) and the results were similar to the primary analysis (LSMD = 3.8; 95% CI, 2.9 to 4.7).⁹

Absolute change from baseline in ppFEV₁ through 8 weeks in the ELX-TEZ-IVA group compared to the control group was a pre-specified key secondary end point of Study 104.⁹ Treatment with ELX-TEZ-IVA was associated with a statistically significant improvement in ppFEV₁ compared to the control group (LSMD = 3.5%; 95% CI, 2.2 to 4.7; P < 0.0001) (Table 22).⁹ Similar results were obtained with a sensitivity analyses using MMRM with multiple imputation (LSMD = 3.6%; 95% CI, 2.3 to 4.8; P < 0.0001).⁹

Subgroup analyses based on the comparator group (i.e., patient genotype) demonstrated improvements in ppFEV₁ through 8 weeks with ELX-TEZ-IVA versus IVA (LSMD = 5.8; 95% CI, 3.5 to 8.0) and a smaller effect versus TEZ-IVA (LSMD = 2.0; 95% CI, 0.5 to 3.4).