Reimbursement Review

Elexacaftor-Tezacaftor-Ivacaftor and Ivacaftor (Trikafta)

Sponsor: Vertex Pharmaceuticals (Canada) Incorporated

Therapeutic area: Cystic fibrosis, responsive CFTR mutations

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

^aThis review focuses only on non-F508del mutations, which are responsive to elexacaftor-tezacaftor-ivacaftor plus ivacaftor based on clinical and/or in vitro data.

Introduction

Trikafta (elexacaftor-tezacaftor-ivacaftor plus ivacaftor [ELX-TEZ-IVA]) is a fixed-dose combination product previously reviewed for the treatment of cystic fibrosis (CF) caused by F508del mutations of the CFTR gene. ELX-TEZ-IVA is available as both oral tablets and oral granules in the following dosage strengths:

• tablets for patients 6 years and older:

  • elexacaftor (ELX) 50 mg, tezacaftor (TEZ) 25 mg, and ivacaftor (IVA) 37.5 mg co-packaged with a tablet containing IVA 75 mg

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

• granules for patients aged 2 to less than 6 years:

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

  • ELX 80 mg, TEZ 40 mg, and IVA 60 mg (granules) plus IVA 59.5 mg (granules), oral.

The current review is for an expanded indication that would include 152 additional non-F508del mutations in the CFTR gene. The sponsor has categorized the additional CFTR mutations as follows:

• Fischer rat thyroid (FRT)-responsive mutations supported by clinical data (68 mutations)

• FRT-responsive mutations with no available supporting clinical data (79 mutations)

• noncanonical splice mutations (4 mutations): 4 CFTR mutations that result in small amounts of functional, normal CFTR protein. The sponsor has reported that these mutations cannot be evaluated in the FRT system, and it provided some form of clinical data for each of the mutations included in the application

• N1303K mutation: A CFTR mutation that was initially identified as nonresponsive to ELX-TEZ-IVA in the FRT in vitro study that has subsequently been studied in a phase II clinical trial as well an investigator-sponsored real-world evidence study.

Figure 1: Additional CFTR Mutations Within the Expanded Indication

Note: CFTR mutations for which Health Canada concluded there is significant clinical evidence of efficacy in response to elexacaftor-tezacaftor-ivacaftor plus ivacaftor, independent of the mutation on the second allele, are underscored and shaded in grey.

* Complex and/or compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

^† CFTR mutations for which in vitro and/or clinical data supports some efficacy with ivacaftor monotherapy.

This is the fourth submission to Canada’s Drug Agency (CDA-AMC) for ELX-TEZ-IVA. We previously reviewed ELX-TEZ-IVA for the treatment of CF in patients aged 12 years and older who have 1 or more F508del mutations in the CFTR gene (final recommendation issued in August 2021); those aged 6 years and older (final recommendation issued in June 2022); and those aged 2 to 5 years (final recommendation issued in November 2023). For all of the previous reviews, the Canadian Drug Expert Committee (CDEC) recommended that ELX-TEZ-IVA be reimbursed with conditions. All of the indications for ELX-TEZ-IVA have been accepted as priority reviews by Health Canada.

The sponsor requested that the current submission for ELX-TEZ-IVA focus only on the expanded patient population (i.e., those aged 2 years and older with non-F508del mutations that are responsive to ELX-TEZ-IVA based on clinical and/or in vitro data). The drug combination comes in 2 dosage formats: orally administered tablets for those aged 6 years and older, and orally administered granules for those aged 2 to 5 years.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to the call for input and from clinical experts consulted for the purpose of this review.

Patient Input

Two submissions were received from Cystic Fibrosis Canada (CF Canada). Information from CF Canada was based on a focus group of residents of Canada with rare mutations who are being treated with ELX-TEZ-IVA, those with rare mutations who do not have access to ELX-TEZ-IVA, and caregivers of patients with rare mutations that cause CF. In addition, data were retrieved from a survey of patients and caregivers with access to ELX-TEZ-IVA conducted in 2021, medical and scientific publications, as well as the Canadian Cystic Fibrosis Registry (CCFR). CF Canada also measured the burden of CF at the individual, family, health systems, and societal levels, using preliminary findings from phase I of the Burden of Disease Study, which is considered to be among the most comprehensive studies of the burden of CF in the world. The second input was authored by a patient with end-stage CF with a rare class II mutation (M1101K).

According to the patient group, although life-changing treatments are increasingly reaching the 4,445 people in Canada living with CF, and those born with CF today will live longer than those who came before them, many are still seriously ill and 1 in 7 living with the disease today is ineligible for the treatments that are making such a positive difference for others with CF.

The input stated that, from a health care and quality-of-life perspective, challenges remain for patients living with CF, including those who are unable to benefit from recent life-changing treatments. For example, in Canada, the 40 patients who died of CF in 2022 had a median age of 38; patients with CF collectively had 17,000 clinic visits, spent 10,000 days in hospital, and spent nearly 6,000 days on IV antibiotics in 2022 alone. For 1 in 5 adults with CF, depression or anxiety was recorded as a complication in the CCFR. As the disease progresses, more time and effort are needed for frequent clinic visits and hospital stays to manage the progressive and debilitating symptoms. This overwhelming treatment regimen has multiple side effects and a significant impact on patients’ and caregivers’ day-to-day activities and quality of life, and it creates a major financial burden for families.

Data from the CCFR on patients in Canada with CF who do not currently have a Health Canada indication for CFTR modulators show that 246 patients have rare mutations known to respond to ELX-TEZ-IVA. The patient input indicated that many of these patients come from diverse and often racialized backgrounds, they are already disadvantaged by health care systems that were not designed with them in mind, and they deserve the right to try ELX-TEZ-IVA, even when efficacy and safety evidence is limited.

Patients with rare mutations and their caregivers shared their hopes to access ELX-TEZ-IVA as they saw the benefits for those who are able to access it. Few patients in Canada with rare CF mutations have access to ELX-TEZ-IVA. Those who reported taking ELX-TEZ-IVA responded exceptionally well to therapy, even those who have mutations for which the clinical evidence of a therapeutic response is limited.

Clinician Input

Input From Clinical Experts

All CDA-AMC review teams include at least 1 clinical specialist with expertise in 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). For this review of ELX-TEZ-IVA, a panel of 3 clinical experts provided input to characterize unmet therapeutic needs, helped identify and communicate gaps in the evidence that could be addressed through the collection of additional data, promoted the early identification of potential implementation challenges, gained further insights into the clinical management of patients living with CF, and explored the potential place in therapy of the drug combination. A summary of input from the clinical experts follows.

Unmet Needs

All patients living with CF have significant unmet therapeutic needs. No treatments are currently available that can effectively achieve the most important goals of therapy: prolong survival, prevent the need for a lung transplant, 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. The majority of patients with a non-F508del mutation that is responsive to ELX-TEZ-IVA do not currently have access to therapy that involves a modulator of the CFTR protein.

Place in Therapy

ELX-TEZ-IVA is a modulator that functions by 2 mechanisms: ELE and TEZ increase the amount of CFTR protein at the cell surface while IVA improves the transport of chloride ions through the CFTR protein. ELX-TEZ-IVA is attractive because it acts directly on the CFTR protein to address the defects responsible for the CF phenotype. ELX-TEZ-IVA would be added to existing treatments such as physiotherapy, mucolytics, anti-infectives, and anti-inflammatory treatments (such as azithromycin). The clinical experts noted that ELX-TEZ-IVA has replaced earlier CFTR modulators that are significantly less effective (e.g., lumacaftor-ivacaftor [LUM-IVA] and IVA alone) for patients with 1 or more F508del mutations in the CFTR gene. For the current target patient population, the clinical specialists anticipated that all patients in the expanded population (i.e., those with a non-508del mutation that is responsive to ELX-TEZ-IVA) would be considered candidates for the therapy. This would include those with a gating mutation who are currently receiving treatment with IVA, provided they meet eligibility and age criteria.

It is anticipated that ELX-TEZ-IVA would be used as a preventive therapy, with treatment initiated 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-stage organ disease (e.g., lung transplant).

The indication currently under review is for patients aged 2 years or older. We previously recommended that ELX-TEZ-IVA be reimbursed for patients ages 2 to 5 years and those 6 years and older. The clinical experts consulted for this review and those who previously responded to the call for clinician input noted that children aged between 2 to 5 years will often have structural lung disease (e.g., bronchial wall thickening, mucus plugging, and/or bronchiectasis),¹ but that detection is challenging using the tools available to evaluate lung function in clinical practice (i.e., spirometry) or as part of a research protocol (e.g., lung clearance index). However, despite younger patients with CF often exhibiting normal lung function, the early stages of lung abnormalities can be visualized using CT, and the underlying disease will continue to progress.¹

Overall, all the clinicians who provided input for this review recommend initiating treatment with ELX-TEZ-IVA as soon as possible. This aligns with the previously published Canadian Clinical Consensus Guideline for Initiation, Monitoring and Discontinuation of CFTR Modulator Therapies for Patients with Cystic Fibrosis, which also recommends initiating CFTR modulators at the youngest age possible, with the goal of attenuating disease progression and improving clinical status. All contributors agreed that no data support withholding initiation of treatment with a CFTR modulator until clinical symptoms of CF have developed.

Patient Population

The diagnosis of CF is not challenging in routine clinical practice. As all provinces and territories are now screening newborns for CF, and most people with CF are identified at an early age and have a confirmed diagnosis by the age of 1 month (on average). Sweat chloride (SwCl) testing is available and can be used reliably to confirm the results of a screening test. The provinces and territories have slightly different testing algorithms and screening panels for CFTR mutations; however, all jurisdictions have effective processes. Almost 100% of newly diagnosed infants would have their CFTR mutations identified. Infants who are not identified via newborn screening (i.e., false negatives), are usually diagnosed before the age of 1 year after the development of clinical symptoms of CF. The diagnostic guidelines are clear and there is little variability in expert opinion. Misdiagnosis and underdiagnosis of CF is exceedingly rare in clinical practice in Canada.

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

For the expanded indication (i.e., a non-F508del mutation that is responsive to ELX-TEZ-IVA), the clinical experts consulted for this review noted that nearly all patients would initiate therapy with ELX-TEZ-IVA as soon as possible, provided it is safe to start treatment. The clinical experts emphasized that ELX-TEZ-IVA has been a transformative and disease-modifying therapy for CF and that it would not be appropriate to wait until the patient shows worsening symptoms, more frequent exacerbations, or a decline in lung function to initiate treatment with ELX-TEZ-IVA.

Applicability of Existing Reimbursement Criteria to the Expanded Population

In discussions with the review team, the sponsor noted that nearly all patients in Canada aged 6 years and older who are eligible for treatment have initiated therapy with ELX-TEZ-IVA. (Some may have elected to discontinue treatment, but all who are interested have been given the opportunity to access the drug combination.) For those who have initiated treatment with ELX-TEZ-IVA, the sponsor noted that initial renewal criteria were met for all patients in Canada who started the therapy and wanted to continue (i.e., 100% of patients met the renewal criteria recommended by CDA-AMC and/or applied by the public drug programs). The clinical experts consulted for this review expressed general agreement with the sponsor’s position, noting that rates of initial access and renewal are high within their individual clinics. With nearly all patients currently achieving the recommended renewal criteria, the sponsor noted requiring these assessments consumes health care resources (e.g., the time required by health care practitioners to administer and document results for each of the required tests) without adding value to patients or the health care system.

The clinical experts consulted for this review support the application of the existing criteria recommended for the reimbursement of ELX-TEZ-IVA. Consistent with input from the participating drug programs, the clinical experts noted that a lack of alignment across CDA-AMC recommendations for the reimbursement of ELX-TEZ-IVA in patients with and without 1 or more F508del mutations could pose implementation challenges in clinical practice.

Clinician Group Input

Three groups of clinicians responded to the call for input: CF Canada Accelerating Clinical Trials Network (CanACT), the Edmonton Adult Cystic Fibrosis Clinic and Calgary Adult Cystic Fibrosis Clinic, and the CF Canada Health Care Advisory Council. The input from the clinician groups and the consulted clinical experts identified the same unmet medical needs for patients with CF and potential place in therapy for the drug under review. The clinician groups noted that there is a significant treatment gap in CF care. Of patients with CF in Canada with rare mutations who do not carry a copy of the F508del CFTR mutation but may be responsive to ELX-TEZ-IVA, 10% (n = 246) do not have access to the drug as no clinical trials have been conducted. The CF Canada Health Care Advisory Council added that recipients of lung transplants, particularly those with significant sinus disease, may still benefit from CFTR-modulator therapy; however, they were excluded from the clinical trials.

According to the clinician groups, any patient who carries 1 or more CFTR mutations that is responsive to ELX-TEZ-IVA should have access to this therapy. CanACT added that, for those with rare CFTR mutations for which data to support the use of ELX-TEZ-IVA are limited, it is incumbent on regulators to use all available evidence or generate the evidence needed to allow access to this life-saving drug, as each patient’s life may depend on access to this medication.

Drug Program Input

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

• potential challenges with implementation if different reimbursement criteria were recommended for patients with non-F508del CFTR mutations compared with the existing recommendations for patients who have 1 or more F508del mutations in the CFTR gene

• potential challenges with identifying objective reimbursement criteria for patients aged less than 6 years.

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

Evidence Included in Submission

The current review is for an expanded indication that would include 152 additional non-F508del mutations in the CFTR gene. The sponsor categorized the additional CFTR mutations as follows: 147 FRT-responsive mutations; 4 noncanonical splice mutations; and the N1303K mutation. Evidence supporting the use of ELX-TEZ-IVA in the expanded population consisted of the following: 1 double-blind, placebo-controlled randomized controlled trial (RCT) in FRT-responsive patients (Study 124; N = 307; 18 CFTR mutations); 1 long-term extension study (Study 125; same population as Study 124); 1 retrospective observational study (Study 14; N = 422; 64 CFTR mutations); 4 nonrandomized studies involving patients with 1 or more N1303K mutations (Solomon et al. [2024],² N = 20; Burgel et al. [2023],³ N = 8; Burgel et al. [2024],⁴ N = 35; Sadras et al. [2023],^14-16 N = 8). The sponsor reports that there are no clinical data for 79 FRT-responsive mutations (i.e., those considered responsive to ELX-TEZ-IVA in the in vitro model) and 1 of the noncanonical splice mutations.

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In Vitro Evidence

Overview of In Vitro Fischer Rat Thyroid Assay

The sponsor used an in vitro FRT-cell model to characterize individual CFTR mutations that produce at least some amount of full-length CFTR protein, for responsiveness to CFTR modulators. The model expresses a CFTR protein with a single mutation to test for responsiveness to CFTR modulators. Each FRT-cell line is engineered to express proteins with a specific CFTR mutation in a stable, epithelial-cell background. CFTR mutations selected for inclusion in the FRT assay study were those that were expected to produce full-length CFTR proteins. Protein-truncating CFTR mutations, whole or partial CFTR gene deletions, and noncanonical splice mutations were excluded from the in vitro study. Positive controls and negative controls were also included in the experiments.

• The positive controls included G551D and R117H mutations that were IVA-responsive in previous FRT assays and have been demonstrated in clinical trials to provide clinical benefit for patients. (IVA is approved for use in the treatment of CF in patients who have a G551D and R117H CFTR mutation.)

• The negative controls included G1061R, R1066C, N1303K mutations and untransfected FRT cells. These 3 CFTR mutations were identified as being nonresponsive to IVA or tezacaftor-ivacaftor plus ivacaftor (TEZ-IVA) in previous in vitro studies.

The function of CFTR at the cell surface was assessed in Ussing chamber studies, a procedure that quantifies the amount of CFTR-mediated chloride ion (Cl⁻) transport in FRT cells expressing each CFTR mutation as a fraction of the Cl⁻ transport in FRT cells expressing normal CFTR (% normal).

Definition of In Vitro Responsive to ELX-TEZ-IVA

Responsive CFTR mutations were those that demonstrated an increase of 10% in Cl⁻ transport over baseline when expressed as a percentage of normal CFTR Cl⁻ transport. The sponsor selected this threshold because the analyses of CFTR activity and disease phenotype showed that a 10% increase in CFTR activity is associated with improved clinical status. The sponsor reported that patients with a severe CF phenotype generally have a CFTR function of less than 5% of normal, whereas the severity of CF begins to diminish in patients who have a CFTR function of 10% or more of normal. An increase in CFTR function of 10% or more is therefore expected to affect the disease phenotype for those living with CF.⁵

CFTR Mutations Identified as Responsive to ELX-TEZ-IVA

Using the in vitro FRT model, the sponsor identified 177 CFTR mutations as responsive to ELX-TEZ-IVA. These additional mutations do not include F508del, which has been studied in multiple clinical trials already reviewed by CDEC. Importantly, the sponsor notes that the 10% threshold should be considered conservative, citing the following additional mutations that have been included in this reimbursement review application:

• The N1303K mutation did not meet the 10% threshold to be considered responsive to ELX-TEZ-IVA in the FRT model. (This mutation was chosen as 1 of the negative controls for the FRT model.) However, the sponsor has filed submissions with Health Canada and CDA-AMC citing real-world evidence that suggest these patients benefit from treatment with ELX-TEZ-IVA.

• The R117C and S1255P mutations included in this reimbursement review application did not meet the 10% threshold in the FRT assay; however, previous in vitro FRT data and/or clinical data support the responsiveness of these mutations to IVA and/or TEZ-IVA (both of which are components of ELX-TEZ-IVA).

Regulatory Perspective

Health Canada considered the evidence derived from the FRT-cell model sufficient to warrant expanding the indication for ELX-TEZ-IVA to 152 additional mutations sought by the sponsor. The sponsor’s application was filed on a pre–Notice of Compliance basis and included an additional 31 CFTR mutations that were not approved by Health Canada for the following reasons:

• Fifteen mutations were considered by Health Canada as not causative of CF, based on the CFTR2 and CFTR-France databases: D836Y, F508C, G576A, I148T, I807M, I1027T, L320V, L997F, R75Q, R170H, R668C, R1162L, T1053I, V562I, and V754M.

• Ten mutations were excluded because of unknown clinical significance or were only reported as causing a CFTR-related disease (i.e., not CF), and which retain at least 50% of normal Cl⁻ transport function: G178E, G576A;R668C, I1139V, K1060T, R31L, R553Q, R751L, R792G, V1293G, Y1014C.

• Five mutations were excluded because they result in a cryptic splice mutation and insufficient full-length CFTR: H939R, I175V, M152V, E403D, and S589N.

• One mutation was excluded because of the absence of in vitro or clinical data provided in the current submission: E831X.

Health Canada concluded that the CFTR mutations for which the sponsor has provided sufficient clinical evidence of efficacy are also among those more commonly harboured by patients with CF in Canada. As such, the requested indication for ELX-TEZ-IVA would be expected to significantly expand access to effective CF therapy in Canada. Health Canada noted that the inclusion of other CFTR variants to the product monograph as being responsive to ELX-TEZ-IVA treatment is based mainly on biological plausibility. In cases where the mutation is known to have the potential to cause CF because of the production of a dysfunctional full-length CFTR variant that has demonstrated in vitro responsiveness to ELX-TEZ-IVA (i.e., FRT-responsive mutations), or when a reduced amount of CFTR is produced and its function can be augmented (i.e., splicing mutations), ELX-TEZ-IVA treatment has the potential to provide clinically meaningful benefit to patients.

Clinical Expert Commentary on In Vitro Evidence

The clinical experts consulted for this review noted that responsiveness to ELX-TEZ-IVA using the in vitro model applied by Vertex in the clinical development program for patients with rare CFTR mutations is sufficient evidence to support prescribing it to these patients. In addition to regulatory approval (e.g., from the FDA) and based on this information, the clinical experts cited the following considerations that would support the use of ELX-TEZ-IVA in clinical practice:

• Alternative treatment options are lacking for patients with a severe and progressive case of CF.

• In vitro data demonstrating activity on the CFTR channel for patients with these rare mutations support extrapolation of the clinical benefit demonstrated in studies involving more common CF-causing mutations in the CFTR gene.

• Concerns exist about equity for those living with CFTR mutations the incidence of which is sufficiently low to preclude the generation of robust clinical evidence. The clinical experts noted CF with a non-F508del mutation is more likely to be diagnosed in racial minorities who may already be encountering systemic disadvantages within the health care system. Based on the rarity of these “rarer” mutations, it would be impossible to include participants with each mutation in clinical trials. The current focus on clinical trial data alone for drug approval is resulting in ethnic and racial inequity in medication access. It is well known that patients from minority groups are underrepresented in clinical trials for a multitude of reasons (the accompanying Ethics Review Report discusses these issues in detail).

• A mounting body of evidence from case reports, case series, and clinical experience indicates that ELX-TEZ-IVA can have a clinically meaningful impact on patients with rare CFTR mutations that in vitro data show are responsive to the drug combination.

In addition, the clinical experts noted that patients with CF in Canada are monitored in specialized clinics with well-organized and frequent clinical and laboratory evaluations to ensure treatment is used appropriately and safely in clinical practice. The clinical specialists emphasized that the in vitro data should not be viewed in insolation and that it is important to consider the large body of evidence demonstrating the clear and clinically important benefits of ELX-TEZ-IVA and the relatively few serious harms with the treatment (i.e., this is no longer a new drug in the management of CF). The specialists noted that the totality of information, including real-world experience with the drug for those with 1 or more F508del mutations, supports the expanded use of the drug for those with rare CFTR mutations.

Clinical Evidence

Systematic Review

Description of Studies

Evidence supporting the use of ELX-TEZ-IVA in the expanded population consisted of the following: 1 double-blind, placebo-controlled RCT in patients with FRT-responsive mutations (Study 124; N = 307; 17 Health Canada–approved CFTR mutations); 1 long-term extension study (Study 125; same population as Study 124); 1 retrospective observational study (Study 16; N = 422; 64 Health Canada–approved CFTR mutations); 4 nonrandomized studies involving patients with 1 or more N1303K mutations (Solomon et al. [2024],² N = 20; Burgel et al. [2023],³ N = 8; Burgel et al. [2024],⁴ and N = 35; Sadras et al. [2023],^14-16 N = 8). The sponsor reports that there are no clinical data for 79 FRT-responsive mutations approved by Health Canada (i.e., those that were considered responsive to ELX-TEZ-IVA in the in vitro model) and 1 of the noncanonical splice mutations.

The objective of Study 124 was to evaluate the efficacy, pharmacodynamics, and safety of ELX-TEZ-IVA in patients with a non-F508del ELX-TEZ-IVA–responsive CFTR mutation. This study was a phase III, double-blinded, randomized, placebo-controlled trial. Patients aged 6 years of age and older were recruited from 84 sites across Europe and Canada and randomized, with 205 patients enrolled in the ELX-TEZ-IVA treatment arm and 102 participants enrolled in the placebo-controlled arm.

Eligible participants included those with a non-F508del ELX-TEZ-IVA–responsive CFTR mutation based on the FRT assay with no exclusionary CFTR mutations (i.e., F508del, S549N, G551S, S1255P, R117H, S549R, G1244E, G1349D, G178R, G551D, and S1251N). The sponsor reported that 18 of the most prevalent CFTR mutations in Europe and Canada that are not currently indicated for a CFTR modulator were eligible (representing approximately 80% of the target patient population). The use of ELX-TEZ-IVA was approved by Health Canada for 17 of the 18 CFTR mutations included in Study 124 (1 mutation [L997F] was excluded by Health Canada on the basis that it has not been demonstrated to cause CF). Patients had to have a percent predicted forced expiratory volume in 1 second (ppFEV₁) of 40% or greater, but no more than 100% of the predicted mean for age, sex, and height. Patients were excluded if they had an acute upper or lower respiratory infection, pulmonary exacerbation (PEx), change in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of the study drug, or lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus).

ELX-TEZ-IVA was orally administered as fixed-dose combination tablets in the morning along with oral administration of IVA tablets in the evening. Placebo-arm treatments were matched to both ELX-TEZ-IVA and IVA administrations in dose and timing.

The primary end point was change from baseline in ppFEV₁ through 24 weeks. Secondary end points included absolute change from baseline in SwCl (through 24 weeks), Cystic Fibrosis Questionnaire–Revised (respiratory domain) (CFQ-R [RD]) score (through 24 weeks), body mass index (BMI) and BMI z score (at 24 weeks), and body weight and body weight z score (at 24 weeks). The number of PEx events was also a secondary end point in Study 124.

Efficacy Results

Treatment with ELX-TEZ-IVA resulted in a statistically significant improvement in ppFEV₁ compared with placebo through 24 weeks (least squares [LS] mean difference = 9.2%; 95% confidence interval [CI], 7.2 to 11.3; P < 0.0001). A reduction from baseline was observed at all postbaseline assessments (i.e., 2, 4, 8, 16, and 24 weeks).

Those in the ELX-TEZ-IVA group also demonstrated statistically significant improvement in CFQ-R (RD) scores compared with those in the placebo group (LS mean difference = 19.5 points; 95% CI, 15.5 to 23.5; P < 0.0001). This difference exceeded the minimally important difference (MID) for the CFQ-R (RD), which is typically cited as 4.0 points.

Patients in the ELX-TEZ-IVA group experienced an estimated 0.17 PEx events per year compared with 0.63 in the placebo group (rate ratio = 0.28; 95% CI, 0.15 to 0.51; P < 0.0001). Compared with placebo, treatment with ELX-TEZ-IVA also demonstrated statistically significant reductions in SwCl through 24 weeks (LS mean difference = −28.3 mmol/L; 95% CI, −32.1 to −24.5; P < 0.0001), increases in body weight at 24 weeks (LS mean difference = 1.3 kg; 95% CI, 0.6 to 1.9; P < 0.0001), and increases in BMI at 24 weeks (LS mean difference = 0.47 kg/m²; 95% CI, 0.24 to 0.69; P < 0.0001). In patients aged less than 20 years, there was no statistically significant difference between ELX-TEZ-IVA and placebo for the absolute change from baseline in body weight z score (LS mean difference = 0.06; 95% CI, −0.06 to 0.18) or BMI z score (LS mean difference = 0.08, 95% CI, −0.06 to 0.22).

Harms Results

The proportions of patients who experienced at least 1 AE were 94.1% in the ELX-TEZ-IVA group and 95.1% in the placebo group. The majority of adverse events (AEs) were mild or moderate in severity. Serious adverse events (SAEs) occurred in 18 patients (8.8%) in the ELX-TEZ-IVA group and 15 patients (14.7%) in the placebo group. SAEs that occurred in 2 or more patients in the ELX-TEZ-IVA group included infective PEx of CF (5 patients) and bronchopulmonary aspergillosis allergic (2 patients). The only SAE that occurred in 2 or more patients in the placebo group was infective PEx of CF (13 patients). Drug interruptions because of AEs were reported in 12.2% patients in the ELX-TEZ-IVA group and 1.0% in the placebo group.

Elevated transaminase was considered an adverse event of special interest (AESI) and occurred in | ██████ patients in the ELX-TEZ-IVA group and ██ patients in the placebo group. All elevated-transaminase events were mild or moderate in severity, and none were serious. Rash events, which were also considered AESIs, occurred in 55 patients (26.8%) in the ELX-TEZ-IVA group and 3 patients (2.9%) in the placebo group. The majority of rash events were mild or moderate in severity. One patient (0.5%) in the ELX-TEZ-IVA group had a serious rash event that was considered related to study drug treatment. Health Canada reviewers noted that long-term safety has already been established for ELX-TEZ-IVA and no data from the pivotal clinical study indicate the existence of CFTR genotype–dependent safety concerns.

Critical Appraisal

Baseline and demographic characteristics were generally well balanced across the ELX-TEZ-IVA and placebo groups in Study 124. Both study treatments (ELX-TEZ-IVA and placebo) were administered in a double-blind manner. The AE profile of ELX-TEZ-IVA was unlikely to compromise blinding in the study, except in patients who experienced a rash (a well-known AE associated with ELX-TEZ-IVA treatment) after initiating treatment (22% in the ELX-TEZ-IVA versus 1% in the placebo group). Patient disposition was thoroughly documented and well reported by the sponsor. Few patients discontinued the trials (the completion rate was 96.1% for ELX-TEZ-IVA and 100% for placebo). Adherence to study treatments was reported to be greater than 98.9%.

Study 124 evaluated the impact of ELX-TEZ-IVA on a range of different outcomes that are important in the management of CF. These included respiratory function (i.e., ppFEV₁), nutritional status and growth (e.g., weight and BMI), health-related quality of life (Cystic Fibrosis Questionnaire–Revised [CFQ-R]), and clinical events (e.g., pulmonary exacerbations). As noted in the input from clinician groups, the end points in the clinical trials largely align with those that are evaluated in routine clinical practice. Spirometry measurements were standardized and performed according to American Thoracic Society guidelines (e.g., prebronchodilator and before dosing). There are no globally accepted definitions for PEx events in patients with CF. The definitions used in Study 124 were considered appropriate by regulatory authorities and the clinical experts consulted for this review. The key secondary end points were tested using a hierarchical approach to control the overall type I error rate at 0.05.

The diagnostic criteria used in the screening process for Study 124 were consistent with Canadian clinical practice for identifying patients with CF. The sponsor and clinical experts consulted for this review reported that all patients with CF in Canada have their genotype evaluated, and therefore identifying members of the expanded patient population would not be problematic in practice. As with previous CFTR-modulator studies, Study 124 excluded patients with a history of colonization with B. cenocepacia, B. dolosa, and/or M. abscessus. CDA-AMC committees have previously acknowledged the unmet need for these patients.

The use of placebo as the comparator in Study 124 is appropriate given CFTR modulators are not approved for the target patient population except for the subset of patients who have a CFTR gating mutation and are currently eligible for treatment with IVA. Study 124 investigated the use of ELX-TEZ-IVA at the dosage recommended in the Canadian product monograph. All studies compared the addition of the study treatments to ongoing standard CF-management therapies, which is reflective of how ELX-TEZ-IVA and other CFTR modulators would be administered in clinical practice. In general, the background therapies that were reported at baseline in the included studies were consistent with those used in Canadian clinical practice.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

Table 3: Summary of Findings for ELX-TEZ-IVA Versus Placebo From RCT

BMI = body mass index; CF = cystic fibrosis; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; MID = minimally important difference; NA = not applicable; PEx = pulmonary exacerbation; ppFEV₁ = percent predicted forced expiratory volume in 1 second; RCT = randomized controlled trial; SwCl = sweat chloride.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aWhile no published information on the MID in absolute change in ppFEV₁ in CF was identified, the clinical experts consulted for this review noted that CF specialists would generally consider an absolute improvement in ppFEV₁ of at least 5% to be clinically relevant.

^bCertainty of evidence cannot be evaluated as the sponsor did not report the absolute difference between groups and did not provide this information upon request. While no published information on the MID for reducing PEx in CF was identified, the clinical experts consulted for this review noted that CF specialists would generally consider the reduction in PEx observed in the study to be clinically relevant.

^cWhile no published information on the MID for absolute change in BMI in CF was identified, the clinical experts consulted for this review noted that CF specialists would generally consider the improvements observed in the study to be clinically relevant.

^dRated down 1 level for imprecision because of the smaller sample size and wide CIs.

^eA difference of at least 4 points in the respiratory domain score of the CFQ-R is commonly cited as the MID for patients with CF.

^fRated down 1 level for indirectness because SwCl is a biomarker, and evidence for a relationship between SwCl and clinical outcomes is uncertain.

^gBetween-group differences in harms were not statistically tested.

^hThe product monograph provides recommendations for baseline assessment and ongoing monitoring of alanine transaminase and aspartate transaminase. The clinical experts consulted for this review noted that these recommendations for monitoring are typically followed in clinical practice and that patients in Canada are monitored in specialized clinics.

ⁱStudy 124 found that discontinuations because of rash were uncommon, and the clinical experts consulted for the review similarly noted that these events do not typically result in long-term discontinuation of the treatment.

Source: Sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

Description of Studies

Study 125 is an open-label long-term extension phase of Study 124 conducted to assess the long-term safety and efficacy of ELX-TEZ-IVA in patients with CF aged 6 years and older with non-F508del mutations in the CFTR gene that are responsive based on clinical and/or in vitro data. The data cut-off date in the submission to CDA-AMC is August 28, 2023, with results reported for the 4 weeks after the end of Study 124. Of the patients who were randomized to placebo in the parent study, 15 had been treated with ELX-TEZ-IVA for a total of 4 weeks, and those who were randomized to ELX-TEZ-IVA in Study 124 had been treated for 28 weeks.

Efficacy Results

Those who switched from placebo to ELX-TEZ-IVA demonstrated improvements in ppFEV₁ (mean change = 7.1 percentage points; standard deviation [SD] = 7.3), SwCl (mean change = −27.4 mmol/L; SD = 18.9), and CFQ-R (RD) (mean change = 14.7 points; SD = 22.6) after receiving ELX-TEZ-IVA for 4 weeks. For those who received ELX-TEZ-IVA in the parent study, improvements in ppFEV₁ (mean change = 10.1 percentage points; SD = 11.0), SwCl (mean change = −30.3 mmol/L; SD = 21.9), and CFQ-R RD (mean change = 20.1 points; SD = 20.7) were maintained after 4 additional weeks.

Harms Results

Harms data were not yet reported for Study 125.

Critical Appraisal

Study 125 is an ongoing, uncontrolled, open-label trial that enrolled patients who had completed Study 124. As this was an unblinded extension phase, patient’s expectations of treatment could influence 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 125 and other ELX-TEZ-IVA studies, the risk of selection bias is generally low, given that nearly all patients from the primary study enrol in the extension study. Overall, there are limited data from the extension phase, as only 4 weeks of additional data were available. Issues with the generalizability of these data are the same as for Study 124 (e.g., a patient population reflective of those with mild to moderate disease, exclusion of patients with unstable disease or colonization with B. cepacia complex, and increased exposure to health care professionals).

Indirect Comparisons

The sponsor reported that an indirect treatment comparison (ITC) is not required for approximately 80% of the patients in the target patient population because no CFTR modulators are currently approved for use in these patients. The remaining 20% of patients in the target patient population could be eligible for treatment with IVA monotherapy. The sponsor conducted a feasibility assessment to determine whether an ITC could inform the comparative clinical benefits of ELX-TEZ-IVA versus IVA monotherapy. The sponsor concluded it was not feasible to conduct a robust ITC because of uncertainty in the degree of population overlap, low individual-patient-data sample sizes, incompatibility of outcomes, and different treatment histories and follow-up times.

The review team has no concerns regarding the absence of an ITC for the following reasons:

• The dosage of ivacaftor administered as part of the ELX-TEZ-IVA combination regimen is the same as what patients would receive with IVA monotherapy (e.g., 150 mg in the morning and 150 mg in the evening).

• Previous trials have demonstrated that patients with 1 or more F508del mutations and a gating mutation benefited from switching to ELX-TEZ-IVA from IVA monotherapy.

• The submitted price for ELX-TEZ-IVA is the same as the current list price for IVA monotherapy.

Studies Addressing Gaps in the Evidence from the Systematic Review

Clinical evidence from 5 additional studies addressing gaps in evidence were included in the review:

• 1 study involving patients with 64 FRT-responsive CFTR mutations (Study 16 [N = 422])⁶

• 4 studies involving patients with 1 or more N1303K mutations (Solomon et al. [2024],² N = 20); Burgel et al. [2023],³ N = 8) Burgel et al. [2024],⁴ N = 35); and Sadras et al. [2023],^14-16 N = 8).

The sponsor included evidence from 3 additional abstracts and/or publications for patients with 1 or more N1303K mutations (Dreano et al. [2023],⁷ Livnat et al. [2023],⁸ and Pranke et al. [2022]⁹). These studies are not summarized in this report as the review team concluded that they do not address a gap in the evidence relative to the larger studies submitted in support of the expanded use of ELX-TEZ-IVA for patients with CF who have 1 or more N1303K mutations in the CFTR gene. In addition to the smaller sample sizes, the following additional concerns were noted: the reporting of these studies is insufficient for the review team to fully appraise the methodology used in the evaluation of patients; the publications by Dreano et al. (2023) and Pranke et al. (2022) refer to the same source of patients that was used in the larger studies reported by Burgel (2023) (N = 8) and Burgel et al. (2024) (N = 34). The sponsor was unable to confirm if there is overlap between the patient populations in these studies and the review team notes that these analyses were not included in the submission to Health Canada.

FRT-Responsive CFTR Mutations

Description of Study

Study 16 was a retrospective, observational, cohort study evaluating real-world clinical outcomes in patients with CF with non-F508del mutations that are responsive to ELX-TEZ-IVA. Data were sourced from the US Cystic Fibrosis Foundation Patients Registry (CFFPR). Index dates for patients were defined as the date of ELX-TEZ-IVA treatment initiation ranging from October 21, 2019, to December 1, 2022. Data from patients were evaluated for up to 2 years before the index date through December 31, 2022 (the follow-up period), or until loss to follow-up, death, treatment discontinuation, or lung transplant, whichever was earlier. The objective of Study 16 was to supplement Study 124 with respect to a further 64 mutations with data on the effectiveness of ELX-TEZ-IVA on lung function, PEx, and nutritional parameters in a real-world setting of patients with CF in the target population using data from the CFFPR patient registry.

Patients aged at least 6 years were included in the analysis if they had data recorded in the CFFPR; a select ELX-TEZ-IVA–responsive non-F508del CFTR genotype; received treatment with ELX-TEZ-IVA during the patient-accrual period; at least 1 ppFEV₁ measurement in the 12 months before the index date; and at least 1 ppFEV₁ measurement taken at least 4 weeks after the index date. Patients were excluded if they had received a lung transplant before the index date.

Efficacy Results

Change from baseline in ppFEV₁ was the primary end point of Study 16. The overall patient population demonstrated a mean change from baseline of 4.53% (95% CI, 3.50 to 5.56). Study 16 included patients with and without prior exposure to a CFTR modulator (55.5% and 44.1%, respectively). The sponsor-reported subgroup analyses, which were based on prior CFTR-modulator exposure, found that the mean changes from baseline with ELX-TEZ-IVA were 6.11 (95% CI, 4.40 to 7.81) for those who were CFTR modulator–naive and 3.3% (95% CI, 2.06 to 4.58) for those who had prior exposure to a CFTR modulator.¹⁰

Change from baseline in BMI and body weight were secondary end points. The sponsor reported an increase from baseline in BMI and body weight after ELX-TEZ-IVA initiation (mean change = 0.65 kg/m²; 95% CI, 0.41 to 0.89; and 2.91 kg; 95% CI, 2.24 to 3.58, respectively) compared to baseline. Mean change from baseline in z scores for BMI and body weight were −0.05 (SD = 0.53) and −0.04 (SD = 0.48), respectively.

The number of PEx events and the annualized PEx rate were also assessed. The results suggest the PEx rate decreased by 53% (95% CI, 42% to 62%) after ELX-TEZ-IVA initiation. The annualized PEx rates were 0.43 in the pre-initiation period and 0.20 in the follow-up period.¹⁰

Harms Results

Adverse events were not investigated in Study 16.

Critical Appraisal

Study 16 was a retrospective observational study with no comparator treatment group. Given the real-world treatment setting, there was no blinded administration of ELX-TEZ-IVA (i.e., investigators, patients, and caregivers were aware of the treatment). Limitations common to observational studies apply to these data, including potential variability in timing of assessments for patients; no standardized definition for pulmonary exacerbations; variation in the duration of therapy; lack of information regarding adherence to ELX-TEZ-IVA during the treatment period; and the potential for missing data in the registry database. The index dates for patients spanned October 21, 2019, to December 1, 2022. This overlapped with the COVID-19 pandemic, which had a considerable impact on the baseline PEx rate for patients with CF. Because of isolation measures, the risk of pulmonary exacerbations was reduced during the pandemic period (from 0.70 to 0.31 events per year) making it challenging to interpret the overall pretreatment baseline rate (0.43 events per year) and the posttreatment rate of exacerbations (0.20 events per year). Overall, the number of patients with each of the individual mutations was variable and generally small across the population. The sponsor emphasized that, given the variability of the real-world data and the interpretability of data from small strata (e.g., mutation-level data), these analyses should be viewed with caution.

Patients evaluated in Study 16 were identified from the CFFPR. The clinical specialists consulted by the review team noted that baseline characteristics of patients with CF in the US are generally similar to those living in Canada and that the results would be considered generalizable to the target population in Canada. Study 16 included patients with and without prior exposure to a CFTR modulator. Given that treatment with a CFTR modulator is expected to improve the end points evaluated in clinical trials (e.g., baseline lung function, BMI, and SwCl), this prior exposure could bias the overall effective size reported for the study against ELX-TEZ-IVA for the target population in Canada (the majority of whom are expected to be CFTR-naive, except for those who have received IVA monotherapy). The sponsor reported results for patients with and without prior exposure to a CFTR modulator.

Health Canada reviewers noted that the differences between the mean and median change from baseline in ppFEV₁ indicates that a few good responders may have skewed the average in favour of treatment (i.e., the mean change from baseline was 4.53 [SD = 9.84] and median change from baseline was 2.76 [range = −31.67 to 59.19]); however, definitive conclusions cannot be drawn because of variability in the timing of the baseline and posttreatment initiation spirometry tests. Health Canada concluded that data from Study 16 do not provide significant clinical evidence for ELX-TEZ-IVA responsiveness beyond providing some support for the efficacy of a few mutations, with sufficient evidence of efficacy already provided in Study 124.

N1303K CFTR Mutation

Description of Studies

This Clinical Review included 4 nonrandomized studies that investigated the use of ELX-TEZ-IVA in patients with 1 or more N1031K mutations in the CFTR gene. All of the studies were investigator-initiated (i.e., not sponsored by Vertex Pharmaceuticals).

• Solomon et al. (2023)^11,12 reported the results of a prospective, open-label trial assessing patients with 1 or more N1303K mutations (N = 20). Patients were treated with ELX-TEZ-IVA for 4 weeks. End points included change from baseline in ppFEV₁, SwCl, CFQ-R scores, and body weight.

• Burgel et al. (2024)⁴ reported the results of ELX-TEZ-IVA in patients with 1 or more N1303K mutations who received the treatment as part of a compassionate use program in France. The results were based on a retrospective observational cohort, pooled analyses from cohort studies, case reports, and unpublished data. The patients who received the treatment all had advanced lung disease (e.g., a ppFEV₁ < 40%). The observational period ranged from 4 weeks to 8 weeks.

• Burgel et al. (2023),^3,13 similar to Burgel et al. (2024),⁴ this study investigated the use of ELX-TEZ-IVA in patients with 1 or more N1303K mutations who received the treatment as part of a compassionate use program in France. The study was a prospective observational cohort study with a treatment period of 4 to 6 weeks.

  • Sadras et al. (2023)^14-16 was an observational prospective analysis from a multicentre registry in Israel investigating the use of ELX-TEZ-IVA in patients with CF who have 1 or more N1303K mutations in the CFTR gene. Patients were included if they had CF and carried 1 or more N1303K mutations on 1 allele and a nonsense or frameshift mutation on the other allele (i.e., a mutation that would not be expected to respond to ELX-TEZ-IVA for a period of 8 weeks). Efficacy end points included change from baseline in ppFEV₁, SwCl, body weight, and the lung clearance index.

Efficacy Results

Key efficacy results from the nonrandomized studies for patients with 1 or more N1303K mutations in the CFTR gene are summarized in Table 4.

• Solomon et al. (2023): After 4 weeks of treatment with ELX-TEZ-IVA, patients demonstrated statistically significant improvements from baseline in ppFEV₁ (mean change = 9.5%; 95% CI, 6.7 to 12.3; P < 0.001), BMI (mean change = 0.4 kg/m²; 95% CI, 0.2 to 0.7; P = 0.002), and CFQ-R (RD) (mean change = 20.8; 95% CI, 11.9 to 29.8; P < 0.001). There was no statistically significant difference in change from baseline in SwCl (−1.1 mmol/L; 95% CI, −5.3 to 3.1; P = 0.61).^11,12

• Burgel et al. (2024): After 4 to 8 weeks of treatment with ELX-TEZ-IVA, patients demonstrated a statistically significant improvement in ppFEV₁ from baseline (median change = 17.0%; interquartile range [IQR] = 10.0 to 25.0; P < 0.0001). Median body weight increased by 2.0 kg (IQR = 1.0 to 3.5) and median SwCl was reduced by −9.0 mmol/L (IQR = 3.5 to 21).⁴

• Burgel et al. (2023): The authors reported that all patients with 1 or more N1303K mutations (N = 8) were considered ELX-TEZ-IVA responders. After 4 to 8 weeks of treatment with ELX-TEZ-IVA, the median change in ppFEV₁ was 27.5% (IQR = 20.7% to 41.2%) and the median change in SwCl was –9 mmol/L (IQR = −5 to −36).^3,13

• Sadras et al. (2023): After 8 weeks of treatment, patients treated with ELX-TEZ-IVA demonstrated statistically significant improvements from baseline in ppFEV₁ (mean change = 18.4; 95% CI, 12 to 24; P < 0.0001) and BMI (mean change = 0.79 kg/m²; 95% CI, 0.51 to 1.07; P < 0.0001). There was no statistically significant difference in change from baseline in SwCl (mean change = −7 mmol/L; 95% CI, not reported; P < 0.054).^14-16

Harms Results

Adverse events were not investigated and/or reported in the studies by Solomon et al. (2023),^11,12 Burgel et al. (2024),⁴ Burgel et al. (2023),^3,13 or Sadras et al. (2023).^14-16

Critical Appraisal

Overall, the 4 observational studies provided descriptive data on the effects of ELX-TEZ-IVA in patients with CF with 1 or more N1303K mutations at various stages of lung disease. The short-term results showed acute increases in ppFEV₁ and weights that were comparable to or exceeded those reported in the clinical trials for ELX-TEZ-IVA conducted in patients with other CFTR mutations; however, these results should be interpreted with caution because of the uncontrolled, observational study designs, and the small sample sizes (N ranged from 8 to 35). All of studies had a short duration of treatment and follow-up. As all of the studies were investigator-sponsored, the available information regarding studies methods and results is limited to publications and abstracts.

Table 4: Summary of Findings for ELX-TEZ-IVA From Nonrandomized Studies

BMI = body mass index; CFQ-R = Cystic Fibrosis Questionnaire–Revised; CFTRm = CFTR modulator; CI = confidence interval; IQR = interquartile range; NA = not applicable; SwCl = sweat chloride.

Conclusions

The current review is for an expanded indication that would include 152 additional non-F508del of in the CFTR gene. The sponsor has categorized the additional CFTR mutations as follows: 147 FRT-responsive mutations; 4 noncanonical splice mutations; and the N1303K mutation. Evidence supporting the use of ELX-TEZ-IVA in the expanded population consisted of the following: 1 double-blind, placebo-controlled RCT of FRT-responsive patients (Study 124; N = 307; 18 CFTR mutations); 1 long-term extension study (Study 125; same population as Study 124); 1 retrospective observational study (Study 16; N = 422; 64 CFTR mutations); 4 nonrandomized studies involving patients with 1 or more N1303K mutations (Solomon et al. [2024], N = 20; Burgel et al. [2023], N = 8; Burgel et al. [2024], N = 35; and Sadras et al. [2023], N = 8). Evidence for 79 of the additional mutations is exclusively from the in vitro FRT model.

For the clinical studies in FRT-responsive mutations, Studies 124 and 16 demonstrated that ELX-TEZ-IVA resulted in clinically meaningful improvements in lung function (an increase in ppFEV₁), nutritional status (an increase in BMI), health-related quality of life (an increase in CFQ-R [RD] scores), CF biomarkers (a reduction in SwCl), and a reduced rate of pulmonary exacerbations. For the clinical studies in patients with 1 or more N1303K mutations, the short-term results showed acute increases in ppFEV₁ and weight that were suggestive of a clinically meaningful benefit with ELX-TEZ-IVA in these patients; however, the results cannot be considered conclusive of a clinically important effect because of the limitations of the open-label, noncomparative, observational study designs, with relatively the small sample sizes (N ranged from 8 to 35), short durations, limited reporting of important information, and several potential sources of bias and uncertainty. For all of the mutations for which clinical data were available, the clinical specialists consulted for this review considered the results to be clinically meaningful and indicative that ELX-TEZ-IVA would benefit patients in the target population. The experts emphasized that there is a high level of unmet need among these patients as they currently do not have access to CFTR-modulator therapy in Canada (outside of enrolment in a clinical study).

For the 79 mutations that have been assessed exclusively from the in vitro FRT model, the sponsor defined responsive CFTR mutations as those that resulted in an increase of 10% in Cl⁻ transport over baseline when expressed as a percentage of normal CFTR Cl⁻ transport. The sponsor’s selection of a threshold increase in CFTR function of 10% or more is therefore expected to affect the disease phenotype for those living with CF. The CF specialists consulted by the review team pointed out that prescribers in Canada are not concerned about the absence of clinical data for patients with rare CFTR mutations. They noted the practical challenges in conducting clinical trials for patients with rare CFTR mutations and emphasized that there are important concerns regarding equity of access to CFTR modulators. Health Canada considered the data derived from the FRT-cell model to be acceptable evidence to warrant expanding the indication for ELX-TEZ-IVA. Health Canada concluded that the CFTR mutations for which the sponsor has provided sufficient clinical evidence of efficacy are also among those more commonly harboured by patients with CF in Canada. As such, expanding the indication for ELX-TEZ-IVA would be expected to significantly broaden access to effective CF therapy in Canada. They noted that inclusion of other CFTR variants to the product monograph because they are responsive to ELX-TEZ-IVA treatment is based mainly on biological plausibility. When the mutation is known to have the potential to cause CF because of the production of a dysfunctional full-length CFTR variant that has demonstrated in vitro responsiveness to ELX-TEZ-IVA (i.e., FRT-responsive mutations), or when a reduced amount of CFTR is produced and its function can be augmented (i.e., splicing mutations), ELX-TEZ-IVA treatment has the potential to provide clinically meaningful benefits to patients.

ELX-TEZ-IVA was well tolerated in the target patient populations (i.e., those aged at least 2 years with at least 1 mutation that is responsive to ELX-TEZ-IVA based on clinical and/or in vitro data). There have been no updates to the warnings and precautions section of ELX-TEZ-IVA product monograph since the previous CDA-AMC reviews.

Introduction

The objective of this review was to evaluate the beneficial and harmful effects of ELX-TEZ-IVA at recommended dosages for the treatment of patients aged 2 years and older with CF and who have at least 1 non-F50del mutation in the CFTR gene that is responsive to ELX-TEZ-IVA based on clinical and/or in vitro data.

Disease Background

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was validated by the review team.

Cystic fibrosis, an autosomal recessive condition, is the most common fatal genetic disease affecting children and young adults in Canada. It is caused by mutations in the CFTR gene, which is located on chromosome 7. The CFTR gene encodes a chloride channel that regulates ion and fluid transport across cell membranes. When the CFTR protein is dysfunctional, secretions become tenacious and sticky, resulting in pathology in multiple organs, including the lungs, large and small intestines, pancreatic and bile ducts, and the vas deferens. A deletion of phenylalanine 508 in the first nucleotide-binding domain (F508del) is the most common mutation that results in CF.¹⁷ The CCFR reported that 4,338 patients in Canada were living with CF in 2021. Of these, 87.6% carried 1 or more F508del mutations.¹⁸

More than 2,090 CFTR mutations have been identified among patients with CF.¹⁷ The mutations are 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).¹⁹ CFTR mutations within classes I to III are associated with severe CF as they are considered nonfunctional, while mutations in classes IV to VI may retain CFTR function.^19,20 Genotyping for mutations in the CFTR gene is performed routinely on almost all patients with CF in Canada and is also part of the newborn screening process.¹⁷

Based on CF registry data, the sponsor estimates that there were 573 patients with non-F508del mutations in Canada, of whom 163 were responsive to ELX-TEZ-IVA (excluding Québec). The total target population for the current review represents an estimated 5% of the total CF population in Canada. The percentage of patients in Canada with CF in each province based on the 2021 CF registry was used to stratify patients by province (Table 5).

Table 5: Number of Patients in the Target Patient Population by Region

NA = not applicable.

^aThe total number of patients included in the target patient population in each province for 2024 is based on 2023 numbers and assumes 1 year of growth in the CF population.

Source: Sponsor’s Summary of Clinical Evidence.

Cystic fibrosis results in airway obstruction, chronic endobronchial infection, and inflammation, which ultimately lead to destruction of lung tissue through development of bronchiectasis and loss of lung function.²¹ 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 forced expiratory volume in 1 second (FEV₁) over the following 4 years in those who were homozygous for the F508del mutation.²² Chronic endobronchial infection of the airways with bacterial pathogens, such as Pseudomonas aeruginosa (reported in 34.6% of patients with CF in Canada in 2021),¹⁸ is associated with a more rapid loss of lung function.²³ 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 (> 80%) of deaths in patients with CF.^17,24

Pulmonary exacerbations are associated with lung-function decline and mortality and may require treatment with IV antibiotics and hospitalization. The Cystic Fibrosis Foundation has reported that approximately a third of patients with CF will have at least 1 PEx per year requiring IV antibiotics.²⁵

Maintenance of pulmonary function (higher FEV₁) and fewer respiratory exacerbations are associated with increased survival.²⁶ Pulmonary management of CF therefore aims to clear the airways of secretions and treat lung pathogens to minimize inflammation.

Patients typically have pancreatic, gastrointestinal, and nutritional disease as well as progressive pulmonary damage. Gastrointestinal and pancreatic involvement results in pancreatic exocrine insufficiency in most individuals with CF, causing malabsorption of fats and fat-soluble vitamins, which leads to malnutrition. Maintaining adequate nutrition is associated with improved clinical outcomes and longevity for patients with CF.²⁷ 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 2021, CF-related diabetes was reported in 22.0% of patients in Canada with CF (32.6% of adults and 2.8% of children).¹⁸

The median age of survival in Canada for a child born with CF is estimated to be 57.3 years.¹⁸ The CCFR has reported in increase in the median age of death for patients with CF in Canada since the year 2000.¹⁷ The median age of death was 38.7 years in 2021, compared to 26.6 years in 2002.¹⁸ There is a clear unmet need for improved CF therapies (as described in the Patient Group Input and Clinician Input sections).

Standards of Therapy

Contents within this section were informed by materials submitted by the sponsor and clinical expert input. The following summary was validated by the review team.

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

Treatments that are approved and/or available can be broadly classified 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 drugs such as inhaled antibiotics (e.g., tobramycin, aztreonam, colistin), anti-inflammatory agents, or mucolytics (e.g., hypertonic saline and/or dornase alfa).²⁸ Nutritional treatments consist of high-calorie and high-fat diets and pancreatic enzyme replacement for those with pancreatic insufficiency.^24,28 PEx events are treated with oral or IV antibiotics.²⁹ These treatments do not halt, but only slow, the decline in lung function and the progression of disease.

CFTR Modulators

The CFTR modulators that are currently marketed in Canada or other jurisdictions are classified as: potentiators, which function by increasing the channel-open probability of the CFTR protein at the cell surface (IVA is a CFTR potentiator); or correctors, which function by improving the conformational stability of F508del-CFTR proteins, resulting in an increased expression of the F508del-CFTR protein at the cell surface. Lumacaftor, TEZ, and ELX are CFTR correctors.

Table 9 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 1 or more F508del mutations. The approved indications currently cover those who are homozygous for F508del mutations (LUM-IVA and TEZ-IVA), heterozygous for the 508del mutation and who also have a residual function mutation (TEZ-IVA), or a non-F508del gating mutation (IVA).

Drug Under Review

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

• Tablets for patients 6 years and older:

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

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

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

  • ELX 100 mg, TEZ 50 m, and IVA 75 mg co-packaged with IVA 75 mg

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

Indication Under Review

The current review is for an expanded indication that would include 152 additional non-F508del mutations of the CFTR gene (Figure 1). The sponsor categorized the additional CFTR mutations as follows:

• FRT-responsive mutations supported by clinical data (68 mutations)

• FRT-responsive mutations with no available clinical data to support (79 mutations)

• Noncanonical splice mutations (4 mutations): mutations that result in small amounts of functional, normal CFTR protein; the sponsor has reported that these mutations cannot be evaluated in the FRT system and provided some form of clinical data for each of the mutations included in the application

• N1303K mutation: A CFTR mutation that was initially identified as nonresponsive to ELX-TEZ-IVA in an FRT in vitro study that has subsequently been studied in a phase II clinical trial as well an investigator-sponsored real-world evidence study.

Sponsor’s Requested Reimbursement Criteria

The sponsor has requested reimbursement in accordance with the Health Canada–approved indication.

Table 6: Reimbursement Criteria Requested by the Sponsor

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

^aThe sponsor has requested the initial renewal criteria be 12 months to align with patients aged 2 to 5 years according to the last CDA-AMC recommendation.

^bThe sponsor requested this additional criterion (i.e., clinical judgment in the renewal process), citing the elimination of unnecessary burden to patients, CF specialists, and their administrative teams, and the need to ensure the renewal criteria remain consistent across Canada. The sponsor noted that Québec has removed the need for documentation and evaluation of ppFEV₁, BMI, CFQ-R, and pulmonary exacerbation frequency from the reimbursement criteria for ELX-TEZ-IVA on the basis of a revised recommendation from the Institut national d'excellence en santé et services sociaux.

Mechanism of Action

ELX-TEZ-IVA is the third treatment specifically indicated for patients with CF who have 1 or more F508del mutations in the CFTR gene. This mutation is believed to be associated with misfolding of the CFTR protein, which reduces 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:^30-32

• 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 dosing of ELX-TEZ-IVA is summarized in Table 7. For patients aged 2 to less than 6 years who weigh less than 14 kg, the recommended dosage regimen is 1 packet of granules comprising ELX 80 mg, TEZ 40 mg, and IVA 60 mg in the morning and 1 packet of IVA 59.5 mg granules in the evening. For those who weigh at least 14 kg, the recommended dose is 1 packet of granules of ELX 100 mg, TEZ 50 mg, and IVA 75 mg in the morning and 1 packet of ivacaftor 75 mg granules in the evening.

Both tablets and granules are administered orally and should be taken approximately 12 hours apart with fat-containing food. Table 8 provides a summary of the recommended dose adjustments for patients with hepatic insufficiency or those receiving concomitant treatment with moderate CYP3A inhibitors (e.g., fluconazole, or erythromycin) or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin).

Table 7: Recommended Doses

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

Source: Product monograph.³⁰

Table 8: Recommended Dose Adjustments

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

Source: Product monograph.³⁰

Previous Reimbursement Reviews

This is the fourth reimbursement review submission for ELX-TEZ-IVA. We previously reviewed ELX-TEZ-IVA for the treatment of CF in patients who have 1 or more F508del mutations in the CFTR gene for those aged 12 years and older (final recommendation issued in August 2021); those aged 6 years and older (final recommendation issued in June 2022); and those aged 2 to 5 years (final recommendation issued in November 2023). For all of the previous reviews, CDEC recommended that ELX-TEZ-IVA be reimbursed with conditions.^1,33,34 All of the indications for ELX-TEZ-IVA have been accepted as priority reviews by Health Canada.

In addition, we previously reviewed IVA alone for the following indications: patients aged 6 years and older who have a G551D mutation in the CFTR gene; patients aged 6 years and older who have 1 of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or G970R; and patients aged 18 years and older who have an R117H mutation in the CFTR gene.^35-37 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.^38,39 CDA-AMC was unable to recommend reimbursement for TEZ-IVA as a submission was not filed by the sponsor.⁴⁰

Key characteristics of ELX-TEZ-IVA and other CFTR modulators approved in Canada are summarized in Table 9.

Table 9: Key Characteristics of CFTR Modulators

CFTR = cystic fibrosis transmembrane conductance regulator; ELX = elexacaftor; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; IVA = ivacaftor; LUM-IVA = lumacaftor-ivacaftor; TEZ-IVA = tezacaftor-ivacaftor plus ivacaftor.

^aHealth Canada–approved indications.

Sources: Product monographs for Trikafta and Kalydeco.^5,30,41,42

Perspectives of Patients, Clinicians, and Drug Programs

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups. The full original patient inputs received by the team are included in the report.

Two submissions were received from CF Canada to the call for patient input for the current review of ELX-TEZ-IVA for the treatment of CF in patients aged 2 years and older who have 1 or more F508del mutations in the CFTR gene or a mutation in the CFTR gene that is responsive based on clinical and/or in vitro data. CF Canada is a national not-for-profit corporation committed to improving and lengthening the lives of people living with CF through treatments, research, information, and support.

Information from CF Canada was based on a focus group with individuals in Canada with rare mutations who are being treated with ELX-TEZ-IVA, those with rare mutations who do not have access to ELX-TEZ-IVA, and caregivers of those in Canada with rare mutations that cause CF. In addition, data were retrieved from a 2021 survey of patients and caregivers with access to ELX-TEZ-IVA, medical and scientific publications, as well as the CCFR. CF Canada also supplied preliminary findings from phase I of the Burden of Disease Study, which measured the burden of CF at the individual, family, health systems, and societal levels and is considered to be among the most comprehensive studies of the burden of CF in the world. The second input was authored by a patient with end-stage CF with a rare class II mutation (M1101K).

According to the patient group, although life-changing treatments are increasingly reaching the 4,445 patients with CF in Canada, and those born with CF today will live longer than those who came before them, many are still ill and 1 in 7 living with the disease today is ineligible for the treatments that are making such a positive difference for others with CF.

The input stated that, from a health care and quality-of-life perspective, there are continued challenges for those living with CF, including patients who are unable to benefit from recent life-changing treatments. For example, the 40 patients in Canada who died of CF in 2022 had a median age of 38; those with CF collectively made 17,000 clinic visits, spent 10,000 days in hospital, and spent nearly 6,000 days on IV antibiotics in 2022 alone; and for 1 in 5 adults with CF, depression or anxiety was recorded as a complication in the CCFR. As the disease progresses, more time, effort, frequent clinic visits, and hospital stays are needed to manage the progressive and debilitating symptoms. This overwhelming treatment regimen has many side effects and a significant impact on patients’ and caregivers’ day-to-day activities and quality of life and creates a huge financial burden for families.

Data from the CCFR on patients in Canada with CF who do not currently have a Health Canada indication for CFTR modulators show that 246 patients have rare mutations known to respond to ELX-TEZ-IVA. The patient input indicated that many of these patients come from diverse and often racialized backgrounds, they are already disadvantaged by health care systems that were not designed with them in mind, and they deserve the right to try ELX-TEZ-IVA, even when evidence of efficacy and safety is lacking.

According to the patient group input, patients with rare mutations and their caregivers shared their hopes to access ELX-TEZ-IVA, as they saw the benefits of the medications for those who were able to access it. Few Canadians with rare mutations that lead to CF have access to ELX-TEZ-IVA; all members of the focus groups who have rare mutations and are taking ELX-TEZ-IVA responded exceptionally well to therapy, even those who have mutations for which evidence is scarce.

Clinician Input

Input From Clinical Experts

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the review of ELX-TEZ-IVA, a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, help identify and communicate situations for which 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 input from this panel follows.

Unmet Needs

All patients living with CF have unmet therapeutic needs. No treatments are currently available that can effectively achieve the most important goals of therapy: prolong survival, prevent the need for a lung transplant, prevent an accelerated decline in lung function over time, and reverse the course of the disease. In addition, the current standard treatments are burdensome for patients and their caregivers. Patients may not respond or may stop responding over time to the currently available treatments. The majority of patients with non-F508del mutations that are responsive to ELX-TEZ-IVA do not currently have access to therapy with a CFTR modulator (only those who are currently eligible to receive IVA monotherapy).

Place in Therapy

ELX-TEZ-IVA is a CFTR modulator that functions through 2 mechanisms: ELX and TEZ increased the amount of CFTR protein at the cell surface and IVA improves the transport of chloride ions through the CFTR protein. The mechanism of action for ELX-TEZ-IVA is attractive because it acts directly on the CFTR protein to address the defects responsible for the CF phenotype. ELX-TEZ-IVA would be added to existing treatments, such as physiotherapy, mucolytics, anti-infectives, and anti-inflammatory treatments (such as azithromycin). The clinical experts noted that ELX-TEZ-IVA has replaced earlier CFTR modulators (e.g., LUM-IVA and IVA) that are, in their opinion, less effective for patients with 1 or more F508del mutations in the CFTR gene. For the current target patient population, the clinical specialists anticipated that all patients in the expanded population (i.e., those with a non-508del mutation that is responsive to ELX-TEZ-IVA) would be considered candidates for the therapy. This would include those with a gating mutation who are currently receiving treatment with IVA, provided they meet eligibility and age criteria.

It is anticipated that ELX-TEZ-IVA would be used as a preventive therapy with the goal of initiating treatment before the patient develops significant lung disease. The current treatment paradigm would be significantly altered if ELX-TEZ-IVA can successfully prevent or delay progression to end organ disease (e.g., lung transplant).

The indication currently under review is for patients aged 2 years or older. CDA-AMC has previously recommended that ELX-TEZ-IVA be reimbursed for patients aged 2 to 5 years and those 6 years and older. The clinical experts consulted for this review and those who previously responded to the call for clinician input noted that children aged between 2 and 5 years will often have structural lung disease (e.g., bronchial wall thickening, mucus plugging, bronchiectasis),¹ but that detection is challenging using the tools available to evaluate lung function in clinical practice (i.e., spirometry) or as part of a research protocol (e.g., lung clearance index). These early stages of lung abnormalities can be visualized using CT; therefore, despite younger patients with CF often demonstrating normal lung function, the underlying disease will continue to progress.¹

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

Patient Population

The diagnosis of CF is not challenging in routine clinical practice. Because all provinces and territories screen newborns for CF, most people with CF have a confirmed diagnosis by the age of 1 month (on average). SwCl testing is available and can be used reliably 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. The diagnostic guidelines are clear and there is 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 current or past treatment regimens. From a medical perspective, there is no rationale for requiring a patient to demonstrate an inadequate response or loss of response to prior therapies before initiating treatment with ELX-TEZ-IVA. It would be reasonable to require patients to complete important standard CF therapies at the same time as receiving treatment with ELX-TEZ-IVA. In clinical practice, eligible patients would be identified based on their CFTR genotype and all patients would be expected to respond to the treatment.

For the expanded indication (i.e., with a non-F508del mutation that is responsive to ELX-TEZ-IVA), the clinical experts consulted for this review noted that nearly all patients would initiate therapy with ELX-TEZ-IVA as soon as possible, provided it is safe to start to treatment. The clinical experts emphasized that ELX-TEZ-IVA has been a transformative and disease-modifying therapy for CF and that it would not be appropriate to wait until the patient shows worsening symptoms, more frequent exacerbations, or a decline in lung function to initiate treatment with ELX-TEZ-IVA.

Applicability of Existing Reimbursement Criteria to the Expanded Population

In discussions with the review team, the sponsor noted that nearly all patients in Canada aged 6 years and older who are eligible for treatment have initiated therapy with ELX-TEZ-IVA. (Some may have elected to discontinue, but all who are interested have been given the opportunity to access the drug.) For those who have initiated treatment, the sponsor noted that initial renewal criteria were met for all patients in Canada who started the therapy and wanted to continue (i.e., 100% of patients met the renewal criteria recommended by CDA-AMC and/or applied by the public drug programs). The clinical experts consulted for this review expressed general agreement with the sponsor’s position, noting that rates of initial access and renewal are high within their individual clinics. With nearly all patients currently achieving the CDA-AMC–recommended renewal criteria, the sponsor noted that requiring these assessments consumes health care resources (e.g., the time required by health care practitioners to administer and document results for each of the required tests) without adding value to patients or the health care system.

The clinical experts consulted for this review supported application of the existing criteria recommended for the reimbursement of ELX-TEZ-IVA. Consistent with input from the participating drug programs, the clinical experts noted that lack of alignment across CDA-AMC recommendations for the reimbursement of ELX-TEZ-IVA in patients with and without 1 or more F508del mutations could create implementation challenges in clinical practice.

Table 10: Current Recommended Reimbursement Conditions for Patients Aged 2 to 5 Years and 6 Years and Older

BMI = body mass index; CF = cystic fibrosis; CFQ-R = Cystic Fibrosis Questionnaire–Revised; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor.

Clinician Group Input

This section was prepared by the Clinical Review team based on the input provided by clinician groups. The full original clinician group inputs received by the review team are included in the report.

Three groups of clinicians responded to call for input: CanACT (4 clinicians contributed to the input), Edmonton Adult Cystic Fibrosis Clinic and Calgary Adult Cystic Fibrosis Clinic (2 clinicians contributed to the input), and the CF Canada Health Care Advisory Council (5 clinicians contributed to the input). The input from the clinician groups identified the same unmet medical needs for patients with CF and potential place in therapy for the drug under review as the clinical experts consulted for this review.

According to clinician groups, the treatment paradigm in Canada for patients with CF aims to maintain health (delay disease progression, improve lung function, reduce the risk for pulmonary exacerbations, and prevent the need for organ transplant), maintain or improve quality of life, and prolong life. This includes nonpharmacological approaches such as nasal sinus saline irrigation, airway clearance, and high-protein, high-calorie nutrition. Medications commonly used in CF include antibiotics, mucolytics, bronchodilators, pancreatic enzymes, fat-soluble vitamins, anti-inflammatories, insulin for people with CF-related diabetes, ursodiol for liver disease, and chest physiotherapy. Oxygen, noninvasive positive-pressure ventilation, and lung transplant are treatments for those with end-stage CF lung disease. A transformational change was the introduction of CFTR modulators, which correct the basic defect in CF by improving the production and function of the abnormal CFTR protein. The first (IVA) and second-generation (LUM-IVA and IVA-TEZ) modulators had a modest but important clinical effect, but the response to the third-generation modulator (ELX-TEZ-IVA) is substantially greater.

Clinician groups noted that there is a significant treatment gap in CF care. Of patients with CF with rare mutations who do not carry a copy of the F508del CFTR mutation but may be responsive to ELX-TEZ-IVA, 10% (n = 246) do not have access to the drug as no clinical trials have been conducted. Benefit relies solely on reports of real-world evidence, in vitro data, or individual therapy trials. The CF Canada Health Care Advisory Council added that lung-transplant recipients, particularly those with significant sinus disease, may still benefit from CF modulator therapy; however, they were excluded from the clinical trials.

The 3 clinician groups noted that ELX-TEZ-IVA is an improvement on the existing CFTR modulators and the most effective. It addresses the underlying disease process and is complementary to the existing standard of care for CF that would improve adherence, potentially delay disease progression and therefore delay the need for other therapies, including lung transplants. The CF Canada Health Care Advisory Council stated that expanding access to those patients with other responsive CFTR mutations will give another 246 patients lifelong benefits and improve equitable access to those from marginalized communities in whom these rare mutations are often found.

According to the clinician groups, any patient who carries 1 or more CFTR mutations responsive to ELX-TEZ-IVA should have access to this therapy. CanACT added that, for those with rare CFTR mutations, for whom data to support the use of ELX-TEZ-IVA are limited, each patient’s life may depend on access to this medication, and it is incumbent on regulators to use all available evidence or generate the evidence needed to allow access to this life-saving drug.

All clinician groups indicated that the outcomes of interest include meaningful clinical responses such as improvement and stabilization in lung function as measured by FEV₁ or lung clearance index (where available) obtained at a time of clinical stability, and for individuals aged 6 years or older, reduction of pulmonary exacerbations, reduction or stabilization of respiratory symptoms, stabilization or improvement in nutritional and growth status, improvement in quality-of-life scores, and reduction in SwCl.

The 3 clinician groups noted that discontinuation of therapy should be considered if there is a lack of clinical response following a therapy trial or if a severe side effect, allergy, or other AE occurs (e.g., elevation of liver function or allergic reaction). Clinician groups stated that treatment of patients with CF with ELX-TEZ-IVA should be performed by CF specialists practising at CF clinics.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 11.

Table 11: Summary of Drug Plan Input and Clinical Expert Response

CDEC = Canadian Drug Expert Committee; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor.

In Vitro Evidence

This section of the clinical report provides a summary of the FRT in vitro data used to identify the CFTR mutations that are considered to be responsive to ELX-TEZ-IVA treatment. This data has not been appraised by the review team and commentary is limited to the opinion of Canadian and international regulatory authorities regarding the validity and relevance of the study results. Perspectives from CF clinical specialists regarding the absence of clinical data for many of the CFTR mutations in the target population are also included.

Overview of In Vitro Fischer Rat Thyroid Assays

The sponsor used an in vitro FRT-cell model to characterize individual CFTR mutations that produce at least some amount of full-length CFTR proteins, for responsiveness to CFTR modulators.⁴³ The in vitro cell model uses FRT cells that express a CFTR gene with a single mutation to test for responsiveness to CFTR modulators. Each FRT-cell line is engineered to express a specific CFTR mutation in a stable, epithelial-cell background. DNA sequencing is performed on each cell line to confirm the presence of the specific CFTR mutation and quantitative polymerase chain reaction analysis is used to confirm the expression of mRNA.

The selection of CFTR mutations for inclusion in the in vitro study was based on a comprehensive understanding of CFTR mutations and the mechanism of action of CFTR modulators. Despite the occurrence of multiple CFTR mutation classes, the resulting functional abnormality is ultimately either a decreased quantity and/or decreased function of the CFTR protein. CFTR mutations selected for inclusion in the FRT assay study were based on evidence that the mutation caused CF, based on CFTR2 and/or scientific literature and in silico translation consistent with production of full-length CFTR proteins.⁵ Protein-truncating CFTR mutations, whole or partial CFTR gene deletions, and noncanonical splice mutations were excluded from the study. Positive controls and negative controls were also included in the experiments.

• The positive controls included G551D and R117H that were found in previous FRT assays to be IVA-responsive and have been demonstrated in clinical trials to provide clinical benefit for patients. (IVA is approved for use in the treatment of CF in patients who have a G551D and R117H CFTR mutation.)

• The negative controls included G1061R, R1066C, N1303K and untransfected FRT cells. These 3 CFTR mutations were identified as nonresponsive to IVA or TEZ-IVA in previous in vitro studies.

The function of CFTR at the cell surface was assessed in Ussing chamber studies, a procedure that quantifies the amount of CFTR-mediated Cl⁻ transport in FRT cells expressing each CFTR mutation form as a fraction of the Cl⁻ transport in FRT cells expressing normal CFTR (% normal).

Definition of In Vitro Response to ELX-TEZ-IVA

Responsive CFTR mutations were those that demonstrated an increase of 10% in Cl⁻ transport over baseline when expressed as a percentage of normal CFTR Cl⁻ transport. The sponsor selected this threshold because the analyses of CFTR activity and disease phenotype showed that a 10% increase in CFTR activity is associated with improved clinical status.⁴⁴ The sponsor reported that patients with a severe CF phenotype generally have CFTR function of less than 5% of normal, whereas the sponsor reported that the severity of CF begins to diminish in patients who have CFTR function of 10% of normal or higher. An increase in CFTR function of 10% or more is therefore expected to affect the disease phenotype for those living with CF.

CFTR Mutations Identified as Responsive to ELX-TEZ-IVA

Using the in vitro FRT model, the sponsor identified 177 CFTR mutations as responsive to ELX-TEZ-IVA. These additional mutations do not include F508del, which has been studied in multiple clinical trials already reviewed by CDEC. Importantly, the sponsor noted that the 10% threshold for a response should be considered conservative, citing the following additional mutations that have been included in this reimbursement review application:

• The N1303K mutation did not meet the 10% threshold in the FRT model to be considered responsive to ELX-TEZ-IVA (this mutation was chosen as 1 of the negative controls for the FRT model). However, the sponsor has filed submissions with Health Canada and CDA-AMC on the basis of real-world evidence that suggests that these patients benefit from treatment with ELX-TEZ-IVA.

• The R117C and S1255P mutations included in this reimbursement review application did not meet the 10% threshold for the FRT assay; however, previous in vitro FRT data and/or clinical data support the responsiveness of these mutations to IVA and/or TEZ-IVA (both of which are components of ELX-TEZ-IVA).

Regulatory Perspectives and Approval History

FDA Conclusions

The FDA considered the evidence from the FRT-cell model sufficient to warrant expanding the indications for ELX-TEZ-IVA, TEZ-IVA, and IVA. The FDA was the first regulatory authority to expand the use of CFTR modulators (including ELX-TEZ-IVA) based on in vitro data from the FRT model. As shown in Table 12, the FDA initially expanded the use of IVA monotherapy based on in vitro data in May 2017. Subsequent approvals followed for TEZ-IVA in June 2019, and for ELX-TEZ-IVA, TEZ-IVA, and IVA monotherapy in December 2020. In total, the FDA has approved ELX-TEZ-IVA for 178 CFTR mutations, TEZ-IVA for 154 CFTR mutations, and IVA for 97 CFTR mutations.

Table 12: FDA Approvals for CFTR Modulators Based on In Vitro Evidence

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

Health Canada Conclusions

Health Canada–approved the use of ELX-TEZ-IVA for 147 of the 177 mutations that were responsive to ELX-TEZ-IVA in the FRT model, based on pivotal and/or supporting clinical data, the biological plausibility that the treatment would provide a substantive beneficial treatment effect, and the rarity of the CFTR mutations that are the subject of this review (i.e., clinical evidence collection would be challenging because of the small number of patients with each of the mutations). Of the 177 FRT-responsive CFTR mutations approved by the FDA and submitted for review to Health Canada and CDA-AMC, Health Canada did not authorize use for 30 of the mutations for the following reasons:

• 15 mutations were considered by Health Canada as not causative of CF, based on the CFTR2 and CFTR-France databases: D836Y, F508C, G576A, I148T, I807M, I1027T, L320V, L997F, R75Q, R170H, R668C, R1162L, T1053I, V562I, and V754M.

• 10 mutations were excluded because of unknown clinical significance, were only reported as causing a CFTR-related disease (i.e., not CF), and retain at least 50% of normal chloride-transport function: G178E, G576A;R668C, I1139V, K1060T, R31L, R553Q, R751L, R792G, V1293G, Y1014C.

• 5 mutations were excluded because they result in a cryptic splice mutation, and insufficient full-length CFTR: H939R, I175V, M152V, E403D, and S589N.

The Health Canada–approved product monograph states the following regarding the interpretation of the in vitro data: The in vitro CFTR-mediated chloride-transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or is reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated Cl⁻ transport in vitro is not correlated with the magnitude of clinical response. Not all mutations can be tested in the FRT system, but patients harbouring some mutations not amenable to testing in this system may demonstrate clinical benefit. Clinical outcomes were consistent with in vitro results and indicate that a single mutation responsive to ELX-TEZ-IVA is sufficient to generate a significant clinical response.

Perspectives of Cystic Fibrosis Specialists

The clinical experts consulted for this review noted that responsiveness to ELX-TEZ-IVA using the in vitro model applied by Vertex in the clinical development program for patients with rare CFTR mutations is sufficient evidence to support prescribing it to these patients. In addition to regulatory approval based on this information (e.g., FDA approvals), the clinical experts cited the following considerations that would support the use of ELX-TEZ-IVA in clinical practice:

• There is a lack of alternative treatment options for these patients and the severe progressive nature of CF.

• In vitro data demonstrating activity on the CFTR channel for patients with these rare mutations supports extrapolation of the clinical benefit demonstrated in studies involving more common CF-causing mutations in the CFTR gene.

• There are concerns about equity for those living with CFTR mutations for which the incidence is sufficiently low to preclude the generation of robust clinical evidence. The clinical experts noted that CF with a non-F508del mutation is more likely to be diagnosed in racial minorities who may already be encountering systemic disadvantages within the health care system. Based on the rarity of these “rarer” mutations, it would be impossible to include participants with each mutation into clinical trials. The current focus on clinical trial data alone for drug approval is resulting in ethnic and racial inequity in medication access. It is well known that patients from minority groups are underrepresented in clinical trials for a multitude of reasons (as discussed in the Ethics Review Report).

• There is a mounting body of evidence from case reports, case series, and clinical experience that ELX-TEZ-IVA can have a clinically meaningful impact on patients with rare CFTR mutations shown to be responsive based on in vitro data.

In addition, the clinical experts noted that patients with CF living in Canada are monitored in specialized clinics with well-organized and frequent clinical and laboratory evaluations to ensure the treatment is used appropriately and safely in clinical practice. The clinical specialists emphasized that the in vitro data should not be viewed in insolation and that is important to consider the large body of evidence demonstrating the clear and clinically important benefits of ELX-TEZ-IVA and the relatively few serious harms associated with the treatment (i.e., this is no longer a new drug in the management of CF). The specialists noted that the totality of information, including real-world experience with the drug, for those with 1 or more F508del mutations, supports the expanded use of the drug by those with rare CFTR mutations.

Clinical Evidence

The objective of the Clinical Review is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of ELX-TEZ-IVA in the treatment of CF in patients aged 2 years and older who have a non-F508del mutation in the CFTR gene that is responsive to ELX-TEZ-IVA based on in vitro and/or clinical data. The focus will be placed on comparing ELX-TEZ-IVA to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of ELX-TEZ-IVA is presented in 4 sections, with critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted long-term extension studies. The third section includes indirect evidence from the sponsor (not submitted). The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

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

• 1 RCT identified in systematic review (Study 124)

• 1 long-term extension study (Study 125)

• 5 additional studies addressing gaps in evidence:

  • 1 study involving patients with FRT-responsive mutations (64 mutations)

  • 4 studies involving patients with at least 1 N1303K mutation.

Systematic Review

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 13.

Table 13: Details of Studies Included in the Systematic Review

AE = adverse event; BMI = body mass index; CF = cystic fibrosis; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; IVA = ivacaftor; PEx = pulmonary exacerbations; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SAE = serious adverse event; SwCl = sweat chloride.

Source: Clinical Study Report.⁴⁵

The objective of Study 124 was to evaluate the efficacy, pharmacodynamics, and safety of ELX-TEZ-IVA in patients with a non-F508del ELX-TEZ-IVA–responsive CFTR mutation. This study was a phase III double-blinded, randomized, placebo-controlled trial. Participants aged 6 years and older from 84 sites across Europe and Canada were recruited and randomized, with 205 participants enrolled in the ELX-TEZ-IVA treatment arm and 102 participants enrolled in the placebo-controlled arm. To achieve balanced treatment arms, randomization utilized stratification based on ppFEV₁ at screening (< 70% versus ≥ 70%), age at screening (< 18 years versus ≥ 18 years), and mutation groups (≥ 1 residual function [RF]-like] mutation versus no RF-like mutation). A summary timeline of the study duration in available in Figure 2.

Figure 2: Design of Study 124

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

Populations

Inclusion and Exclusion Criteria

Eligible participants with stable CF, as judged by investigators, were at least 6 years of age with a non-F508del CFTR mutation responsive to ELX-TEZ-IVA based on the FRT assay with no exclusionary CFTR mutations (i.e., F508del, S549N, G551S, S1255P, R117H, S549R, G1244E, G1349D, G178R, G551D, and S1251N). The sponsor reported that 18 of the most prevalent CFTR mutations in Europe and Canada that are not currently indicated for a CFTR modulator were eligible (representing approximately 80% of the target patient population). The use of ELX-TEZ-IVA was approved by Health Canada for 17 of the 18 CFTR mutations included in Study 124 (1 mutation [L997F] was excluded by Health Canada on the basis that it has not been demonstrated to cause CF). Participants had to have a ppFEV₁ value of between 40% and 100% of predicted mean for age, sex, and height.

Participants were excluded if they had an acute upper or lower respiratory infection, PEx, or change in therapy (including antibiotics) for sinopulmonary disease within 28 days before the first dose of the study drug, or a lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, B. cenocepacia, B. dolosa, and M. abscessus). Participants with the following laboratory measures and illnesses were excluded: hemoglobin less than 10 g/dL; total bilirubin at least twice the upper limit of normal (ULN); aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, or alkaline phosphatase at least 3 times the ULN; abnormal renal function was defined as glomerular filtration rate of up to 50 mL/min/1.73 m² (calculated by the modification of diet in renal disease study equation) for patients aged 18 years of age or older and up to 45 mL/min/1.73 m² (calculated by the Counahan-Barratt equation) for patients aged younger than 18 years.

Interventions

ELX-TEZ-IVA was orally administered as fixed-dose combination tablets in the morning along with an oral administration of IVA tablets in the evening. Placebo-arm treatments were matched to both ELX-TEZ-IVA and IVA administrations in dose and timing.

Outcomes

A list of efficacy end points assessed in this Clinical Review is provided in Table 14, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review by the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were considered most relevant to inform the expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations were also assessed using GRADE.

Percent Predicted FEV₁

The ppFEV₁ (in litres) was calculated using the ratio of FEV₁ to the predicted FEV₁. The ppFEV₁ was calculated using the equations of the Global Lung Function Initiative. Absolute change from baseline was calculated as postbaseline value minus baseline value. Absolute change from baseline in ppFEV₁ was the primary end point of Study 124 (evaluated through 24 weeks). The clinical experts consulted for this review noted that an absolute improvement of 5% is typically considered to be meaningful for acute changes in ppFEV₁; however, they noted that even stabilization of ppFEV₁ can be meaningful for patients, particularly those who are at risk of rapid decline.

Table 14: Outcomes Summarized From the Studies Included in the Systematic Review

AE = adverse event; BMI = body mass index; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); PEx = pulmonary exacerbations; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SAE = serious adverse event; SwCl = sweat chloride.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Sweat Chloride

As a biomarker of CFTR activity, SwCl testing is a standard diagnostic tool for CF. SwCl tests were conducted before administration of the morning dose of the study drug. Absolute change from baseline in SwCl through 24 weeks was a secondary end point in Study 124.

CFQ-R Respiratory Domain

The CFQ-R is a disease-specific, health-related quality-of-life instrument designed for patients with CF that is available in age-appropriate versions for children aged 6 to 13 years, parents who serve as a proxy for their child, and individuals 14 years of age and older.⁷³ For children aged 6 to 11 years, the questionnaire is interviewer-administered, and for those aged 12 and 13 years, it is self-administered.⁷⁴ The number of items and domains vary between versions; the children’s version includes 35 items within 8 domains, the parent version has 44 items and 11 domains, and the adolescent and adult version has 50 items within 12 domains.^73,74 The domains in the adolescent and adult version have a health-related quality-of-life module that include physical functioning, vitality, emotional functioning, social or school functioning, role functioning, body image, eating problems, and 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, or never), intensity (a great deal, somewhat, a little, or not at all), and true-false scales (very true, somewhat true, somewhat false, or 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. The scales are designed to measure symptoms and functioning during the 2-week period before administration of the questionnaire. A difference of at least 4 points in the respiratory domain score of the CFQ-R is commonly cited as the MID for patients with CF.

Pulmonary Exacerbations

PEx was defined as a new or 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 above 38°C (equivalent to approximately 100.4°F)

• anorexia or weight loss

• sinus pain or tenderness

• change in sinus discharge

• change in physical examination of the chest

• decrease in pulmonary function by 10%

• radiographic changes indicative of pulmonary infection.

Adverse Events

An AE is defined as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or worsening of a pre-existing condition (e.g., an increase in its severity or frequency).

Statistical Analysis

Clinical Trial End Points

Primary End-Point Analysis (ppFEV₁)

The primary analysis was performed using a mixed-effects model for repeated measures (MMRM) with change from baseline at day 15, week 4, week 8, week 16, and week 24 as the dependent variables. The model included treatment group, visit, and treatment by visit interaction as fixed effects, with continuous baseline ppFEV₁, age at screening (< 18 versus ≥ 18 years), and mutation group (contains ≥ 1 RF-like mutation versus does not contain an RF-like mutation) as covariates.

Secondary Continuous End-Point Analysis (SwCl, CFQ-R [RD], BMI, and Weight)

The analysis of absolute change from baseline in SwCl, CFQ-R (RD), BMI, and weight was based on an MMRM similar to the analysis of the primary end point, with absolute change from baseline at day 15 (if applicable), week 4, week 8, week 16, and week 24 as the dependent variables. For SwCl and CFQ-R (RD), the primary result obtained from the model was the estimated treatment difference through week 24 defined as the averaged treatment effects estimated at week 4, week 8, week 16, and week 24.

Secondary End-Point Analysis (Number of PEx Events)

A PEx event was defined as new or change in antibiotic therapy (IV, inhaled, or oral) in 4 or more sinopulmonary signs and/or symptoms. The number of PEx events during the PEx analysis period for week 24 was performed using a negative binomial regression model with a fixed effect for treatment, as well as continuous baseline ppFEV₁, age at screening (< 18 years versus ≥ 18 years), and mutation group (contains 1 or more RF-like mutations versus does not contain an RF-like mutation) as covariates. The logarithm of the subject-specific PEx analysis period duration (in years) was treated as the offset in the model. The estimated rate ratio and the associated 2-sided 95% CI and 2-sided P value were provided.

BMI Z Score and Weight Z Scores

The BMI and weight z scores were calculated by using Centers for Disease Control and Prevention growth charts.⁴⁶ Analysis of BMI z scores and weight z scores were based on an MMRM similar to that of the analysis of the primary efficacy variable, excluding the covariate of age at screening (< 18 years versus ≥ 18 years), for patients aged 20 years or younger at baseline. Data obtained from visits at day 15, week 4, week 8, week 16, and week 24 were included in the model.

Safety Analyses

All safety analyses were based on data from the treatment-emergent period, which included the time from the date of the first dose of the study drug to 28 days after the last dose of the study drug or to the completion of study participation date, whichever occurred first.

Sample Size and Power Calculation

Approximately 270 patients were planned to be enrolled and randomized (2:1) to the ELX-TEZ-IVA or placebo groups. The primary end point was the absolute change from baseline in ppFEV₁ through week 24. The primary null hypothesis to be tested was that the mean absolute change from baseline in ppFEV₁ through week 24 is the same for the ELX-TEZ-IVA and placebo treatment groups. The null hypothesis was tested at a 2-sided significance level of 0.05. Assuming a within-group SD of 9 percentage points and a 10% dropout rate at week 24, a total sample size of 270 patients (180 patients in the ELX-TEZ-IVA group and 90 in placebo group) was estimated to have an approximately 90% power to detect a difference of 4.0 percentage points for the mean absolute change from baseline in ppFEV₁ through week 24 between the 2 treatment groups, based on a 2-sided, 2-sample t test at a significance level of 0.05.

Statistical Test or Model

An MMRM approach was used to assess the primary and most secondary end points. The model was estimated using a restricted maximum likelihood. Denominator degrees of freedom for the F test for fixed effects were estimated using the Kenward-Roger approximation. An unstructured covariance structure was used to model the within-subject errors. If the model estimation did not converge, a compound symmetry covariance structure was used instead. Depending on the observed data and covariates, missing data were assumed to be missing at random.

Multiple Testing Procedure

The secondary end points were formally tested at an alpha of 0.05. A hierarchical testing procedure was used to control the type I error rate for the multiple secondary end points tested at an alpha of 0.05. For a test at any step to be considered statistically significant within the testing hierarchy, it must have been statistically significant, and all previous tests (if any) within the hierarchy must also have been statistically significant at the 0.05 level. The testing order of the secondary end points was as follows:

• First secondary end point: absolute change in SwCl from baseline through week 24

• Second secondary end point: absolute change in CFQ-R RD from baseline through week 24

• Third secondary end point: absolute change in BMI from baseline at week 24

• Fourth secondary end point: absolute change in weight from baseline at week 24

• Fifth secondary end point: number of PEx events through week 24.

Subgroup Analyses

The MMRM used for the primary analysis was used for the subgroup analysis, with the same model applied to each category of the subgroup: age at screening (< 18 years versus ≥ 18 years), ppFEV₁ (< 70 versus ≥ 70), and sex (male or female). For the subgroup analysis based on age, the covariate of age at screening (< 18 years versus ≥ 18 years) from the MMRM was removed. The adjusted means with 2-sided 95% CIs were provided. The estimated between-group difference through week 24 within a subgroup was also presented in a forest plot.

Analysis Populations

A summary of analysis sets defined in Study 124 is presented in Table 16.

Table 15: Statistical Analysis of Efficacy End Points of Study 124

BMI = body mass index; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; MMRM = mixed-effects model for repeated measures; NR = not reported; PEx = pulmonary exacerbation; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Table 16: Analysis Populations of Study 124

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

A summary of patient dispositions for Study 124 is presented in Table 17.

Baseline Characteristics

The baseline characteristics outlined in Table 18 are limited to those that are most relevant to this review or were assumed to affect the outcomes or interpretation of the study results.

Table 17: Summary of Patient Disposition From Study 124

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; NR = not reported.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Table 18: Summary of Baseline Characteristics From Study 124

BMI = body mass index; CFQ-R (RD) = Cystic Fibrosis Questionnaire-Revised (respiratory domain); ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in 1 second; RF = residual function; SD = standard deviation.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

A summary of patient exposure to ELX-TEZ-IVA or placebo for Study 124 is presented in Table 19.

Concomitant Medications and Co-Interventions

Table 20 provides a summary of concomitant medications used among patients in Study 124.

Table 19: Summary of Patient Exposure From Study 124

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; SD = standard deviation.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Table 20: Summary of Concomitant Medications From Study 124 (At Least 20% of Patients)

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

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Efficacy

Absolute Change in ppFEV₁

In Study 124, totals of 192 and 98 patients in the full analysis set (FAS) were evaluated through week 24 in the ELX-TEZ-IVA and placebo arms, respectively. Results showed an LS absolute change from baseline in ppFEV₁ of 8.9 (SD = 0.6) in the ELX-TEZ-IVA arm versus −0.4 (SD = 0.8) in the placebo arm (Figure 3). MMRM analysis of this primary end point showed an LS mean difference for ELX-TEZ-IVA versus placebo of 9.2% (95% CI, 7.2 to 11.3; P < 0.0001).

Figure 3: MMRM Analysis of Absolute Change From Baseline in ppFEV₁ (Percentage Points) at Each Visit up to Week 24 (Full Analysis Set)

ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; LS = least squares; MMRM = mixed-effects model for repeated measures; ppFEV1 = percent predicted forced expiratory volume in 1 second; SE = standard error.

Source: Clinical Study Report.⁴⁵

Absolute Change in Sweat Chloride

In Study 124, totals of 200 and 100 patients in the FAS were evaluated through week 24 in the ELX-TEZ-IVA and placebo arms, respectively. Results showed an absolute change from baseline for SwCl, with an LS mean of −27.8 (SD = 1.1) in the ELX-TEZ-IVA arm versus 0.5 (SD = 1.6) in the placebo arm. An MMRM analysis of this secondary end point showed a statistically significant improvement (i.e., a reduction) in absolute change from baseline in SwCl for ELX-TEZ-IVA versus placebo, with an LS mean difference from placebo of −28.3 mmol/L (95% CI, −32.1 to −24.5; P < 0.0001).

Absolute Change in CFQ-R (RD) Score

In Study 124, totals of 202 and 102 patients in the FAS were evaluated through week 24 in the ELX-TEZ-IVA and placebo arms, respectively. Results showed an LS absolute change from baseline in CFQ-R (RD) score of 17.5 (SD = 1.2) in the ELX-TEZ-IVA arm versus −2.0 (SD = 1.6) in the placebo arm (Figure 4). MMRM analysis of this secondary end point showed a statistically significant LS mean difference for ELX-TEZ-IVA versus placebo of 19.5 points (95% CI, 15.5 to 23.5; P < 0.0001).

Figure 4: MMRM Analysis of Absolute Change From Baseline in CFQ-R (RD) Score at Each Visit up to Week 24 (Full Analysis Set)

CFQ-R = Cystic Fibrosis Questionnaire-Revised; ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; LS = least squares; MMRM = mixed-effects model for repeated measures; SE = standard error.

Source: Clinical Study Report.⁴⁵

Absolute Change in BMI

In Study 124, totals of 196 and 102 patients in the FAS were evaluated through week 24 in the ELX-TEZ-IVA and placebo arms, respectively. Results showed an absolute change from baseline for BMI with an LS mean of 0.81 (SD = 0.07) in the ELX-TEZ-IVA arm versus 0.35 (SD = 0.09) in the placebo arm (Figure 5). MMRM analysis of this secondary end point revealed a statistically significant change in absolute change from baseline in BMI for ELX-TEZ-IVA versus placebo, with an LS mean difference from placebo of 0.47 kg/m² (95% CI, 0.24 to 0.69; P < 0.0001).

Figure 5: Absolute Change From Baseline in BMI at Each Visit up to Week 24 (FAS)

BMI = body mass index; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; FAS = Full Analysis Set; LS = least squares; SE = standard error.

Source: Clinical Study Report.⁴⁵

Absolute Change in Weight

Results showed an absolute change from baseline for weight with an LS mean of 2.4 (SD = 0.2) in the ELX-TEZ-IVA arm versus 1.2 (SD = 0.3) in the placebo arm. MMRM analysis of this secondary end point showed a statistically significant change in absolute change from baseline in weight for ELX-TEZ-IVA versus placebo, with an LS mean difference from placebo of 1.3 kg (95% CI, 0.6 to 1.9; P < 0.0001).

Number of PEx Events

Results showed an estimated event rate per year of 0.17 in the ELX-TEZ-IVA arm versus 0.63 in the placebo arm. Analysis of this secondary end point showed a statistically significant reduction in PEx events through week 24, with a PEx rate that was 72% lower in the ELX-TEZ-IVA arm versus placebo (rate ratio = 0.28; 95% CI, 0.15 to 0.51; P < 0.0001).

Absolute Change in BMI Z Score (Patients Aged 20 Years or Younger)

Results showed an absolute change from baseline for BMI z score, with an LS mean of 0.22 (SD = 0.04) in the ELX-TEZ-IVA arm versus 0.14 (SD = 0.06) in the placebo arm. MMRM analysis of this end point showed a change in absolute change from baseline in BMI z score for ELX-TEZ-IVA versus placebo, with an LS mean difference from placebo of 0.08 (95% CI, −0.06 to 0.22).

Absolute Change in Body Weight Z Score (Patients Aged 20 Years or Younger)

Results showed an absolute change from baseline for weight z score, with an LS mean of 0.21 (SD = 0.03) in the ELX-TEZ-IVA arm versus 0.14 (SD = 0.05) in the placebo arm. MMRM analysis of this end point showed a change in absolute change from baseline in weight z score for ELX-TEZ-IVA versus placebo, with an LS mean difference from placebo of 0.06 (95% CI, −0.06 to 0.18).

Table 21: Summary of Results From Study 124 (Full Analysis Set)

BMI = body mass index; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; LS = least squares; NR = not reported; PEx = pulmonary exacerbations; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation; SwCl = sweat chloride.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Subgroup Analyses for Noncanonical Splice Mutations

Study 124 enrolled patients with 3 of the 5 noncanonical splice mutations in the target patient population for this review (2789 + 5G > A, 3272 to 26A > G, and 3849 + 10kbC > T). The sponsor conducted subgroup analyses for absolute change from baseline through 24 weeks in ppFEV₁, SwCl, and CFQ-R (RD) (Table 22). Results of these analyses were consistent with the primary analyses.

Table 22: Results of Splicing Mutation Subgroup from Study 124 (Full Analysis Set)

CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation; SwCl = sweat chloride.

Source: Clinical Study Report.⁴⁵

Subgroup Analyses for Patients With Only 1 Responsive Mutation

The majority of patients enrolled in Study 124 were heterozygous for the CFTR mutations and some patients carried complex alleles (i.e., multiple mutations on 1 allele), Health Canada requested that the sponsor provide additional analyses for Study 124 showing a by-mutation analysis for patients who have only a single potentially responsive target mutation on 1 allele, and either the same single mutation on the second allele or a mutation expected to be nonresponsive (e.g., a frameshift, large deletion, or premature stop codon). The results are summarized in Table 23, with the majority showing within-group improvements comparable to the primary analysis Comparisons for these subgroups were not provided versus placebo. The sample sizes were small for these subgroups and baseline values varied, which may affect the magnitude of change observed after the 24-week treatment period.

Table 23: Redacted

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Harms

Table 24 provides a summary of harms data.

Adverse Events

The proportions of patients who experienced at least 1 AE were 94.1% in the ELX-TEZ-IVA group and 95.1% in the placebo group. The majority of AEs were mild or moderate in severity. Severe AEs occurred in 15 patients (7.3%) in the ELX-TEZ-IVA group and 12 patients (11.8%) in the placebo group.

Serious Adverse Events

Serious AEs occurred in 18 patients (8.8%) in the ELX-TEZ-IVA group and 15 patients (14.7%) in the placebo group. SAEs that occurred in 2 or more patients in the ELX-TEZ-IVA group included infective PEx of CF (5 patients) and bronchopulmonary aspergillosis allergic (2 patients). The only SAE that occurred in 2 or more patients in the placebo group was infective PEx of CF (13 patients).

Withdrawal Due to Adverse Events

Drug interruptions due to AEs were reported in 12.2% of patients in the ELX-TEZ-IVA group and 1.0% of the placebo group. AEs that led to treatment interruption for at least 1 patient in the ELX-TEZ-IVA group were rash (n = 14), increased alanine transaminase (n = 3), increased aspartate transaminase (n = 3), and increased gamma-glutamyl transferase (n = 3). Five (2.4%) patients in the ELX-TEZ-IVA group discontinued due to AEs (1 patient because of liver function test elevations, 1 patient due to AEs of lung adenocarcinoma and pneumonia, 1 patient because of diarrhea, 1 patient because of hepatic cytolysis, and 1 patient because of rash maculopapular). No patients in the placebo group discontinued due to an AE.

Mortality

One patient in the ELX-TEZ-IVA group (0.5%) died due to an SAE of lung adenocarcinoma that was not considered related to study drug treatment.

Notable Harms

Elevated transaminase events were considered AESIs and occurred in | ██████ patients in the ELX-TEZ-IVA group and no patients in the placebo group. All elevated transaminase events were mild or moderate in severity, and none were serious. Rash events were also considered AESIs and occurred in 55 patients in the ELX-TEZ-IVA group (26.8%) and 3 patients in the placebo group (2.9%). The majority of rash events were mild or moderate in severity. One subject in the ELX-TEZ-IVA group (0.5%) had a serious rash event that was considered related to study drug treatment.

Table 24: Summary of Harms Results From Studies Included in the Systematic Review

AE = adverse event; CF = cystic fibrosis; CK = creatine kinase; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; PEx = pulmonary expulsion; SAE = serious adverse event.

^aLabelled in ELX-TEZ-IVA controlled-drug delivery system.

^bAE belongs to 1 subject.

^cAE belongs to 1 subject.

Sources: Clinical Study Report⁴⁵ and the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Randomization was performed using an appropriate methodology with adequate allocation concealment (i.e., an interactive web response system) and stratification based on relevant prognostic factors (i.e., age [aged < 18 years versus ≥ 18 years], baseline ppFEV₁ [< 70% versus ≥ 70%], and CFTR genotype [contains ≥ 1 RF-like mutation versus does not contain an RF-like mutation]). Baseline and demographic characteristics were generally well balanced across the ELX-TEZ-IVA and placebo groups. Baseline BMI z scores and weight z scores were lower in the placebo group (−0.2 and −0.3, respectively) compared with the ELX-TEZ-IVA group (−0.3 and −0.4, respectively). The clinical experts consulted for this review noted these differences are unlikely to be clinically relevant.

Minor imbalances with the prior and concomitant medications were reported. A greater proportion of patients in the placebo group compared with the ELX-TEZ-IVA group reported prior use of inhaled hypertonic saline at baseline (52.0% versus 44.4%, respectively) and used inhaled hypertonic saline during the study (61.8% versus 56.6%, respectively). A greater proportion of patients in the ELX-TEZ-IVA group reported use of dornase alfa during the study compared with the placebo group (61.8% versus 56.6%, respectively). Any potential impact of these imbalances is uncertain (e.g., concomitant therapies could potentially benefit respiratory end points, or they could be indication that these patients had more severe disease that required additional treatment). The clinical experts consulted for this review noted that the differences are unlikely to be clinically relevant.

Study treatments were administered in a double-blind manner, with all groups issued the same number of tablets each day. The ELX-TEZ-IVA tablets were identical in appearance to the placebo tablets. The AE profile of ELX-TEZ-IVA was unlikely to compromise blinding in the study, except for those who experienced a rash after initiating treatment with ELX-TEZ-IVA (22% in the ELX-TEZ-IVA versus 1% in the placebo group). Rash is a well-known AE associated with ELX-TEZ-IVA treatment and is documented in the Canadian product monograph, which notes that the event is more common in females using hormonal contraceptive therapy. The observation of an elevated incidence of rash in the ELX-TEZ-IVA group is consistent with previous ELX-TEZ-IVA pivotal trials, although the proportion of patients affected in Study 124 (22%) is higher than in the other pivotal trials (approximately 10% for both the adolescent and adult and the pediatric trials). The clinical experts noted that these events would likely have compromised blinding for those affected but does not affect the overall interpretation of the results. The review team agreed that, given assessment of the efficacy outcomes investigated, and with the exception of health-related quality of life, the study’s results are relatively objective and less susceptible to bias from unblinding or patients or investigators.

Patient disposition was thoroughly documented and well reported by the sponsor in its application to CDA-AMC. Few patients discontinued the trials (the completion rate was 96.1% with ELX-TEZ-IVA and 100% with placebo), although the studies were relatively short in duration, which may in part explain the high percentage of patients who completed. Each FAS included all randomized patients.

Adherence to the study treatments, which was evaluated by counting the number of study drugs at each visit, was reported to exceed 98.9% in Study 124. In accordance with the study protocol, the use of concomitant medications remained stable throughout the treatment period.

There are no globally accepted definitions for PEx events in patients with CF. The definitions used in Study 124 were considered appropriate by regulatory authorities and the clinical experts consulted for this review. There was no independent adjudication of PEx events. When evaluated as an efficacy end point, fewer patients in Study 124 met the criteria for a PEx compared to the number of events reported as AEs (i.e., 36.3% versus 25.5% in the placebo group and 15.1% versus 8.8% in the ELX-TEZ-IVA group). Unlike previous ELX-TEZ-IVA clinical trials, Study 124 did not include a separate evaluation of PEx events that required the use of IV antibiotics and/or hospitalization. The clinical experts consulted for this review were not concerned about the absence of separate end points evaluating potential reductions in PEx events that required the use of IV antibiotics and/or hospitalization. The 24-week study period reduces the accuracy and variance of the point estimates for the PEx rates because of seasonal variation and other temporal factors that require longer follow-up to accurately estimate (ideally, at least 12 months of follow-up would account for these variables).

Statistical power calculations were reported for Study 124 and a sufficient number of patients were enrolled and completed the study. The number of withdrawals from the trials was well below the 10% proportion assumed in the sponsor’s statistical power calculations. The MMRM analyses for the primary and secondary evaluations assumed data were missing at random, which may not be a valid assumption. However, the amount of missing data in the trials was low and sensitivity analyses using multiple imputation were supportive of the primary analyses. The analyses in Study 124 were not true intention-to-treat analyses, although the majority of patients enrolled in the study were accounted for in the analyses (e.g., 95% of patients included in the primary analysis for change from baseline in ppFEV₁).

In Study 124, the primary end point was the absolute change from baseline in ppFEV₁ through 24 weeks. The key secondary end points were tested using a hierarchical approach to control the overall type I error rate at 0.05. All end points within the statistical testing hierarchies were statistically significant. Subgroup analyses and exploratory end points were tested without adjustment for multiple comparisons and all P values are considered nominal.

External Validity

The diagnostic criteria used in the screening process for Study 124 were consistent with Canadian clinical practice for identifying patients with CF. Because the sponsor reported that all patients with CF in Canada have their genotype evaluated, identification of those who could be considered candidates for ELX-TEZ-IVA based on the expanded patient population would not be problematic in practice. The clinical experts consulted for this review noted that prescribing ELX-TEZ-IVA to patients with these additional CFTR mutations would be integrated into Canadian clinical practice in the same manner as done for previous mutations (i.e., all patients would be considered candidates as there are no other potential disease-modifying therapies available for the target population).

Patients with CF with more severe lung disease (e.g., a ppFEV₁ < 40% at screening) were excluded from Study 124; the results are therefore primarily applicable to patients with moderate (i.e., an FEV₁ of 40% to 69%) to mild (i.e., FEV₁ of 70% to 89%) lung disease. This is identical to the phase III trials previously conducted by the sponsor for ELX-TEZ-IVA and for other approved combination CFTR modulators (LUM-IVA and TEZ-IVA). The sponsor has previously reported that this population was selected because it was considered to be the most likely patient group to show an improvement in lung function in a clinical trial based on their experience with other therapies targeting CF lung disease. These screening criteria resulted in trial populations for which the proportion of patients with mild lung disease was generally similar to that of the adult CF population in Canada (approximately 27% of patients had mild lung disease in 2019).¹⁷ The proportion of patients with moderate lung disease in Study 124 was comparable to that of the overall adult CF population in Canada (approximately 38% in 2019).¹⁷ Previous CDA-AMC reviews evaluated data for the use of ELX-TEZ-IVA in patients with 1 or more F508del mutations who had more severe disease lung disease at the time of treatment initiation. Consistent with input from clinical specialists, these studies suggest that patients with advanced lung disease benefit from ELX-TEZ-IVA. In the current application, the sponsor has included 2 studies from a compassionate-access program in France that evaluated the use of ELX-TEZ-IVA in patients with advanced lung disease who have 1 or more N1303K mutations (Burgel et al. [2023]^3,13 and Burgel et al. [2024]⁴ in the Studies Addressing Gaps in the Systematic Review Evidence section).

A majority of the participants in Study 124 were from Europe (92.2%) and the remaining patients were from sites in Canada (7.8%). Study 124 was conducted to support regulatory applications in Europe and Canada, which explains the absence of sites in the US (where ELX-TEZ-IVA has been approved for use in responsive nonF508del mutations since 2020). The clinical experts consulted noted that the results from centres in Europe would be generalizable to the Canadian setting. Study 124 was conducted at specialized CF clinics, which is consistent with Canadian clinical practice.

The Cystic Fibrosis Foundation clinical practice guidelines recommend that adult women and men (aged ≥ 20 years) maintain a BMI at or above 22 kg/m² and 23 kg/m², respectively. Mean baseline BMI was similar in Study 124 was 22.46 (SD = 4.45) which is similar to the estimated national median BMI for adult patients with CF (22.7 kg/m²) in Canada.¹⁷

As with previous CFTR-modulator studies, Study 124 excluded patients with a history of colonization with B. cenocepacia, B. dolosa, and/or M. abscessus. The CCFR indicated that 3.9% of patients with CF in Canada (88.4% of whom are adults) were infected with B. cepacia complex species in 2021.¹⁸ The clinical experts consulted for this review noted that the exclusion of such patients does not significantly lower the generalizability of the study results, given that these patients represent a small minority of those who could be eligible for ELX-TEZ-IVA and that the clinical management of such patients is more complex and variable than those without B. cepacia infection. CDA-AMC committees have previously acknowledged the unmet need for these patients.

The studies included excluded patients who had a respiratory infection, PEx, or changes in their therapy for pulmonary disease within 4 weeks before the first dose of the study drug. These are identical to the exclusion criteria used in the pivotal trials for the other CFTR modulators that are currently approved. The clinical experts consulted for this review noted that the exclusion of these patients is unlikely to limit the generalizability of the results to the broader population of patients with CF.

The use of placebo as the comparator in Study 124 is appropriate given CFTR modulators are not approved for the target patient population, except for the subset of patients who have a CFTR gating mutation and are currently eligible for treatment with IVA monotherapy. As noted in the Indirect Evidence section, the exclusion of an indirect comparison evaluating the comparative efficacy of ELX-TEZ-IVA versus IVA from the application is not considered an important limitation by the review team.

Study 124 investigated the use of ELX-TEZ-IVA at the dosage recommended in the Canadian product monograph. All studies compared the addition of the study treatments to ongoing standard CF-management therapies, which is reflective of how ELX-TEZ-IVA and other CFTR modulators would be administered in clinical practice. In general, the background therapies that were reported at baseline in the included studies were consistent with those used in Canadian clinical practice.

Similar to the pivotal trials for LUM-IVA⁴⁷ and TEZ-IVA,^48,49 patients in Study 124 were permitted to use inhaled hypertonic saline, which is commonly used in Canadian clinical practice. This feature improves the generalizability of the studies compared with the pivotal studies for ivacaftor (i.e., the STRIVE, ENVISION, and KONNECTION studies),^50-52 during which patients were required to discontinue use of hypertonic saline. CDEC had previously noted that the exclusion of concomitant inhaled hypertonic saline was an important limitation of the IVA clinical study.^35,36

Study 124 evaluated the impact of ELX-TEZ-IVA on a range of different outcomes that are important in the management of CF. These included respiratory function (ppFEV₁), nutritional status and growth (e.g., weight and BMI), health-related quality of life (CFQ-R), and clinical events (PEx events). As noted in the input from clinician groups, the end points in the clinical trials largely align with those that are evaluated in routine clinical practice. Spirometry measurements were standardized and performed according to American Thoracic Society guidelines (e.g., prebronchodilator and before dosing).^53,54

The 24-week treatment period used in Study 124 was sufficient for observing treatment differences in the primary and secondary end points; however, the duration was insufficient to determine whether treatment with ELX-TEZ-IVA has the potential to modify the course of disease for patients with CF. Previous CDA-AMC reviews of ELX-TEZ-IVA have evaluated evidence indicating that the impact of the treatment is durable; this is consistent with input from clinicians in Canada who have noted important long-term improvements in patients who initiate and continue with treatment. The reduction in PEx rates reported in Study 124 may not be observed to the same extent in clinical practice because of the relatively short duration of the trial and the effect on the accuracy of the rates (although the clinical specialists consulted during this review supported the effectiveness of ELX-TEZ-IVA for reducing exacerbations based on real-world use in their clinics for those with 1 or more 508del mutations in the CFTR gene).

As with the pivotal trials conducted for IVA, LUM-IVA, and TEZ-IVA, patients with CF who had received a lung transplant (or any organ or hematological transplant) were excluded from Study 124. According to the CF Canada registry, 7.8% of the Canadian CF population had received a lung transplant as of 2019;¹⁷ this is a relatively large subpopulation patients who were not studied in the clinical trials. The applications filed with CDA-AMC for ELX-TEZ-IVA have not included evidence regarding the use of the treatment in patients with CF who have had a lung transplant. The experts consulted for this review noted that ELX-TEZ-IVA would not likely be initiated in patients who have undergone a lung transplant. For those who have undergone a liver transplant, ELX-TEZ-IVA could be initiated as the drug may benefit the patient’s lung function. After a liver transplant, patients would likely receive additional monitoring for potential toxicity with a lower threshold for interrupting or discontinuing the drug (because of the potential risk of hepatic adverse events with ELX-TEZ-IVA). The sponsor expressed disagreement with this perspective and noted that input received from clinician groups (CF Canada Health Care Advisory Council and CanACT) suggests that patients who have undergone a lung transplant, particularly those who have significant sinus disease, could still benefit from ELX-TEZ-IVA. CanACT noted that, because ELX-TEZ-IVA could diminish the risk of developing chronic rejection after a lung transplant, ELX-TEV-IVA should be considered in those lung-transplant recipients with significant sinus disease. CanACT added that these patients see an improvement in their SwCl values and therefore avoid episodes of severe dehydration that can otherwise occur. Data for use in patients after a lung transplant have not been submitted for review by the sponsor.

As is common in clinical trial settings, patients enrolled in Study 124 received extensive contact with health professionals over the study period (e.g., 7 clinic visits and 1 telephone contact over a 6-month period). This level of contact is not reflective of routine care for patients with CF with relatively stable disease. The clinical experts consulted for this review and the clinician groups who provided input noted that patients with CF are typically seen once every 3 months. The experts noted that the level of contact in the clinical trials is typical for CF studies and would not affect the generalizability of the results to the target population in Canada.

Adherence to study treatment was high (> 99%) throughout the treatment periods of all studies. The clinical experts consulted for this review noted that the level of adherence observed in the included studies is typical of adults and adolescents with CF in Canada, where adherence with treatments, including orally administered treatments, is considerably lower.⁶⁶

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform the expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^55,56

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 3 presents the GRADE summary of findings for ELX-TEZ-IVA versus placebo.

Long-Term Extension Studies

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the review team.

Description of Studies

Study 125 is an open-label, long-term extension phase of Study 124 conducted to assess the long-term safety and efficacy of ELX-TEZ-IVA in patients with CF aged 6 years and older with non-F508del mutations in the CFTR gene that are responsive based on clinical and/or in vitro data. The data cut included in the submission to CDA-AMC is from August 28, 2023, and reports the results for 4 weeks after the end of Study 124. A timeline of the study time points and transitions is presented in Figure 6.

Figure 6: Duration of Study 125

E/T/I = elexacaftor-tezacaftor-ivacaftor; PBO = placebo.

Source: Clinical Study Report.⁵⁷

Populations

Patients were eligible for Study 125 if they were aged 6 years or older and completed study drug treatment in Study 124 or had study drug interruption(s) in the parent study but completed the study visits up to the last scheduled visit. Patients were excluded if they demonstrated intolerance to ELX-TEZ-IVA in Study 124.

Interventions

ELX-TEZ-IVA was administered at the same dosage as in Study 124. For those aged 12 years or younger, the doses were adjusted upwards if the patient increased in age and weight.

Outcomes

All AEs and SAEs are to be assessed as primary end points from baseline until week 100. Absolute changes from baseline for ppEV1, SwCl, CFQ-R (RD), BMI, weight, and number of PEx are all to be measured from baseline until week 96 as secondary end points of interest. Results are currently available and presented for ppEV1, SwCl, and CFQ-R (RD) for the 4-week data cut-off.

Statistical Analysis

Methods for statistical analysis were not reported.

Results

Patient Disposition

Only an additional 4 weeks of exposure was available for Study 125 and patient disposition was not reported.

Efficacy

A summary of efficacy results from Study 125 is presented in Table 25. Those who switched from placebo to ELX-TEZ-IVA demonstrated improvements in ppFEV₁ (mean change = 7.1 percentage points [SD = 7.3]), SwCl (mean change = −27.4 mmol/L [SD = 18.9]), and CFQ-R RD (mean change = 14.7 points [SD = 22.6]) after receiving ELX-TEZ-IVA for 4 weeks. For those who received ELX-TEZ-IVA in the parent study, improvements in ppFEV₁ (mean change = 10.1 percentage points [SD = 11.0]), SwCl (mean change = −30.3 mmol/L [SD = 21.9]), and CFQ-R (RD) (mean change = 20.1 points [SD = 20.7]) were maintained after 4 additional weeks.

Table 25: Summary of Efficacy Data

CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation; SwCl = sweat chloride.

^aBaseline was defined as the most recent nonmissing measurement (scheduled or unscheduled) collected before the first dose of study drug in the parent study.

Source: Clinical Study Report.⁵⁷

Harms

Harms data were not reported for Study 125.

Critical Appraisal

Internal Validity

Study 125 is an ongoing, uncontrolled, open-label trial that enrolled patients who had completed Study 124. 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 125 and other ELX-TEZ-IVA studies, the risk of selection bias is generally low, given that nearly all patients enrol in the extension study. Overall, there are limited data from the extension phase as only 4 weeks of additional data were available, and the results are uninterpretable.

External Validity

Issues with the generalizability of these data are the same as for Study 124.

Indirect Evidence

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the review team.

The sponsor reported that an ITC is not required for approximately 80% of the patients in the target patient population because no CFTR modulators are currently approved for use in these patients. The remaining 20% of patients in the target patient population could be eligible for treatment with IVA. The sponsor conducted a feasibility assessment to determine whether an ITC could be performed to inform the comparative clinical benefits of ELX-TEZ-IVA versus IVA monotherapy. The sponsor concluded that it was not feasible to conduct a robust ITC because of uncertainty in the degree of population overlap, low individual patient data sample sizes, incompatibility of outcomes, and differences in the treatment history and follow-up time.

The review team agrees with the sponsor that it would not have been feasible to conduct an ITC that would be interpretable for the target population, notably because of the small sample sizes that would result from comparing the patient population in Study 124 that would match that from the IVA trials, and the resulting breaking of randomization that could lead to biased estimates, as well as the differences in treatment history between the populations, among other likely sources of heterogeneity. As well:

• The dosage of ivacaftor administered as part of the ELX-TEZ-IVA combination regimen is the same as what patients would receive with IVA monotherapy (e.g., 150 mg in the morning and 150 mg in the evening).

• Previous trials have demonstrated that patients with 1 or more F508del mutations and a gating mutation benefited from switching to ELX-TEZ-IVA from IVA monotherapy.

• The clinical experts consulted for this review noted that patients on IVA monotherapy would likely be switched to ELX-TEZ-IVA in Canadian practice.

• The submitted price for ELX-TEZ-IVA is the same as the current list price for IVA monotherapy.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section were informed by materials submitted by the sponsor. The following summary was validated by the review team.

Study for FRT-Responsive CFTR Mutations

Table 26: Details of Study 16

BMI = body mass index; CFFPR = Cystic Fibrosis Foundation Patients Registry; CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; PEx = pulmonary exacerbation; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

Study 16

Study Description

Study 16 was a retrospective, observational, cohort study evaluating real-world clinical outcomes in patients with CF with non-F508del mutations that are responsive to ELX-TEZ-IVA based on in vitro testing.⁶ Data were sourced from the CFFPR. Index dates for patients were defined as the date of ELX-TEZ-IVA treatment initiation ranging from 21 October 2019 to 01 December 2022. Data from patients were evaluated for up to 2 years before the index date through December 31, 2022 (follow-up period), or until loss of follow-up, death, treatment discontinuation, or lung transplant, whichever was earlier. A summary of the study timeline is presented in Figure 7. The objective of Study 16 was to supplement Study 124 in a further 64 mutations with data on the effectiveness of ELX-TEZ-IVA on lung function, PEx, and nutritional parameters in a real-world setting of patients with CF in the target patient population using data from the CFFPR patient registry.

Figure 7: Study 16 Design

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

Source: Study 16 Clinical Study Report.⁶

Populations

Patients aged 6 years or older were included in the analysis if they had data recorded in the CFFPR; a select ELX-TEZ-IVA–responsive non-F508del CFTR genotype; received treatment with ELX-TEZ-IVA during the patient-accrual period; at least 1 ppFEV₁ measurement in the 12 months before the index date; and at least 1 ppFEV₁ measurement taken at least 4 weeks after the index date. Patients were excluded if they had a history of lung transplant before the index date.

Interventions

ELX-TEZ-IVA was administered at recommended doses.

Outcomes

The primary efficacy end point was change in ppFEV₁. Nutritional parameters (BMI, weight and associated z scores) from before and after ELX-TEZ-IVA initiation, and exposure-adjusted PEx rate were also assessed.

Statistical Analysis

Continuous variables were summarized using the number of observations (n), mean (SD), median (minimum to maximum), and 95% CI. Precision of measurement for each outcome was used to determine the number of decimal places to present. Categorical variables were summarized using counts and percentages, and 95% CIs. Percentages were presented to 2 decimal places unless specified otherwise.

The pre-initiation period was defined as up to 2 years before the index dates for each patient based on available registry data. If a patient had no encounter data outside of the 2-year period before the index date, then the pre-initiation period was from the first encounter within the 2-year period through the index date. If a patient had encounter data outside of the 2-year period before the index date, then the pre-initiation period was the 2 years before the index date.

For continuous end points, the baseline year was defined as up to the 12 months immediately preceding the index date. The baseline year was used to define the baseline value for ppFEV₁ and nutritional parameters. For PEx, the pre-initiation period was further subdivided into the prepandemic and pandemic baseline periods, with March 13, 2020, as the cut-off date between the 2 periods. The follow-up period was defined as the date of ELX-TEZ-IVA treatment initiation (index date) through December 31, 2022.

Results

Patient Disposition

The selection process of patients from the CFFPR accounting for eligibility criteria is provided in Figure 8.

Figure 8: Study 16 Patient Flow Diagram

CF = cystic fibrosis; CFFPR = Cystic Fibrosis Foundation Patients Registry; ELX/TEZ/IVA = elexacaftor-tezacaftor-ivacaftor; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

Source: Study 16 Clinical Study Report.⁶

Baseline Characteristics

A summary of baseline characteristics for the included patients are presented in Table 27.

Table 27: Summary of Baseline Characteristics in Study 16

BMI = body mass index; CFTRm = CFTR modulator; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation.

Source: Study 16 Clinical Study Report.⁶

Exposure to Study Treatments

The mean ELX-TEZ-IVA exposure in Study 16 was 1.27 years (SD = 0.58).

Efficacy

Detailed efficacy results are presented in Table 28.

Change in ppFEV₁

The ppFEV₁ was assessed as a primary end point, with the overall patient population demonstrating a mean change of 4.53% (95% CI, 3.50 to 5.56) compared to baseline. Study 16 included patients with and without prior exposure to a CFTR modulator (55.5% and 44.1%, respectively). The sponsor reported subgroup analyses based on prior CFTR modulator exposure and reported that the mean change from baseline with ELX-TEZ-IVA was 6.11 (95% CI, 4.40 to 7.81) for those who were CFTR modulator–naive and 3.3% (95% CI, 2.06 to 4.58) for those who had prior exposure to a CFTR modulator.¹⁰

Change in Weight

Weight was assessed as a secondary end point, with results suggesting an increase in weight after ELX-TEZ-IVA initiation in the form of a mean change of 2.91 kg (95% CI, 2.24 to 3.58) compared to baseline. The z score for weight for age remained stable, with a mean change of −0.04 (SD = 0.48) compared to baseline.¹⁰

Change in Body Mass Index

The BMI was assessed as a secondary end point, with results suggesting an increase in BMI after ELX-TEZ-IVA initiation in the form of a mean change of 0.65 kg/m² (SD = 2.11) compared to baseline. Z scores for BMI for age remained stable, with a mean change of −0.05 (SD = 0.53) compared to baseline.¹⁰

Summary of PEx Events

The number of PEx events and the annualized PEx rate were also assessed. The results suggest the PEx rate decreased by 53% (95% CI, 42% to 62%) after ELX-TEZ-IVA initiation. The annualized PEx rates were 0.43 in the pre-initiation period and 0.20 in the follow-up period.¹⁰

Table 28: Summary of Efficacy Results From Study 16

BMI = body mass index; CI = confidence interval; PEx = pulmonary exacerbation; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

Source: Study 16 Clinical Study Report.⁶

Table 29: ppFEV1 Subgroup Based on Prior CFTR-Modulator Treatment

ppFEV₁ = percent predicted forced expiratory volume in 1 second; SD = standard deviation.

Source: Study 16 Clinical Study Report.⁶

Splicing Mutations

Study 16 reported subgroup analyses for individual CFTR mutations that had 5 or more patients enrolled in the trial. This included 2 of 5 the noncanonical splicing mutations (2789 + 5G→A [n = 7] and 3849 + 10kbC→T [n = 16]). Results for change from baseline in these subgroups were 3.6% (SD = 6.4) and 2.5% (SD = 6.4) for 2789 + 5G→A and 3849 + 10kbC→T, respectively.

Table 30: Redacted

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Critical Appraisal

Internal Validity

Study 16 was a retrospective observational study with no comparator treatment group. In general, the lack of an unexposed or other comparator group means any observed changes in patient outcomes cannot be definitively attributed to the treatment, as they could be because of other factors, including variation in the disease course or other unmeasured factors.

Limitations common to observational studies apply to this data, including:

• lack of control over the timing of scheduled patient visits

• lack of standardized timing for assessments

• lack of standardized definitions for pulmonary exacerbations (e.g., this would be at the discretion of the treating physician in the real-world setting)

• variation in the duration of therapy

• lack of information regarding adherence to ELX-TEZ-IVA during the treatment period

• potential for missing data in the registry database.

Key limitations with the CFFPR include the potential for selection bias as the data are only entered into the CFFPR for patients who are treated at accredited care centre programs and who consent to participate (estimated to be 81% to 84% of patients). In addition, missing data have been identified as a challenge with the dataset. The index dates for patients spanned October 21, 2019, to December 1, 2022. This overlapped with the COVID-19 pandemic, which had a considerable impact on the baseline rate PEx for patients with CF. Because of isolation measures, the risk of pulmonary exacerbations was reduced during the pandemic period (0.70 events per year before versus 0.31 after) making it challenging to interpret the overall pretreatment baseline rate (0.43 events per year) and the posttreatment rate of exacerbations (0.20 events per year).

The target patient population for this review spans 152 additional CFTR mutations; patients with 64 of these mutations were evaluated in Study 16 (clinical data for 46 Health Canada–approved mutations was exclusively from Study 16). The number of patients with each of the individual mutations was variable and generally small across the population. The sponsor noted that, given the variability of the real-world data and the interpretability of data from small strata (e.g., mutation-level data), these analyses should be viewed with caution. As shown in Table 28, the sample sizes varied across the different outcomes (e.g., n = 352 and n = 298 for change from baseline in for ppFEV₁ and BMI, respectively).

Health Canada reviewers noted that the differences between the mean and median change from baseline in ppFEV₁ suggests that a few good responders may have skewed the average in favour of treatment (i.e., the mean change from baseline was 4.53 [SD, 9.84] and the median change from baseline was 2.76 [range = −31.67 to 59.19]). However, definitive conclusions cannot be drawn because of variability in the timing of the baseline and posttreatment initiation spirometry tests. Health Canada concluded that data from Study 16 does not provide significant clinical evidence for ELX-TEZ-IVA responsiveness beyond providing some support for the efficacy of a few mutations with sufficient evidence of efficacy already provided in Study 124.

External Validity

Patients evaluated in Study 16 were identified from the CFFPR. As shown in Figure 8, this is a comprehensive patient registry that included 34,567 patients with CF during the study index period. The clinical specialists consulted for this review have noted that baseline characteristics of patients with CF in the US are generally similar to those living in Canada and that the results would be considered generalizable to the target population in Canada.

For the target population in Canada, the majority of patients do not currently have access to a CFTR modulator as ELX-TEZ-IVA, LUM-IVA, and TEZ-IVA are only approved for use in patients who are homozygous or heterozygous for the F508del mutation in the CFTR gene. The approved label for TEZ-IVA is broader in the US as the FDA has also approved that drug for use in patients who have at least 1 mutation in the CFTR gene that is responsive to TEZ-IVA based on in vitro data and/or clinical evidence. As such, Study 16 included patients with and without prior exposure to a CFTR modulator. Given that treatment with a CFTR modulator is expected to improve the end points evaluated in clinical trials (e.g., baseline lung function, BMI, and SwCl), this prior exposure could bias the overall effective size reported for the study against ELX-TEZ-IVA for the target population in Canada (the majority of whom are expected to be inexperienced with a CFTR modulator, except for those who have received IVA monotherapy). The sponsor has reported results for patients with and without prior exposure to a CFTR modulator. The subgroup of patients in Study 16 with prior CFTR-modulator exposure demonstrated an improvement from baseline in ppFEV₁ of 3.3% (95% CI, 2.1% to 4.6%) which was lower than the improvement of 6.11% (95% CI, 4.40 to 7.81) for those who were CFTR modulator–naive. In both populations the results were lower than what was reported in Study 124. As noted previously, observational datasets may have important limitations that make it difficult to accurately quantify the impact of the treatment on patient outcomes and makes it challenging to evaluate the consistency of results across the 2 studies.

Studies for N1303K CFTR Mutation

The sponsor included evidence from 7 publications that described the use of ELX-TEZ-IVA in patients with 1 or more N1303K mutations of the CFTR gene. Following review of the publications, CDA-AMC included data from 4 of the publications in the Clinical Review (Solomon et al. [2024],² N = 20; Burgel et al. [2023],³ N = 8; Burgel et al. [2024],⁴ N = 35; and Sadras et al. [2023],^14-16 N = 8).

The 3 additional abstracts and/or publications for patients with 1 or more N1303K mutations (Dreano et al.,[2023];⁷ Livnat et al. [2023];⁸ and Pranke et al. [2022]⁹) have not been summarized in this report as the review team concluded that these studies do not address a gap in the evidence that is not already addressed by the other 4 studies submitted in support of the expanded use of ELX-TEZ-IVA for patients with CF who have 1 or more N1303K mutations in the CFTR gene. The additional reasons are:

• The reporting of these studies is insufficient for CDA-AMC to conduct an appropriate appraisal of the methodology used in the evaluation of patients as information is only available in abstract format.

• The publications by Dreano et al. (2023) and Pranke et al. (2022) refer to the same source of patients that was used in the studies by Burgel et al. (2023), N = 8; and Burgel et al. (2024), N = 34, which also had larger sample sizes. The sponsor was unable to confirm if there is overlap between the patient populations in these studies.

• These analyses were not included in the submission to Health Canada.

The study population from Sadras et al. (2023)^14-16 was included in the study by Burgel et al. (2024),⁴ but this was still reviewed and appraised because it was included as a separate additional study in the submission to Health Canada for ELX-TEZ-IVA.

A summary of the key results from Solomon et al. (2024),² Burgel et al. (2023),³ Burgel et al. (2024),⁴ and Sadras et al. (2023)^14-16 is provided in Table 4. A summary and appraisal of each of the individual studies is provided in the following section.

Solomon (2024)

Description

Solomon et al. (2024) was a prospective, open-label trial assessing patients with CF carrying partial function or N1303K mutations not currently approved for treatment by ELX-TEZ-IVA.² The study was divided into 2 subsections, with 1 enrolling 22 patients with rare genotypes and the other enrolling 20 participants carrying 1 or more N1303K mutations. Both populations were treated with ELX-TEZ-IVA for 4 weeks and assessed for efficacy and health-related quality-of-life outcomes.

Figure 9: Solomon et al. (2024) Study Design

Source: Common Technical Document.¹²

Populations

Patients were eligible if they were at least 12 years of age, had a diagnosis of CF, were clinically stable in the past 4 weeks with no evidence of CF exacerbation, and had 1 of the following: a partial function mutation not currently covered or likely to be covered for treatment with a CFTR modulator (Substudy 1); or an N1303K mutation and a minimal function mutation (Substudy 2). Key exclusion criteria included cirrhosis or elevated liver transaminases greater than 3 times the ULN; history of solid organ transplant; or treatment in the last 6 months with an approved CFTR modulator.¹⁰

Interventions

ELX-TEZ-IVA was taken for 28 days among patients with CF (tablets comprised 100 mg of ELX, 50 mg of TEZ, and 75 mg of IVA [2 tablets taken in the morning], and 150 mg of IVA taken in the evening).¹⁰

Outcomes

Changes in ppFEV₁and SwCl were the primary clinical outcomes of interest and changes in CFQ-R scores and weight were secondary outcomes of interest.¹⁰

Statistical Analysis

Statistical methods were not reported as only abstracts were included in the application.

Results

Patient Disposition

Patient disposition was not reported.

Baseline Characteristics

Table provides a summary of the baseline and demographic characteristics from Solomon et al. (2023).¹²

Table 31: Summary of Baseline Characteristics in Solomon et al. (2023)

ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; CF = cystic fibrosis; MF = minimal function; ppFEV₁ = percent predicted forced expiratory volume in 1 second.

^aMF mutations included (n) W1282X (5), G542X (2), deltaI507 (2), E60X (1), 2490 + 1G > A (1), 3905insT (1), 1717 to 1 G > A (1), Q1100P (1), 2184delA (1), 2184insA (1), 711 + 1G > T (1), 11454insTC (1), 3120 + 1 G > A (1), and CFTRdele17a,17b (1).

Source: Common Technical Document.¹²

Efficacy

Table 32 provides a summary of efficacy results from Solomon et al. (2023).

Table 32: Summary of Results From Solomon et al. (2023)

BMI = body mass index; CFQ-R (RD) = Cystic Fibrosis Questionnaire–Revised (respiratory domain); LS = least squares; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride.

^aResults presented are LS means with 95% confidence intervals.

^bThe difference is the LS mean difference between day 1 and day 28 based on a mixed-effects model for repeated measures.

Source: Solomon et al. (2023).¹²

Internal Validity

Solomon et al. (2023) was a prospective cohort study that was investigator-initiated (i.e., it was not sponsored by Vertex Pharmaceuticals). As an investigator-initiated trial, no clinical study report was available to include in the application to CDA-AMC. Information available for the purposes of appraising and interpreting the evidence is limited to a conference abstract, a presentation, and information included by the sponsor in the regulatory submission (i.e., the Common Technical Document).

The use of a single-arm trial design is inconsistent with the design used for pivotal trials for ELX-TEZ-IVA in patients aged 12 years and older. This approach has been used for trials investigating ELX-TEZ-IVA in younger patients (for whom concerns regarding equipoise may preclude the use of a placebo comparator), but not for those aged 12 years and older. As a single-arm study, there is an increased risk of bias in the estimation of treatment effects because of the potential for confounding related to natural history and prognostic factors. The potential influence of selection bias is also difficult to determine in a single-arm study. As well, too few details about the inclusion (and exclusion) of patients into the study were provided to fully assess the potential for selection bias. No information was provided about concomitant therapies that may have influenced the results of the study.

As ELX-TEZ-IVA was administered in an open-label manner, the investigator and the study participants were aware of their treatment status, potentially increasing the risk of detection and performance biases. Open-label administration limits interpretability of the health-related quality-of-life end point (CFQ-R [RD]).

Insufficient information about the statistical analysis was provided to determine whether the evaluations were robust, including how potential confounders were handled.

External Validity

The study was conducted at centres in the US and (as noted for Study 16) the clinical experts consulted for this review had no concerns about generalizing the study results from US patients to a Canadian setting. The relatively small sample size made it difficult to evaluate the representativeness of the population based on baseline characteristics. The clinical experts noted that the baseline characteristics were a reasonable reflection of the target patient population in Canada. However, the relatively small sample size (N = 20) makes it difficult to determine if the distribution of patient characteristics could be informative for generalizing the results.

Although ELX-TEZ-IVA was administered at recommended dosages, the treatment duration was limited to 4 weeks (28 days), which is shorter than the 24-week duration used in the phase III clinical trials for ELX-TEZ-IVA.

Burgel (2023)

Burgel et al. (2023) reported a prospective observational cohort study from involving patients who received ELX-TEZ-IVA through a French compassionate-access program. Table 33 provides a summary of the study characteristics, results, and an appraisal of the internal and external validity.

Table 33: Summary of Burgel et al. (2023)

BMI = body mass index; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; IQR = interquartile range; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride.

Source: Burgel et al. (2023).³

Burgel (2024)

Burgel et al. (2024) was a retrospective observational cohort study that employed pooled analyses drawn from various sources, including the French compassionate-access program's published reports, a study conducted in Israel (Sadras [2023]), 3 case reports, and unpublished data sourced from the French compassionate-access program. Table 34 provides a summary of the study characteristics, results, and an appraisal of the internal and external validity.

Table 34: Summary of Burgel et al. (2024)

BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; IQR = interquartile range; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride.

Source: Burgel et al. (2024).⁴

Sadras (2023)

Sadras et al. (2023) reported an observational prospective analysis from a multicentre registry in Israel, including in vitro evidence to report the clinical response and in vitro response to ELX-TEZ-IVA in patients who carry 1 or more N1303K mutations on 1 allele and a nonsense or frameshift mutation on the other. Table 35 provides a summary of the study characteristics, results, and an appraisal of the internal and external validity.

Table 35: Summary of Sadras et al. (2023)

BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; ELX-TEZ-IVA = elexacaftor-tezacaftor-ivacaftor plus ivacaftor; NR = not reported; ppFEV₁ = percent predicted forced expiratory volume in 1 second; SwCl = sweat chloride.

Source: Sadras et al. (2023).^14-16

Discussion

Summary of Available Evidence

The current review is for an expanded indication that would include 152 additional non-F508del mutations of the CFTR gene. The sponsor has categorized the additional CFTR mutations as follows: 147 FRT-responsive mutations, 4 noncanonical splice mutations, and the N1303K mutation. Evidence supporting the use of ELX-TEZ-IVA in the expanded population consisted of the following: 1 double-blind, placebo-controlled RCT in patients with FRT-responsive CFTR mutations (Study 124; N = 307; 18 CFTR mutations); 1 long-term extension study (Study 125; same population as Study 124); 1 retrospective observational study (Study 14; N = 422; 64 CFTR mutations); 4 nonrandomized studies involving patients with 1 or more N1303K mutations (Solomon et al. [2024],² N = 20; Burgel et al. [2023],³ N = 8; Burgel et al. [2024],⁴ N = 35; and Sadras et al. [2023],^14-16 N = 8). The sponsor reports that there are no clinical data for 79 FRT-responsive mutations (i.e., those that were considered responsive to ELX-TEZ-IVA in the in vitro model) and 1 of the noncanonical splice mutations.

The sponsor’s application was filed on a pre–Notice of Compliance basis and included an additional 31 CFTR mutations that were not approved by Health Canada for the following reasons:

• Fifteen mutations were considered by Health Canada as not causative of CF, based on the CFTR2 and CFTR-France databases: D836Y, F508C, G576A, I148T, I807M, I1027T, L320V, L997F, R75Q, R170H, R668C, R1162L, T1053I, V562I, and V754M.

• Ten mutations were excluded because of unknown clinical significance or were only reported as causing a CFTR-related disease (i.e., not CF), and which retain at least 50% of normal chloride-transport function: G178E, G576A;R668C, I1139V, K1060T, R31L, R553Q, R751L, R792G, V1293G, Y1014C.

• Five mutations were excluded because they result in a cryptic splice mutation, and insufficient full-length CFTR: H939R, I175V, M152V, E403D, and S589N.

• One mutation was excluded because of the absence of in vitro or clinical data provided in the current submission: E831X.

Similar to the previous reviews for ELX-TEZ-IVA for those with an F508del mutation in the CFTR gene, the expanded indication only requires patients to have 1 mutation causing CF that is considered responsive to ELX-TEZ-IVA. As the majority of patients enrolled in Study 124 were heterozygous for the CFTR mutations and some patients carried complex alleles (i.e., multiple mutations on 1 allele), Health Canada requested that the sponsor provide additional analyses for Study 124 and Study 16 showing a by-mutation analysis for patients who have only a single potentially responsive target mutation on 1 allele, and either the same single mutation on the second allele or a mutation expected to be nonresponsive (e.g., a frameshift, large deletion, or premature stop codon). The sponsor provided the analyses for Study 124 but could not provide that level of detail for Study 16, citing the small sample size and the CFFPR’s restriction in providing data for subgroups with fewer than 5 patients. Health Canada concluded that there was sufficient evidence of efficacy that patients with 1 or more ELX-TEZ-IVA–responsive mutations will benefit from treatment, although a revision to the product monograph was required to identify the specific mutations for which the sponsor provided subgroup analyses demonstrative of efficacy for those who carried only 1 responsive mutation (i.e., those who were homozygous or carried a class I mutation on the other allele). The product monograph states that those specific CFTR mutations have “significant clinical evidence of efficacy for ELX-TEZ-IVA, independent of the mutation on the second allele.” This statement is simply intended to identify the mutations for which evidence has been generated and reported and is not meant to indicate that other mutations involving only a single responsive copy would be expected to show a reduced treatment effect (as this remains a gap in the evidence). Health Canada noted that the actual clinical responsiveness to ELX-TEZ-IVA for any individual patient with CF depends on multiple factors and cannot be predicted before treatment.

Indirect comparison: The sponsor reported that an ITC is not required for approximately 80% of the patients in the target patient population because no CFTR modulators are currently approved for use in these patients. The remaining 20% of patients in the target patient population could be eligible for treatment with IVA monotherapy. The sponsor conducted a feasibility assessment to determine whether an ITC could be performed to inform the comparative clinical benefits of ELX-TEZ-IVA versus IVA monotherapy. The sponsor concluded that it was not feasible to conduct a robust ITC because of uncertainty in the degree of population overlap, low individual-patient-data sample sizes, incompatibility of outcomes, and differences in the treatment history and follow-up time. The review team agreed with the sponsor that it would not have been feasible to conduct an ITC that would be interpretable for the target population, notably because of the small sample sizes that would result from comparing the patient population in Study 124 that would match that from the IVA trials, and the resulting breaking of randomization that could lead to biased estimates, as well as the differences in treatment history between the populations, among other likely sources of heterogeneity. In addition, the dosage of IVA administered as part of the ELX-TEZ-IVA combination regimen is the same that patients would receive with IVA monotherapy (e.g., 150 mg in the morning and 150 mg in the evening); previously reviewed trials have demonstrated that patients with 1 or more F508del mutations and a gating mutation benefited from switching to ELX-TEZ-IVA from ivacaftor monotherapy; the clinical experts consulted for this review noted that, in Canadian practice, patients on IVA monotherapy would likely be switched to ELX-TEZ-IVA; and the submitted price for ELX-TEZ-IVA is the same as the current list price for IVA monotherapy and the total costs of treatment would therefore be unlikely to change.

Interpretation of Results

Prior exposure to a CFTR modulator: For the target population in Canada, the majority of patients do not currently have access to a CFTR modulator as ELX-TEZ-IVA, LUM-IVA, and TEZ-IVA are only approved for use in patients who are homozygous or heterozygous for the F508del mutation in the CFTR gene. The percentage of the population who could receive IVA monotherapy is expected to be relatively small (approximately 20% based on sponsor estimates). The approved label for TEZ-IVA is broader in the US as the FDA has already approved that drug for use in patients who have at least 1 mutation in the CFTR gene that is responsive to TEZ-IVA based on in vitro data and/or clinical evidence. As such, the clinical studies include patients with and without prior exposure to a CFTR modulator. Given that treatment with a CFTR modulator is expected to improve the end points evaluated in clinical trials (e.g., baseline lung function), the results for patients with and without prior exposure to a CFTR modulator are discussed separately.

Efficacy for FRT-Responsive CFTR Mutations — Clinical Data

Lung function: In Study 124, ELX-TEZ-IVA was associated with a clinically meaningful absolute improvement in ppFEV₁ compared with placebo after 24 weeks of treatment (LS mean difference = 9.2%; 95% CI, 7.2% to 11.3%). While no published information on the MID in absolute change in ppFEV₁ in CF was identified by the review team, the clinical experts consulted for this review noted that CF specialists would generally consider an absolute improvement in ppFEV₁ of at least 5% to be clinically relevant. Improvements in ppFEV₁ in patients receiving ELX-TEZ-IVA were observed at the first postbaseline assessment of Study 124 (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. Similar results were reported for placebo-treated patients who were crossed over to ELX-TEZ-IVA in Study 125, which demonstrated an absolute increase from baseline in ppFEV₁ of 7.1% (SD = 7.3) after 4 weeks. Health Canada reviewers concluded that the primary analysis in Study 124 for change in ppFEV₁ produced results comparable to those reported in the studies conducted with F508del patients for the initial approval of ELX-TEZ-IVA and support a significant benefit to lung function in responsive patients.

Patients in Study 16 demonstrated smaller improvements from baseline, with changes in ppFEV₁ of 6.11% (95% CI, 4.40 to 7.81) for those who were CFTR modulator–naive. The subgroup of patients in Study 16 with prior CFTR-modulator exposure demonstrated an improvement from baseline in ppFEV₁ of 3.3% (95% CI, 2.1% to 4.6%). The magnitude of improvement from switching to ELX-TEZ-IVA from TEZ-IVA or IVA was previously reviewed by CDA-AMC in the submission for patients aged 12 years and older (i.e., Study 103 and Study 109 in patients homozygous for the F508del mutation and Study 104 for patients with a single F508del mutation and either an RF or a gating mutation in the CFTR allele). The magnitude of improvement reported in Study 16 is similar to what was reported for those who switch from TEZ-IVA or IVA to ELX-TEZ-IVA in Study 104 (LS mean difference = 3.5%; 95% CI, 2.2 to 4.7; P < 0.0001) and lower than what was reported in the switching studies for patients who were homozygous for the F508del mutation (10.0%; 95% CI, 7.4 to 12.6 and 10.2%; 95% CI, 8.2 to 12.1).

Health Canada reviewers noted that the data from Study 16 did not provide significant support for any individual mutation, citing insufficient information. Health Canada further noted that use of CCFR data (instead of US CFFPR data) would be even less likely to provide clarity, given the rarity of the mutations and the size of the relevant population. Based on this assessment, Study 16 was not considered to be the basis of regulatory approval for the revised indication and the results of this study were removed from the Canadian product monograph.

Pulmonary exacerbations: PEx events are currently the most common reason for hospitalization of patients with CF⁵⁸ and, accordingly, these events were identified as an outcome of interest by the patient groups and clinician groups who provided input for this review. PEx events are clinically significant for patients with CF and are correlated with increased mortality, greater decline in lung function, reduced quality of life, and increased health costs.^59-63 In addition, it has been estimated that many patients with CF experience a permanent reduction in lung function following an exacerbation (i.e., their lung function will not recovery to the level it was before the exacerbation). In a large sample of patients with CF (N = 8,479), Sanders et al. (2010)⁶⁴ estimated that 25% of patients with CF who experienced a PEx failed to recover to their baseline FEV₁. A similar observation has been made in an analysis in pediatric patients with CF, of whom 23% failed to recover to their baseline FEV₁ after being treated with IV antibiotics for a PEx.⁶⁵

Treatment with ELX-TEZ-IVA was associated with a reduction in the risk of PEx events in the 24-week placebo-controlled trial (Study 124). The sponsor also reported a 53% reduction in the risk of a PEx after ELX-TEZ-IVA initiation in Study 16; however, the onset of the COVID-19 pandemic altered the baseline frequency of exacerbations (from 0.70 to 0.31 events per year) making it challenging to interpret the overall pretreatment baseline rate (0.43 events per year) and the posttreatment rate of exacerbations (0.20 events per year). The clinical experts consulted for this review noted that the reduction in PEx events in Study 124 is clinically meaningful. The 24-week study period reduced the accuracy and variance of the point estimates for the PEx rates because of seasonal variation and other temporal factors that require longer follow-up to accurately estimate (ideally at least 12 months of follow-up to account for these variables). Health Canada reviewers noted that the reduction in the number of PEx events in Study 124 was substantiative, albeit over a short 24-week study period. Similar to CDA-AMC, Health Canada noted that the reduction in PEx events observed in Study 16 was confounded by isolation measures that occurred during the COVID-19 pandemic and that the results are challenging to interpret.

There are no globally accepted definitions for a PEx in patients with CF. The definitions used in Study 124 were considered appropriate by regulatory authorities and the clinical experts consulted for this review, who noted there would be some variation in routine clinical practice in the threshold for diagnosing and treating pulmonary exacerbations across different CF clinics and/or physicians. This was also evident in Study 124, in which fewer patients met the criteria for a PEx when evaluated as an efficacy end point compared to the number of exacerbations reported as AEs (25.5% versus 36.3% in the placebo group). Although no standard definitions are currently uses in Canadian clinical practice, the clinical experts consulted for this review noted that the number of exacerbation events experienced by patients with CF is currently tracked in CF clinics.

Nutritional end points: Given that CF affects multiple organ systems, including those in the digestive system, and that CFTR modulators are systemic treatments, the pivotal studies for ELX-TEZ-IVA included BMI and body weight end points to evaluate the effect of treatment on the nutritional status of patients with CF. Treatment with ELX-TEZ-IVA was associated with statistically significant improvements in BMI compared with placebo at 24 weeks in Study 124 (LS mean difference = 0.47 kg/m²; 95% CI, 0.24 to 0.69). Previous CDA-AMC reviews of CFTR modulators noted that 24 weeks is a short period of time to evaluate changes in BMI. As shown in Figure 5, it is unclear if the posttreatment BMI for patients in the ELX-TEZ-IVA had stabilized at the time of the 24-week measurement, and additional data were available from the extension phase (Study 125) at the time of submission to CDA-AMC. The clinical experts noted that the improvements in BMI demonstrate that ELX-TEZ-IVA improves nutritional end points for the target patient population.

Health-related quality of life: As stated in the patient group input, CF has a major impact on the quality of life of patients and their caregivers. Treatment with ELX-TEZ-IVA demonstrated statistically significant and clinically meaningful improvements in health-related quality of life (i.e., CFQ-R) in each of the included studies. The magnitude of improvement in the CFQ-R (RD) scores with ELX-TEZ-IVA was 19.5 (95% CI, 15.5 to 23.5) at 24 weeks compared with placebo in Study 124. This exceeded the MID for the CFQ-R (RD), which is typically cited as 4.0 points. The clinical experts consulted for this review considered the results clinically relevant. Health Canada reviewers similarly concluded that results in Study 124 for change in CFQ-R (RD) scores were comparable to those reported in the studies conducted with F508del.

The patient input emphasized that the therapeutic regimen for patients with CF requires considerable time each day and is both physically and mentally demanding for those living with CF and their caregivers. Patients have expressed interest in therapeutic options that could help alleviate their existing treatment burden. The clinical experts consulted for this review and the clinician groups who provided input all noted that ELX-TEZ-IVA should be used as an add-on therapy. A large RCT (the SIMPLIFY trial) recently reported that patients whose disease is well controlled do not experience a decline in lung function after discontinuation of dornase or inhaled hypertonic saline after stabilization with ELX-TEZ-IVA.^66,67

Efficacy for Noncanonical Splicing Mutations

The target patient population of the current review includes 5 noncanonical splicing mutations in the CFTR gene. These mutations result in small amounts of functional, normal CFTR protein. The sponsor has reported that these mutations cannot be evaluated in the FRT system and provided clinical data for each of the mutations included in the application. The sponsor reported that 4 of the 5 splicing mutations are supported by clinical data while clinical data are currently unavailable for 1 mutation (711 + 3A > G). The sponsor stated that, because CFTR modulators work through the same mechanism associated with all noncanonical splice mutations (i.e., by enhancing the activity of the small amount of full-length CFTR produced by noncanonical splice mutations) the response observed for noncanonical splice mutations with clinical data provides evidence that the additional noncanonical splice mutation will also be clinically responsive.

Study 124 enrolled patients with 3 of the 5 noncanonical splice mutations in the target patient population for this review (i.e., 2789 + 5G > A, 3272 to 26A > G, and 3849 + 10kbC > T). Subgroup analyses for absolute change from baseline through 24 weeks in ppFEV₁, SwCl, and CFQ-R (RD) produced results consistent with those of the primary analyses. Study 16 reported subgroup analyses for individual CFTR mutations that had 5 or more patients enrolled in the trial. This included 2 of 5 of the noncanonical splicing mutations: 2789 + 5G→A (n = 7) and 3849 + 10kbC→T (n = 16). Although the changes from baseline appear lower than what was observed in Study 124 (absolute change from baseline of 3.6% [SD = 6.4]) and 2.5% [SD = 6.4] for 2789 + 5G→A and 3849 + 10kbC→T, respectively), making such judgments is challenging given the uncertainty as to the similarity of the study populations, the much smaller sample size in Study 16, and the aforementioned important limitations of the study and reporting of information. There may be inconsistency across studies in the effects of ELX-TEZ-IVA in patients with noncanonical splice mutations, but the limitations of the available evidence make it difficult to determine the accuracy and precision of the estimated treatment effects. The sponsor reported that clinical data were available for E831X, but no subgroup results were reported in Study 16 (in addition, the sample size would be problematically small). The experts emphasized that these patients have a high level of unmet need as they have no access to CFTR-modulator therapy in Canada (outside of enrolment in a clinical study).

Efficacy for N1303K CFTR Mutations

The N1303K mutation was identified as nonresponsive to ELX-TEZ-IVA in the FRT in vitro test that has subsequently been evaluated in investigator-sponsored studies. The sponsor included evidence from 7 publications that described the use of ELX-TEZ-IVA in patients with 1 or more N1303K mutations on the CFTR gene. Following a review of the publications, we included data from 4 of the publications in the Clinical Review (Solomon et al. [2023],² N = 20; Burgel et al. [2023],³ N = 8; Burgel et al. [2024],⁴ N = 35; and Sadras et al. [2023],^14-16 N = 4).

All of the studies reported an increase in ppFEV₁ following between 4 to 8 weeks of treatment with ELX-TEZ-IVA. The improvement from baseline in ppFEV₁ across studies ranged from 9.5% (95% CI, 6.7 to 12.3; P < 0.001) in Solomon et al. (2023) (N = 20),^11,12 a study that enrolled patients who had moderate lung disease at baseline (i.e., the mean baseline FEV₁ was 76% [SD = 20]). The largest improvements in ppFEV₁ were reported in the publication by Burgel et al. (2023)³ (N = 8), in which only patients with advanced lung disease were evaluated. These patients had a median baseline ppFEV₁ of 32% (95% CI, 26 to 39) and showed a median improvement of 27.5% (IQR = 20.7 to 41.2) after 4 to 6 weeks of treatment with ELX-TEZ-IVA. The clinical specialists consulted for this review considered the results to be clinically meaningful and indicate that ELX-TEZ-IVA would benefit patients with 1 or more N1303K mutations. The experts emphasized that there is a high level of unmet need for these patients as they currently do not have access to CFTR-modulator therapy in Canada (outside of enrolment in a clinical study).

Three studies (Solomon et al. [2023],^11,12 Burgel et al. [2024], and Sadras et al. [2023]^14-16) included change from baseline in BMI or body weight and all reported statistically significant increases from baseline over the short study periods. As with the other clinical studies, the clinical specialists consulted for this review noted that the duration of these studies is too short to accurately evaluate the impact of ELX-TEZ-IVA on increasing the nutritional status of patients with the N1303K mutation. However, the CF specialists emphasized that the results support a finding that ELX-TEZ-IVA is effective for these patients and likely to have a long-term effect on improving BMI and body weight for patients who may be underweight.

Only 1 of the N1303K studies investigated change from baseline in health-related quality of life. Solomon et al. (2023)^11,12 reported a mean increase from baseline in the CFQ-R (RD) score of 20.8 (95% CI, 11.9 to 29.8; P < 0.001). As noted previously, the MID for this instrument is typically cited as a change of 4 units, which was far exceeded in this trial. Similar to the interpretation of the results from Study 124, the clinical specialists consulted by CDA-AMC described this as clinically relevant for patients.

The investigator-sponsored studies failed to consistently demonstrate that ELZ-TEZ-IVA treatment reduced SwCl in the patients with 1 or more N1303K mutations in the CFTR gene (i.e., no statistically significant difference in Solomon et al. [2023] or Sadras et al. [2023]) and the studies that did demonstrate a statistically significant reduction showed a lower magnitude in response in comparison with other mutations that have been studied (median change of –9 mmol/L in both Burgel et al. [2023] and Burgel et al. [2024]). The clinical experts consulted for this review were not concerned about the lack of improvements in SwCl in these trials, as this is more a reflective of mechanism of action of ELX-TEZ-IVA and is not considered a clinically meaningful end point for the evaluation of treatment response. The study authors speculated that ELX-TEZ-IVA may have a different mechanism of action for CFTR proteins with an N1303K mutation and emphasized the need for patients to be evaluated by a range of end points to determine response to treatment. Health Canada noted that alternative approaches to in vitro cell modelling (using human nasal epithelial cells and induced pluripotent stem cell-derived epithelial cells) have shown that ELX-TEZ-IVA can increase Cl⁻ transport in patients with an N1303K or minimal function genotype. Given that the studies involving the N3103K mutation demonstrated consistent improvements in ppFEV₁, but a lack of improvement in SwCl, Health Canada noted that ELX-TEZ-IVA appears to promote CFTR activity in the lungs, but not necessarily in the sweat glands for patients with an N1303K mutation. Health Canada noted that the exact mechanism responsible for the differences in the effects of ELX-TEZ-IVA in those with an N1303K mutation compared with those that were shown to be responsive in the FRT-cell model is unclear. However, Health Canada pointed out that the N1303K CFTR protein is degraded by the autophagy cellular pathway, which is a different than the F508del CFTR protein, and that this could result in different levels of CFTR expression at the cellular membrane of cellular types. In this instance, it has been hypothesized that the CFTR correctors (i.e., ELX and TEZ) may facilitate escape from the endoplasmic reticulum and trafficking to the plasma membrane more efficiently in epithelial cells of the respiratory tract compared to epithelial cells in other parts of the body, such as the skin.

The 4 observational studies have important limitations that make it challenging to determine whether the observed effects of ELX-TEZ-IVA in patients with CF who have 1 or more N1303K mutations at various stages of lung disease are because of the treatment or other factors. The sample sizes of the studies were relatively small (N ranged from 8 to 35). This has implications for the internal validity (e.g., key assumptions of statistical tests may be invalidated) and external validity (representativeness of the results to a wider population) of the studies. There were concerns regarding the selection of patients in all 4 studies and an increased risk of selection bias, as they enrolled patients who were more likely to show larger treatment effects. This partly results from the limited information provided in the description of patient eligibility, recruitment, and insufficient reporting of patient characteristics at baseline. Further, the absence of a comparator (concurrent or external) in the studies precludes the ability to interpret the magnitude of therapeutic benefit in terms of whether the effect was attributable to ELX-TEZ-IVA or other factors. There were several unanswerable questions, in part based on the limited reporting of the methods and analyses in the studies, related to the assessment of bias, particularly how well potentially relevant confounders and/or effect modifiers were accounted for. All of studies had a short duration of treatment and follow-up. None of the studies evaluated the rates of PEx. As all of the studies were investigator-sponsored, the available information regarding studies methods and results is limited to publications and abstracts. Overall, the studies are suggestive of a clinically important benefit with ELX-TEZ-IVA in patients with 1 or more N1303K mutations, but they are not conclusive.

Harms

ELX-TEZ-IVA was well tolerated in the target patient populations (i.e., aged at least 2 years with at least 1 mutation that is responsive to ELX-TEZ-IVA based on clinical and/or in vitro data). The warnings and precautions section of ELX-TEZ-IVA product monograph has not been updated since the previous CDA-AMC reviews. Health Canada reviewers noted that long-term safety has already been established for ELX-TEZ-IVA, and no data from the pivotal clinical study indicate the existence of CFTR genotype–dependent safety concerns.

As with previous CDA-AMC reviews of ELX-TEZ-IVA, SAEs and withdrawals because of AEs were rare in the included studies. The clinical experts consulted for this review noted that intolerance to ELX-TEZ-IVA among adolescents and adults has been rare in clinical practice. The clinical experts noted that patients who experience significant AEs following initial treatment with ELX-TEZ-IVA would not likely be completely discontinued from treatment; rather, treatment with ELX-TEZ-IVA would likely be interrupted and the patient would be rechallenged with the drug following resolution of the event(s). This is consistent with the input received from the 3 clinician groups that 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.

Similar to the development programs for the other CFTR modulators (IVA, LUM-IVA, and TEZ-IVA), patients with abnormal liver function were excluded from the phase III trials of ELX-TEZ-IVA. The clinical experts consulted for this review noted that most patients who could be eligible for ELX-TEZ-IVA would not have hepatic impairment. The product monograph recommends that the dosage of ELX-TEZ-IVA should be adjusted in patients with moderate hepatic impairment and that the drug should not be used in patients with severe hepatic impairment.³⁰ These recommendations are more restrictive than those in the product monographs for IVA, LUM-IVA, or TEZ-IVA,^30,41,42 all of which provide dosage-reduction scenarios for patients with CF who have severe hepatic impairment. The clinical experts suggested that clinicians may attempt to treat those with severe hepatic impairment using ELX-TEZ-IVA at a reduced dosage, as opposed to using the reduced dosages of the alternative CFTR modulators, which are unlikely to provide the same level of clinical benefit.

The product monograph notes that elevated transaminases have been observed in patients treated with ELX-TEZ-IVA and recommends assessing alanine transaminase and aspartate transaminase before initiating treatment with ELX-TEZ-IVA every 3 months during the first year of treatment and annually thereafter.³⁰ The clinical experts consulted for this review noted that the recommendations for monitoring would likely be followed by the clinical community. The clinical experts and the clinician groups who provided input noted that patients with CF are typically seen once every 3 months (although visits have been less frequent in some cases because of COVID-19). As such, the recommended monitoring regimen for ELX-TEZ-IVA was not anticipated to result in a substantial increase in the number of the clinic visits for patients with CF (particularly after the first year of initiating the treatment).

Similar to IVA, LUM-IVA, and TEZ-IVA, the product monograph for ELX-TEZ-IVA notes that cases of noncongenital cataracts without impact on vision have been reported in pediatric patients who were treated with IVA-containing regimens.^30,41,42,68 The product monograph states that the patients who demonstrated these events had other risk factors (e.g., corticosteroid use or exposure to radiation); however, a possible risk attributable to treatment with IVA cannot be excluded. As such, it is recommended that pediatric patients initiating treatment with ELX-TEZ-IVA received baseline and follow-up ophthalmological examinations.³⁰ The clinical experts consulted during this review noted that children with CF currently have an ophthalmological examination before starting treatment with a CFTR modulator and are monitored on an ongoing basis thereafter.

No indirect comparison investigating the comparative safety of ELX-TEZ-IVA versus IVA for the subset of patients with an eligible gating mutation was included in this submission.^69,70 Health Canada noted that some patients could have CFTR mutations that are responsive to IVA monotherapy and that these patients may not experience additional clinical benefit through exposure to the CFTR correctors (i.e., ELX and TEZ), although they could be at an increased risk of AEs.

Other Considerations

Health Canada reviewers noted that patients with many of the included CFTR mutations are potentially treatable with IVA monotherapy. The 2789 + 5G > A, 3272 to 26A > G, 3849 + 10kbC > T, R117C, L206W, V232D, T338I, R347H, A455E, S945L, L997F, and D1152H mutations are all listed as being IVA-responsive in the US product label for Kalydeco, and in vitro data provided in the current submission provides some support for use of IVA monotherapy in patients with these mutations. ██ ████████ ██ ██ ███████ ████ ██████ ███████ ███ ███████ ██████ ████ ████ ███ ███ █████████ ████████ ██ ██████ █ ██████████ ██ ████ ███ ████████ ███████████ ███ ████████ ███████ ██ █████ █████ █████████ ████████ ██ ███ ██████ ███████

Health Canada noted that application for ELX-TEZ-IVA did not specifically identify the patients with CFTR mutations that would benefit the most from receiving a combination therapy (ELX-TEZ-IVA) that includes the CFTR-corrector molecules as opposed to simply receiving monotherapy with a CFTR potentiator (i.e., IVA). This may be important for some patients who are intolerant to the triple-combination therapy, as the monotherapy could offer similar clinical benefit with reduced harms. Data protection for IVA ended on May 26, 2021. Should there be interest from public drug programs and CF clinical community, this product could be eligible for review through the Non-Sponsored Reimbursement Review Procedures.

Conclusion

The current review is for an expanded indication that would include 152 additional non-F508del mutations of the CFTR gene. The sponsor has categorized these mutations as follows: 147 FRT-responsive mutations; 4 noncanonical splice mutations; and the N1303K mutation. Evidence supporting the use of ELX-TEZ-IVA in the expanded population consisted of the following: 1 double-blind, placebo-controlled RCT in patients with FRT-responsive mutations (Study 124; N = 307; 18 CFTR mutations); 1 long-term extension study (Study 125; same population as Study 124); 1 retrospective observational study (Study 14; N = 422; 64 CFTR mutations); 4 nonrandomized studies involving patients with 1 or more N1303K mutations (Solomon et al., [2024], N = 20; Burgel et al. [2023], N = 8; Burgel et al. [2024], N = 35; and Sadras et al. [2023], N = 8). Evidence for 79 of the additional mutations is exclusively from the in vitro FRT model.

With respect to FRT-responsive mutations, Studies 124 and 16 demonstrated that ELX-TEZ-IVA resulted in clinically meaningful improvements in lung function (an increase in ppFEV₁), nutritional status (an increase in BMI), health-related quality of life (an increase in CFQ-R [RD] scores), CF biomarkers (a reduction in SwCl), and a reduced rate of PEx events. For the clinical studies in patients with 1 or more N1303K mutations, the short-term results showed acute increases in ppFEV₁ and weight that were suggestive of a clinically meaningful benefit with ELX-TEZ-IVA in these patients; but the results cannot be considered conclusive of a clinically important effect because of the limitations of the open-label, noncomparative, observational study designs, with relatively small sample sizes (N ranged from 8 to 35), short durations, limited reporting of important information, and several potential sources of bias and uncertainty. For all of the mutations with clinical data, the clinical specialists consulted for this review described the results as clinically meaningful and indicative that ELX-TEZ-IVA would benefit patients in the target population. The experts emphasized the high level of unmet needs for these patients as they currently do not have access to CFTR-modulator therapy in Canada (outside of enrolment in a clinical study).

For the 79 mutations assessed exclusively by the in vitro FRT model, the sponsor defined responsive CFTR mutations as those that demonstrated an increase of 10% in Cl⁻ transport over baseline when expressed as a percentage of normal CFTR Cl⁻ transport. The sponsor’s selection of this threshold is therefore expected to affect the disease phenotype for those living with CF. The CF specialists consulted for this review reported that prescribers in Canada are not concerned about the absence of clinical data for patients with rare CFTR mutations. They noted the practical challenges in conducting clinical trials for patients with rare CFTR mutations and emphasized that there are important concerns regarding equity of access to CFTR modulators. Health Canada considered the evidence from the FRT-cell model sufficient to warrant the indication for ELX-TEZ-IVA. Health Canada concluded that the CFTR mutations for which the sponsor has provided sufficient clinical evidence of efficacy are also among those more commonly harboured by patients with CF in Canada. As such, expansion of the indication for ELX-TEZ-IVA would be expected to significantly increase access to effective CF therapy in Canada. Health Canada noted that the inclusion of other CFTR variants to the product monograph because they are responsive to ELX-TEZ-IVA treatment is based mainly on biological plausibility. In cases where the mutation is known to have the potential to cause CF because of the production of a dysfunctional full-length CFTR variant that has demonstrated in vitro responsiveness to ELX-TEZ-IVA (i.e., FRT-responsive mutations), or when a reduced amount of CFTR is produced and its function can be augmented (i.e., splicing mutations), ELX-TEZ-IVA treatment has the potential to provide clinically meaningful benefit to patients.

ELX-TEZ-IVA was well tolerated in the target patient populations (i.e., those aged at least 2 years with at least 1 mutation that is responsive to ELX-TEZ-IVA based on clinical and/or in vitro data). The warnings and precautions section of ELX-TEZ-IVA product monograph has not been updated since the previous CDA-AMC reviews.

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