Summary Basis of Decision for Alyftrek

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Alyftrek is located below.

Recent Activity for Alyftrek

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Alyftrek, a product which contains the medicinal ingredients vanzacaftor calcium, tezacaftor, and deutivacaftor. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: SBD Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2025-10-10

Drug Identification Number (DIN):

  • DIN 02559676 - vanzacaftor 4 mg / tezacaftor 20 mg / deutivacaftor 50 mg, tablet, oral administration

  • DIN 02559684 - vanzacaftor 10 mg / tezacaftor 50 mg / deutivacaftor 125 mg, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DINs 02559676, 02559684) market notification

Not applicable

Date of first sale:

2025-07-31

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 281029

2024-06-27

Issued NOC:

2025-07-21

NOC issued for the New Drug Submission.
Summary Basis of Decision (SBD) for Alyftrek

Date SBD issued: 2025-10-10

The following information relates to the New Drug Submission for Alyftrek.

Vanzacaftor calcium / tezacaftor / deutivacaftor

Drug Identification Number (DIN):

  • DIN 02559676 - vanzacaftor 4 mg / tezacaftor 20 mg / deutivacaftor 50 mg, tablet, oral administration

  • DIN 02559684 - vanzacaftor 10 mg / tezacaftor 50 mg / deutivacaftor 125 mg, tablet, oral administration

Vertex Pharmaceuticals (Canada) Incorporated

New Drug Submission Control Number: 281029

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): R07 Other respiratory system products

Date Filed: 2024-06-27

Authorization Date: 2025-07-21

On July 21, 2025, Health Canada issued a Notice of Compliance to Vertex Pharmaceuticals (Canada) Incorporated for the drug product Alyftrek.

The market authorization of Alyftrek was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Alyftrek is favourable for the treatment of cystic fibrosis in patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

1 What was approved?

Alyftrek, a combination of cystic fibrosis transmembrane conductance regulator (CFTR) correctors and a CFTR potentiator, was authorized for the treatment of cystic fibrosis in patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Alyftrek is not authorized for use in pediatric patients under 6 years of age, as no clinical safety or efficacy data are available for this pediatric subpopulation.

Clinical studies of Alyftrek did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently to Alyftrek from younger patients.

Alyftrek is presented as a fixed-dose combination tablet containing vanzacaftor 4 mg / tezacaftor 20 mg / deutivacaftor 50 mg or vanzacaftor 10 mg / tezacaftor 50 mg / deutivacaftor 125 mg. Non-medicinal ingredients in the tablet core are croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. In addition, the tablet film coat contains brilliant blue FCF aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide.

The use of Alyftrek is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Product Monograph for Alyftrek is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Alyftrek approved?

Health Canada considers that the benefit-harm-uncertainty profile of Alyftrek is favourable for the treatment of cystic fibrosis in patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic fibrosis is an autosomal recessive disease with serious, chronic, debilitating morbidities and high premature mortality. It is caused by mutations in the CFTR gene, which encodes the CFTR protein, a chloride ion channel at the surface of epithelial cells. Some CFTR mutations result in abnormalities in the electrolyte and water transport across epithelial cells, leading to a multisystem disease affecting the lungs, the pancreas, the intestinal tract, the liver, and reproductive organs. Lung disease is the primary cause of morbidity and mortality in cystic fibrosis. In Canada, there are over 4,500 patients with cystic fibrosis, 35% of whom are children or adolescents.

There are more than 2,000 known mutations of the CFTR gene and many of them are rare. The most commonly found mutation is the F508del which results in protein misfolding and defects in cellular processing and trafficking that reduce the quantity of CFTR protein at the cell surface. The small amount of F508del-CFTR protein that reaches the cell surface is less stable and has a low channel open probability (or gating) compared to the wild-type CFTR protein. In Canada, 45% of patients with cystic fibrosis are homozygous for F508del mutation and 42% are heterozygous for F508del mutation.

The treatment of cystic fibrosis includes supportive therapies to manage symptoms and improve quality of life. Several CFTR modulators, which target the CFTR protein defect, are available as monotherapy, dual and triple therapies, and are indicated for patients harbouring specific CFTR mutations identified as responsive to the drugs. However, there is still a lack of CFTR modulator treatment options for patients with rare CFTR mutations.

Alyftrek is a fixed-dose combination drug product containing vanzacaftor, tezacaftor, and deutivacaftor. Vanzacaftor and tezacaftor, the CFTR correctors, improve the processing and trafficking of CFTR to the cell surface, whereas deutivacaftor, a CFTR potentiator, increases anion transport activity of the CFTR protein at the cell surface.

The market authorization of Alyftrek was based on efficacy and safety data derived from two similar Phase III, randomized, double-blind, active-controlled, non-inferiority studies (Study 121-102 and Study 121-103) in patients with cystic fibrosis aged 12 years and older harbouring at least one F508del mutation or another responsive mutation in the CFTR gene. The efficacy and safety of Alyftrek for patients aged 6 years to under 12 years were extrapolated from the data in adolescents and adults, based on the same disease process and the comparable systemic exposure of Alyftrek between the different age groups. Additionally, pharmacokinetic, safety, and tolerability data for patients aged 6 years to under 12 years were provided from an open-label, 24-week study of Alyftrek (Study 121-105).

In Study 121-102 and Study 121-103, all patients were treated with elexacaftor/tezacaftor/ivacaftor, the current standard of care, in a 4-week run-in period and then randomized (1:1) to Alyftrek (vanzacaftor 20 mg / tezacaftor 100 mg / deutivacaftor 250 mg) once daily or elexacaftor/tezacaftor/ivacaftor (per the approved dosage regimen). Study 121-102 included 398 patients who were heterozygous for F508del and a minimal function mutation (F/MF genotype). Of the 573 patients included in Study 121-103, 446 were homozygous for F508del (F/F genotype), 39 were heterozygous for F508del and a gating mutation (F/G genotype), 46 were heterozygous for F508del and a residual function mutation (F/RF genotype), and 42 had at least one triple combination responsive mutation and no F508del mutation (TCR/non-F genotype).

In both studies, Alyftrek was non-inferior to elexacaftor/tezacaftor/ivacaftor for the primary endpoint of absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline through Week 24. The ppFEV1 is a measurement of lung function. The least-squares mean treatment difference between Alyftrek and elexacaftor/tezacaftor/ivacaftor was 0.2 percentage points (95% confidence interval [CI]: -0.7, 1.1, p<0.0001) in Study 121-102 and 0.2 percentage points (95% CI: -0.5, 0.9, p<0.0001) in Study 121-103. The results demonstrated non-inferiority of Alyftrek to elexacaftor/tezacaftor/ivacaftor, as the lower bounds of the 95% CIs of the absolute change in ppFEV1 from baseline through Week 24 were greater than the prespecified non-inferiority margin of -3.0 percentage points. The least-squares mean treatment difference for absolute change in ppFEV1 from baseline through Week 24 was maintained through Week 52.

For the key secondary endpoint of absolute change in sweat chloride from baseline through Week 24, the mean treatment difference between Alyftrek and elexacaftor/tezacaftor/ivacaftor was -8.4 mmol/L (95% CI: -10.5, -6.3, p<0.0001) in Study 121-102 and -2.8 mmol/L (95% CI: -4.7, -0.9, p = 0.0034) in Study 121-103. The decrease in sweat chloride was maintained to Week 52. The results for other secondary efficacy endpoints, including the rate of pulmonary exacerbations through Week 52 and absolute change from baseline in cystic fibrosis questionnaire-revised respiratory domain (CFQ-R RD) score through Week 24, were similar between Alyftrek and elexacaftor/tezacaftor/ivacaftor treatment groups. Interpretation of these secondary endpoints was limited due to the lack of multiplicity control.

Due to the large number of CFTR mutations, each specific mutation cannot be evaluated in clinical trials. Therefore, the sponsor conducted in vitro studies with Fisher rat thyroid (FRT) cells transfected with CFTR variants with individual mutations. The chloride transport activity of these transfected cells was evaluated in vitro, prior to and after treatment with vanzacaftor/tezacaftor/deutivacaftor. An improvement of at least 10 percentage points in chloride transport activity when treated with vanzacaftor/tezacaftor/deutivacaftor is an established threshold indicating the CFTR mutation is responsive to the treatment. The in vitro studies identified CFTR mutations that were responsive to vanzacaftor/tezacaftor/deutivacaftor. Other CFTR mutations had previously been identified as responsive to elexacaftor/tezacaftor/ivacaftor, and based on the in vitro and clinical data, responsiveness to vanzacaftor/tezacaftor/deutivacaftor was expected for these mutations.

Following a review of the available literature, international CFTR mutation databases, and in vitro and clinical results, 266 CFTR mutations identified as responsive to Alyftrek have been listed in the Product Monograph for Alyftrek. Accordingly, the intended patient population is defined as “patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene”. Thirty-seven mutations were removed from the sponsor’s initially proposed list of 303 CFTR mutations for various reasons: 1) mutations that do not cause cystic fibrosis as per international CFTR mutation databases, 2) mutations that exhibited high (over 100% of the wild-type CFTR protein activity) baseline chloride transport in vitro, and 3) mutations previously removed from the Trikafta (elexacaftor/tezacaftor/ivacaftor) Product Monograph and known to not produce a full-length CFTR protein. Although the sponsor provided extensive rationales for including all of the initially proposed mutations, Health Canada revised the list because the use of a triple-combination drug product which may not provide clinical benefit for patients with some CFTR mutations is concerning, particularly in the context of a lifelong treatment and treatment of young children in whom it is difficult to measure the clinical efficacy via assessment of lung function.

The safety database for Alyftrek was considered adequate and demonstrated a comparable safety profile to that of elexacaftor/tezacaftor/ivacaftor for patients 6 years of age and older. The design of the pivotal clinical trials included an elexacaftor/tezacaftor/ivacaftor run-in period prior to randomization to vanzacaftor/tezacaftor/deutivacaftor or elexacaftor/tezacaftor/ivacaftor as an active control. Additionally, the majority of patients had previously been taking elexacaftor/tezacaftor/ivacaftor. Patients who did not tolerate elexacaftor/tezacaftor/ivacaftor were not eligible to enter the trials. Study 121-102 and Study 121-103 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions between vanzacaftor/tezacaftor/deutivacaftor and elexacaftor/tezacaftor/ivacaftor treatment groups; however, overall, the data supported the safety of Alyftrek. The reported adverse events were comparable between the two treatment arms in terms of the incidence and severity. The most commonly reported adverse reactions in Study 121-102 and Study 121-103 for patients treated with Alyftrek were headache and diarrhea. Other observed adverse reactions included rash, increased blood creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase.

Elevations in liver function tests were also observed with the other CFTR modulators. A Serious Warnings and Precautions box was included in the Product Monograph for Alyftrek to address the risk of hepatotoxicity. It conveys the information that increased transaminases have been observed in patients treated with Alyftrek and that cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease receiving elexacaftor/tezacaftor/ivacaftor, which contains one same (tezacaftor) and one similar (ivacaftor) active ingredient as Alyftrek. Liver function tests are recommended prior to initiating and during treatment with Alyftrek. More frequent monitoring should be considered for patients who had no prior treatment with elexacaftor/tezacaftor/ivacaftor or those with a history of liver disease or elevated liver function tests.

A Risk Management Plan (RMP) for Alyftrek was submitted by Vertex Pharmaceuticals (Canada) Incorporated to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Product Monograph for Alyftrek met the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Alyftrek was accepted.

Overall, Alyftrek has been shown to have a favourable benefit-harm-uncertainty profile for the target patient population. The identified safety issues can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Alyftrek to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Alyftrek?

The review of the New Drug Submission (NDS) for Alyftrek was based on a critical assessment of the data package submitted to Health Canada. In addition, the review completed by the United States Food and Drug Administration (FDA) was used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Alyftrek NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Alyftrek

Submission Milestone

Date

New Drug Submission filed

2024-06-27

Screening

Screening Deficiency Notice issued

2024-08-08

Response to Screening Deficiency Notice filed

2024-08-19

Screening Acceptance Letter issued

2024-09-24

Review

Biostatistics evaluation completed

2025-06-27

Review of Risk Management Plan completed

2025-07-02

Biopharmaceutics evaluation completed

2025-07-16

Non-clinical evaluation completed

2025-07-17

Quality evaluation completed

2025-07-18

Labelling review completed

2025-07-18

Clinical/medical evaluation completed

2025-07-21

Notice of Compliance issued by Director General, Pharmaceutical Drugs Directorate

2025-07-21
4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

5 What post-authorization activity has taken place for Alyftrek?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Alyftrek is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada’s decision?

Refer to the What steps led to the approval of Alyftrek? section for more information about the review process for this submission.

7.1 Clinical Basis for Decision

Clinical Pharmacology

Alyftrek is a fixed-dose combination drug that contains three cystic fibrosis transmembrane conductance regulator (CFTR) modulators: vanzacaftor, tezacaftor, and deutivacaftor. Vanzacaftor and tezacaftor are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR protein (including F508del-CFTR protein) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Deutivacaftor is a CFTR potentiator, as it increases the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of vanzacaftor, tezacaftor, and deutivacaftor is increased quantity and function of the CFTR protein at the cell surface, resulting in increased CFTR activity as measured both by CFTR-mediated chloride transport in vitro and by sweat chloride in patients with cystic fibrosis.

Vanzacaftor and deutivacaftor are new active substances and have not previously been approved in Canada. Deutivacaftor is a deuterated isotopologue of ivacaftor, a CFTR potentiator already approved as monotherapy and as a component in other CFTR corrector-potentiator combinations. Tezacaftor has already been approved as a component in other CFTR corrector-potentiator combinations.

The pharmacokinetics and pharmacodynamics of vanzacaftor, tezacaftor and deutivacaftor were evaluated in numerous studies in which the compounds were administered alone or in a triple combination. The sponsor used population pharmacokinetic modelling and simulations to inform the appropriate dosages for patients with cystic fibrosis aged 6 years and older. In the pivotal Phase III clinical studies, all patients aged 12 years and over received the higher dose (vanzacaftor 20 mg / tezacaftor 100 mg / deutivacaftor 250 mg) once daily regardless of weight. In an open-label, 24-week study, 78 patients aged 6 years to under 12 years received weight-based doses: patients weighing less than 40 kg received vanzacaftor 12 mg / tezacaftor 60 mg / deutivacaftor 150 mg once daily, and patients weighing 40 kg and over received vanzacaftor 20 mg / tezacaftor 100 mg / deutivacaftor 250 mg once daily during the treatment period.

The proposed weight-based dose regimen for pediatric patients aged 6 years and over using 40 kg as a weight cut-off is supported by the final population pharmacokinetic model analyses, taking into account the exposure levels of both the parent drugs and the metabolites, as well as the high accumulation ratio observed for vanzacaftor due to cytochrome P450 (CYP) 3A4 (CYP3A4)-mediated competitive inhibition.

All three compounds of Alyftrek are primarily metabolized by the same enzyme, CYP3A. When Alyftrek is coadministered with a moderate or strong CYP3A inhibitor, the combined effects of CYP3A inhibitor potency, drug-drug interactions among the three compounds, dosing frequency, and patient body weight interact in a complex manner. Hence, the Product Monograph for Alyftrek includes a recommended dosage schedule for concomitant use of Alyftrek with moderate and strong CYP3A inhibitors. In addition, coadministration of Alyftrek with moderate or strong CYP3A inducers is not recommended. The available data also indicate that concomitant use of Alyftrek with P-glycoprotein (P-gp) substrates, breast cancer resistance protein (BCRP) substrates, or CYP2C9 substrates may increase exposure of these substrates. Established or potential drug-drug interactions, along with relevant recommendations, are listed in the Product Monograph for Alyftrek.

Bioavailability data demonstrated that a high-fat, high-calorie meal had a significant impact on the extent of exposure of tezacaftor and on both the rate and extent of exposure of vanzacaftor and deutivacaftor in the commercial formulation of Alyftrek. Therefore, Alyftrek is recommended to be taken with fat-containing food.

For further details, please refer to the Product Monograph for Alyftrek, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Alyftrek in patients with cystic fibrosis aged 12 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was demonstrated in two similar Phase III, randomized, double-blind, active-controlled, parallel-group, multicentre, non-inferiority studies (Study 121-102 and Study 121-103). All patients were treated with elexacaftor/tezacaftor/ivacaftor, the current standard of care, in a 4-week run-in period and then randomized (1:1) to Alyftrek (vanzacaftor 20 mg / tezacaftor 100 mg / deutivacaftor 250 mg) once daily or elexacaftor/tezacaftor/ivacaftor (per the approved dosage regimen). Randomization was stratified by age at the screening visit (under 18 years of age versus 18 years of age and older), percent predicted forced expiratory volume in one second (ppFEV1) determined during the run-in period, sweat chloride levels determined during the run-in period, and prior CFTR modulator use (yes versus no).

Study 121-102 included 398 patients who were heterozygous for F508del and a minimal function mutation (F/MF genotype). The mean age of the patients was 30.8 years (range: 12.2 to 71.6 years) and 59% of the patients were male.

Of the 573 patients included in Study 121-103, 446 were homozygous for F508del (F/F genotype), 39 were heterozygous for F508del and a gating mutation (F/G genotype), 46 were heterozygous for F508del and a residual function mutation (F/RF genotype), and 42 had at least one triple combination responsive mutation and no F508del mutation (TCR/non-F genotype). The mean age of the patients was 33.7 years (range: 12 to 71 years) and 51% of the patients were male.

In both studies, Alyftrek was non-inferior to elexacaftor/tezacaftor/ivacaftor for the primary endpoint of absolute change in ppFEV1 from baseline through Week 24. The least-squares mean treatment difference between Alyftrek and elexacaftor/tezacaftor/ivacaftor was 0.2 percentage points (95% confidence interval [CI]: -0.7, 1.1, p<0.0001) in Study 121-102 and 0.2 percentage points (95% CI: -0.5, 0.9, p<0.0001) in Study 121-103. The results demonstrated non-inferiority of Alyftrek to elexacaftor/tezacaftor/ivacaftor, as the lower bounds of the 95% CIs of the absolute change in ppFEV1 from baseline through Week 24 were greater than the prespecified non-inferiority margin of -3.0 percentage points. In both studies, the least-squares mean treatment difference for the absolute change in ppFEV1 from baseline through Week 24 was maintained through Week 52.

All other efficacy endpoints were evaluated for superiority. Alyftrek led to a statistically significant decrease (i.e., improvement) in the key secondary endpoint of absolute change in sweat chloride from baseline through Week 24 compared to elexacaftor/tezacaftor/ivacaftor, with a mean difference of -8.4 mmol/L (95% CI: -10.5, -6.3, p<0.0001) in Study 121-102 and -2.8 mmol/L (95% CI: -4.7, -0.9, p = 0.0034) in Study 121-103. The decrease in sweat chloride was maintained to Week 52.

The results for other secondary endpoints (not controlled for multiplicity), including the rate of pulmonary exacerbations through Week 52 and absolute change from baseline in cystic fibrosis questionnaire-revised respiratory domain (CFQ-R RD) score through Week 24, were similar between Alyftrek and elexacaftor/tezacaftor/ivacaftor treatment groups.

The efficacy of Alyftrek for patients aged 6 years to under 12 years was extrapolated from the efficacy data in adolescents and adults. Such extrapolation is appropriate based on the same disease process and the comparable systemic exposure of Alyftrek between the different age groups. An open-label, 24-week study (Study 121-105) in 78 patients aged 6 years to under 12 years who received Alyftrek following a treatment with elexacaftor/tezacaftor/ivacaftor demonstrated stability in the ppFEV1 values and slightly improved sweat chloride measurements from baseline values. However, the efficacy results are interpreted with caution, since there was no a placebo or an active-control treatment group.

The use of Alyftrek for the treatment of patients with cystic fibrosis who harbour CFTR mutations not evaluated in the clinical trials is primarily supported by the demonstrated in vitro responsiveness of the individual mutations to CFTR modulators, in a chloride transport assay using Fischer rat thyroid (FRT) cells expressing the individual mutant CFTR proteins. In the FRT assay, 128 CFTR mutations, including F508del, were shown to be responsive to Alyftrek. Furthermore, additional 129 CFTR mutations are predicted to be responsive to Alyftrek based on previous in vitro studies demonstrating their responsiveness to ivacaftor and/or tezacaftor/ivacaftor. For the N1303K mutation, in vitro responsiveness to Alyftrek was only demonstrated with patient-derived bronchial epithelial cells. In total, based on a review of the available literature, international CFTR mutation databases, and in vitro and clinical results, 266 CFTR mutations characterized as responsive to Alyftrek have been listed in the Product Monograph for Alyftrek. The intended patient population is defined in the indication of Alyftrek as “patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the CFTR gene”. The 37 CFTR mutations that were excluded from the sponsor’s initially proposed list comprised: 1) mutations known to not cause cystic fibrosis as per international CFTR mutation databases, 2) mutations that exhibited high (over 100% of the wild-type CFTR protein activity) baseline chloride transport in vitro, and 3) mutations previously removed from the Trikafta (elexacaftor/tezacaftor/ivacaftor) Product Monograph and known to not produce a full-length CFTR protein.

Overall, the available data support the efficacy of Alyftrek in the intended population.

Indication

The New Drug Submission for Alyftrek was filed by the sponsor with the following proposed indication:

Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) is indicated for the treatment of cystic fibrosis in people aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Following a minor text change, Health Canada approved the following indication:

Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) is indicated for the treatment of cystic fibrosis in patients aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

For more information, refer to the Product Monograph for Alyftrek, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Alyftrek in patients with cystic fibrosis aged 12 years and over was primarily evaluated in two randomized, active-controlled, 52-week, Phase III studies (Study 121-102 and Study 121-103, described in the Clinical Efficacy section).

In both studies, patients received a fixed-dose combination of elexacaftor/tezacaftor/ivacaftor (standard-of-care therapy) in a 4-week run-in period prior to randomization. Patients with a prior intolerance to elexacaftor/tezacaftor/ivacaftor (i.e., patients who discontinued or interrupted treatment with elexacaftor/tezacaftor/ivacaftor due to adverse reactions) were excluded from the studies. Hence, the safety profile of Alyftrek in patients who do not tolerate treatment with elexacaftor/tezacaftor/ivacaftor was not established. In addition, a meaningful comparison of adverse drug reactions between the Alyftrek group and the elexacaftor/tezacaftor/ivacaftor group was precluded due to the design of the studies, which included a run-in period with elexacaftor/tezacaftor/ivacaftor.

In the pooled safety data from 480 patients treated with Alyftrek in both Phase III studies, the most commonly reported adverse drug reactions (occurring in at least 10% of patients) were headache (15.8%) and diarrhea (12.1%).

Serious adverse drug reactions that occurred with Alyftrek in 2 or more patients (at least 0.4% of patients) were increased alanine aminotransferase (ALT) (0.4%) and increased aspartate aminotransferase (AST) (0.4%).

The proportion of patients who discontinued Alyftrek prematurely due to adverse events was 3.8% in the Alyftrek group and 3.7% in the elexacaftor/tezacaftor/ivacaftor group. Of the Alyftrek-treated patients, 2.7% discontinued treatment due to elevated transaminases.

The safety profile of Alyftrek was generally similar across all subgroups of patients, including subgroups by age, sex, baseline ppFEV1, and geographic regions. In addition, safety data from a 24-week, open-label study (Study 121-105, Cohort B1) in 78 patients with cystic fibrosis aged 6 years to under 12 years who received Alyftrek were generally consistent with the safety data observed in Study 121-102 and Study 121-103.

Overall, based on the pooled safety data from Study 121-102 and Study 121-103, the safety profile of Alyftrek appeared comparable with that of elexacaftor/tezacaftor/ivacaftor.

A Serious Warnings and Precautions box was included in the Product Monograph for Alyftrek to address the risk of hepatotoxicity. It conveys the information that increased transaminases have been observed in patients treated with Alyftrek and that cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease receiving elexacaftor/tezacaftor/ivacaftor, which contains one same (tezacaftor) and one similar (ivacaftor) active ingredient as Alyftrek. Liver function tests are recommended prior to initiating and during treatment with Alyftrek. More frequent monitoring should be considered for patients who had no prior treatment with elexacaftor/tezacaftor/ivacaftor or those with a history of liver disease or elevated liver function tests.

For more information, refer to the Product Monograph for Alyftrek, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Alyftrek is composed of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators: two CFTR correctors, vanzacaftor and tezacaftor, and one CFTR potentiator, deutivacaftor.

Vanzacaftor and deutivacaftor are new active substances and have not previously been approved in Canada. The non-clinical safety profile of tezacaftor has already been established in non-clinical programs conducted prior to its approval as a component in other CFTR corrector-potentiator combinations; therefore, non-clinical studies of tezacaftor were not carried out for this submission.

The non-clinical program of Alyftrek focused primarily on evaluating vanzacaftor and deutivacaftor, alone or in dual and triple combinations.

Vanzacaftor

Primary pharmacodynamic studies demonstrated that vanzacaftor facilitated the cellular processing and trafficking of F580del-CFTR protein and thereby increased the amount of CFTR protein at the cell surface. In the secondary pharmacodynamic studies, vanzacaftor demonstrated a high degree of selectivity.

The safety pharmacology studies showed a low potential of vanzacaftor to elicit adverse effects on the respiratory, cardiovascular, and central nervous systems.

The primary metabolic pathway for vanzacaftor involves oxidation by cytochrome P450 (CYP) 3A4/5; hence, concomitant use of inhibitors or inducers of CYP3A may affect vanzacaftor exposures. There are no major human circulating metabolites of vanzacaftor.

In repeat-dose toxicity studies, chronic oral administration of vanzacaftor once daily in adult rats for 26 weeks did not result in any adverse effects up to doses which produced exposures corresponding to approximately 21 times (in male rats) and 59 times (in female rats) the anticipated exposure (based on the area under the concentration-time curve [AUC]) at the maximum recommended human dose (MRHD). Chronic oral administration of vanzacaftor once daily in male and female dogs for 39 weeks did not demonstrate any adverse effects at a dose resulting in an exposure corresponding to 105 times the anticipated exposure (based on the AUC) at the MRHD.

Vanzacaftor did not exhibit genotoxic potential in genotoxicity studies. In a 6-month carcinogenicity study in transgenic mice, vanzacaftor did not demonstrate carcinogenic potential up to doses resulting in exposures corresponding to 27 times the anticipated exposure (based on the AUC) at the MRHD.

In reproductive and developmental toxicity studies of vanzacaftor, no effects were observed on fertility and early embryonic development in male and female rats at oral doses resulting in exposures corresponding to approximately 19 times and 30 times, respectively, the anticipated exposure (based on the AUC) at the MRHD. Vanzacaftor did not show teratogenic potential. No fetal malformations were noted in rat and rabbit fetuses following oral administration of vanzacaftor to pregnant rats and pregnant rabbits during the period of organogenesis at systemic exposures approximately 30 and 22 times, respectively, the exposure at the MRHD.

Placental transfer of vanzacaftor was observed in pregnant rats. Vanzacaftor is excreted into the milk of lactating female rats.

Administration of vanzacaftor to pregnant and lactating female rats did not impact the survival, growth, and development of their offspring.

Administration of vanzacaftor to male and female juvenile rats from postnatal days 7 to 70 was well tolerated and showed no adverse effects at exposures corresponding to 28 times and 58 times, respectively, the exposure measured at the MRHD.

Deutivacaftor

Deutivacaftor is a deuterated isotopologue of ivacaftor, a CFTR potentiator previously approved as monotherapy and as a component in other CFTR corrector-potentiator combinations.

The non-clinical data submitted for deutivacaftor indicated qualitative similarity in the disposition and metabolism pathways of deutivacaftor and ivacaftor. Deutivacaftor showed a higher metabolic stability than ivacaftor.

Deutivacaftor is primarily metabolized by CYP3A4/5. It has two major circulating metabolites, M1-D-IVA, which has approximately one-fifth the potency of the parent compound and M6-D-IVA, which is not considered pharmacologically active.

A 13-week repeat-dose toxicity study in rats indicated a comparable toxicity profile between deutivacaftor and ivacaftor. The target organs of toxicity were the kidney and thyroid. The no-adverse-effect level (NOAEL) was determined to be 17.5 mg/kg/day, resulting in exposures that are approximately 5 times the clinical exposure at the MRHD.

In a 28-day repeat-dose toxicity study in dogs, deutivacaftor led to a prolonged PR interval at a dose of 60 mg/kg/day in both males and females during the last week of dosing. The finding was no longer present during the recovery phase. The NOAEL of deutivacaftor in dogs was determined to be 20 mg/kg/day.

In genotoxicity assays, deutivacaftor did not exhibit genotoxic potential. No reproductive and developmental toxicity, or carcinogenicity studies were conducted with the compound.

The non-clinical safety profile of deutivacaftor is considered consistent with that previously established for ivacaftor.

Vanzacaftor/tezacaftor/deutivacaftor

A 13-week repeat-dose toxicity study in rats involving the coadministration of vanzacaftor, tezacaftor and deutivacaftor to assess the potential for additive or synergistic toxicity did not produce any unexpected toxicities or interactions.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Alyftrek. In view of the intended use of Alyftrek, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Alyftrek, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The quality (chemistry and manufacturing) information submitted for Alyftrek has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at a temperature less than or equal to 30 ºC.

The proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies). The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in Alyftrek are prohibited for use in drug products by the Food and Drug Regulations. The excipient carmine is of animal origin. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents. No other excipient in Alyftrek is of animal or human origin.

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