Summary Basis of Decision for Trikafta

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.


Product type:

Drug

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

Recent Activity for Trikafta

SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

The following  table describes post-authorization activity for Trikafta, a product which contains the medicinal ingredients elexacaftor, tezacaftor, and ivacaftor. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-08-02

Drug Identification Number (DIN):

  • DIN 02517140 - 100 mg elexacaftor/50 mg tezacaftor/75 mg ivacaftor and 150 mg ivacaftor, tablets, oral administration
  • DIN 02526670 - 50 mg elexacaftor/25 mg tezacaftor/37.5 mg ivacaftor and 75 mg ivacaftor, tablets, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02526670) market notification Not applicable Date of first sale: 2022-04-22 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 255136 2021-07-27 Issued NOC 2022-04-20 Submission filed as a Level I – Supplement to expand the indication and add a new strength. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication was expanded to patients 6 years and older. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02526670) was issued for the new strength. A Regulatory Decision Summary was published.
Drug product (DIN 02517140) market notification Not applicable Date of first sale: 2021-06-22 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 246955 2020-12-04 Issued NOC 2021-06-18 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Trikafta

Date SBD issued: 2021-10-16

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

Elexacaftor, Tezacaftor, and Ivacaftor

Drug Identification Number (DIN):

  • DIN 02517140 - 100  mg elexacaftor/50  mg tezacaftor/75  mg ivacaftor and 150  mg ivacaftor, tablets, oral administration

Vertex Pharmaceuticals Canada Inc.orporated

New Drug Submission Control Number: 246955

 

On June 18, 2021, Health Canada issued a Notice of Compliance to Vertex Pharmaceuticals (Canada) Incorporated for the drug product Trikafta.

The market authorization 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 benefits-harm-uncertainty of Trikafta is favourable for the treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

 

1 What was approved?

 

Trikafta, a combination of two cystic fibrosis transmembrane conductance regulator (CFTR) correctors and one CFTR potentiator, was authorized for the treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Trikafta is not authorized for use in pediatric patients less than 12 years of age, as no clinical safety or efficacy data are available for this population.

Clinical trials of Trikafta did not include a sufficient number of patients 65 years of age or older to determine whether they respond differently than younger patients.

Trikafta 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.

Trikafta was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Trikafta (100 mg elexacaftor/50 mg tezacaftor/75 mg ivacaftor tablets and 150 mg ivacaftor tablets) is presented as a fixed dose combination medication. In addition to the medicinal ingredient, the tablets contain the following non-medicinal ingredients:

  • Elexacaftor/Tezacaftor/Ivacaftor tablets:
    • croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, hydroxypropyl cellulose, iron oxide red, iron oxide yellow, talc, and titanium dioxide.
  • Ivacaftor tablets:
    • colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, carnauba wax, indigo carmine aluminum lake, PEG 3350, polyvinyl alcohol, talc, titanium dioxide, ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Trikafta Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Trikafta approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Trikafta is favourable for the treatment of cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene. The CFTR protein functions as a chloride and bicarbonate ion channel in epithelial cells. Normal functioning helps to maintain adequate hydration, osmotic pressure, and pH regulation within airway passages. Loss of function of CFTR protein results in abnormal lung function, along with deficiencies in the pancreas, liver, kidneys, and intestines. Cystic fibrosis causes progressive lung disease that eventually leads to irreversible lung damage, respiratory failure, and death. According to Cystic Fibrosis Canada, there are approximately 4,300 individuals in Canada currently affected by the disease. There is currently no cure for cystic fibrosis.

Targeted cystic fibrosis drugs function by facilitating the processing and trafficking of misfolded mutant CFTR protein (correctors) or by promoting channel opening after the insertion of CFTR into the plasma membrane (potentiators). This allows for the correction of CFTR function in patients harbouring mutations that produce CFTR protein resulting in defects with intracellular trafficking and/or channel regulation. The most common among these is the F508del mutation, found in approximately 90% of patients with cystic fibrosis. The F508del-CFTR protein does not mature normally and does not traffic properly to the plasma membrane. Correction of the trafficking defect on its own does not produce a significant amount of functional CFTR. The combination of a corrector(s) and a potentiator are required to produce functional recovery of the F508del-CFTR protein.

Trikafta is intended to treat cystic fibrosis by combining the complementary approaches of elexacaftor and tezacaftor (both CFTR correctors) and ivacaftor (a CFTR potentiator) to increase the amount and function of CFTR at the cell surface. The combination of tezacaftor and ivacator (Symdeko) is currently approved for use in cystic fibrosis patients homozygous for the F508del mutation, or heterozygous for the F508del mutation and having one of several residual function mutations. With Trikafta, the addition of a second corrector, elexacaftor, is intended to improve the efficacy of the combination. Elexacaftor and tezacaftor bind to different parts of the mutant CFTR protein and synergistically facilitate protein processing and trafficking.

Trikafta has been shown to be efficacious in CF patients who have at least one F508del mutation in the CFTR gene. The market authorization was based on the results of three pivotal Phase III, double-blind, controlled clinical trials (Trial 1: 24 weeks, Trial 2: 4 weeks, and Trial 3: 8 weeks) that evaluated efficacy and safety. In these trials, clinically relevant lung function improvement was observed as compared to placebo/active comparator. The treatment differences between Trikafta and placebo for the primary endpoint of absolute change in percent predicted forced expiratory volume in one second (ppFEV1) from baseline through Week 24 reached 14.3 percentage points. Clinically significant advantages were also demonstrated when comparing the triple combination to a dual combination of its monocomponents; 10.0 percentage points between Trikafta- and tezacaftor/ivacaftor-treated patients. Lastly, statistically significant advantages of 3.7 percentage points were demonstrated when comparing the triple combination to a control group of either ivacaftor- or tezacaftor/ivacaftor-treated patients.

The safety profile of Trikafta was based on data from 768 patients in the three pivotal clinical trials in which a total of 389 patients aged 12 years and older received at least one dose of Trikafta. In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for Trikafta-treated patients and 0% for placebo-treated patients. Serious adverse drug reactions that occurred more frequently in Trikafta-treated patients compared to placebo were rash (1.5% versus [vs.] 0.5%) and influenza (1.5% vs. 0%). The most common adverse drug reactions that occurred in more than 10% of Trikafta-treated patients were headache, diarrhea, and upper respiratory tract infection. The safety profile of Trikafta from the Trials 2 and 3 were consistent with the safety profile observed in Trial 1. With the exception of sex differences in terms of the incidence of rash events, the safety profile of Trikafta was generally similar across all subgroups of patients, including analysis by age, sex, baseline ppFEV1, and geographic regions.

At the recommended therapeutic dose, there is the potential for hepatic adverse reactions in all patients. There may be a greater risk of liver injury in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, or hepatic encephalophathy). To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment have been recommended. Dosing is also to be interrupted with elevated liver function tests and reduced when co-administered with a cytochrome P450 (CYP) 3A inhibitor. Caution is recommended in patients with severe renal impairment. Co-administration with a strong CYP3A inducer is not recommended. Patients should be monitored by a practitioner for liver function and for cases of non-congenital lens opacities (cataracts) when taking Trikafta.

Trikafta displayed a safety profile generally similar in adverse reactions when compared to previously approved CFTR modulators (i.e., Kalydeco and Symdeko); however, post-market data indicate the potential of drug induced liver failure in patients with pre-existing cirrhosis and portal hypertension. These issues have been addressed through appropriate labelling in the Product Monograph which includes a warning for potential liver injury.

A Risk Management Plan (RMP) for Trikafta was submitted by Vertex Pharmaceuticals (Canada) Incorporated to Health Canada. Upon review, the RMP was considered to be acceptable. 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.

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

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Trikafta was accepted.

Trikafta has been shown to have a favourable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Trikafta Product Monograph to address the identified safety concerns.

Uncertainties with Trikafta surround the clinical relevance in lung function with regard to the contribution of elexacaftor in the fixed-dose combination, in patients with “residual function” and “gating” mutations studied in Trial 3. Theoretically, the difference observed with Trikafta should be in addition to the treatment differences noted with Kalydeco (gating) and Symdeko (residual function) respectively. Furthermore, the long-term efficacy of Trikafta was not conclusive, due to the short duration (8 weeks for Trial 3 and 4 weeks for Trial 2) of two of the pivotal studies. Ongoing long-term studies with patients rolled over from both studies should help confirm the long-term efficacy in the near future.

Considering the severity of the disease, the lack of treatment in Canada presently for a proportion of the proposed mutations (cystic fibrosis patients with minimal function mutations), the larger overall demonstrated efficacy in lung function compared to previously approved CFTR modulators, and the reported safety of Trikafta, a Notice of Compliance was recommended for Trikafta.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted 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 Trikafta?

 

The drug submission for Trikafta was subject to an expedited review process under the Priority Review Policy. Trikafta is intended for the treatment of a serious, life-threatening, and severely debilitating disease. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Trikafta has the potential to provide a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies for a disease that is not adequately managed by a drug marketed in Canada.

There is currently no cure for cystic fibrosis. Supportive therapies include symptomatic therapies and pharmacological treatment among which CFTR modulators are becoming the standard of care. There is a medical need for a CFTR modulator therapy that can target the underlying cause of cystic fibrosis disease. No currently authorized CFTR modulators have demonstrated efficacy in cystic fibrosis patients heterozygous for F508del and a minimal function (MF) mutation; therefore, Trikafta has the potential to fill an unmet medical need for treatment in these patients.

 

Submission Milestones: Trikafta

Submission Milestone Date
Pre-submission meeting 2020-01-22
Request for priority status  
Filed 2020-11-04
Approval issued by Director, Bureau of Medical Sciences 2020-11-16
Submission filed 2020-12-04
Screening  
Screening Acceptance Letter issued 2020-12-23
Review  
Biopharmaceutics Evaluation complete 2021-05-04
Quality Evaluation complete 2021-05-11
Review of Risk Management Plan complete 2021-05-21
Non-Clinical Evaluation complete 2021-06-14
Clinical/Medical Evaluation complete 2021-06-17
Labelling Review complete 2021-06-17
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2021-06-18

 

The Canadian regulatory decision on the non-clinical and clinical review of Trikafta was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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

 

4 What follow-up measures will the company take?

 

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

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs 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 Trikafta 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?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common among these is the F508del mutation, which results in a mutated F508del-CFTR protein that does not mature normally and does not traffic properly to the plasma membrane. The combination of a corrector(s) and a potentiator are required to produce functional recovery of the F508del-CFTR protein.

Trikafta is composed of three medicinal ingredients: elexacaftor, tezacaftor, and ivacaftor. Elexacaftor and tezacaftor are CFTR correctors. They bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of the F508del-CFTR protein to increase the amount of CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator. It works by increasing the likelihood of the channel-open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of elexacaftor, tezacaftor, and ivacaftor increases the quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR-mediated chloride transport. Clinical outcomes indicate that patients need only harbour a single F508del mutant allele, with the second mutant CFTR allele being variable, to experience a significant clinical response to Trikafta.

The clinical pharmacology studies conducted for Trikafta focused on describing the pharmacokinetics and pharmacodynamics of elexacaftor, the novel component of the triple combination, alone, or in combination with tezacaftor/ivacaftor. The studies demonstrated that the absorption of elexacaftor was increased when it was taken with fat-containing food. Elexacaftor was metabolized mainly by cytochrome P450 (CYP) 3A enzymes and was primarily excreted in feces. Each of these characteristics is similar to the tezacaftor/ivacaftor combination (Symdeko).

The dosage of elexacaftor 200 mg once-daily/tezacaftor 100 mg once-daily/ivacaftor 150 mg every 12 hours was supported by initial safety observations and exposure-response analyses conducted using lung and CFTR function data from patients with cystic fibrosis. The exposure-response analyses demonstrated that systemic exposures resulting from this dosage provided >90% of maximal benefit.

Other studies addressed recommendations for dosage adjustment for patients with hepatic impairment as well as adjustments with concomitant drug use. As all three of the components of Trikafta are primarily metabolized by CYP3A, dose adjustments were recommended for concomitant use with drugs that cause CYP3A inhibition or induction, which increase and decrease Trikafta exposure values, respectively. Strong CYP3A inhibition increased elexacaftor exposure (2.8-fold increase in the area under the curve [AUC]) less than what has been observed for tezacaftor (4.5-fold increase in AUC) and ivacaftor (15.6-fold increase in AUC). Accordingly, the recommended dosage reductions for patients using CYP3A inhibitors are similar between Trikafta and the tezacaftor/ivacaftor combination (Symdeko). Other dosage recommendations for Trikafta with concomitant drug use were mainly based on previous findings for the tezacaftor/ivacaftor combination.

Trikafta also has the potential to inhibit drug transporters that may impact the exposures of other drugs used concomitantly. In vitro data suggests the potential for elexacaftor to contribute an inhibitory effect on organic anion transporting polypeptide (OATP) transporter proteins in addition to a known inhibition by tezacaftor/ivacaftor. This produces a risk of increased exposure to statins used concomitantly, and may also affect bilirubin metabolism. As with Symdeko, concomitant use of Trikafta can also cause increased exposure to P-glycoprotein substrates such as digoxin. No clinical studies were provided to demonstrate any new clinically relevant drug-drug interactions with Trikafta in comparison to Symdeko.

A study conducted in subjects with moderate hepatic impairment was used to assess dosage recommendations. Moderate hepatic impairment (Child-Pugh Class B) increased elexacaftor exposure relative to healthy subjects (AUC increased by 25%), with similar increases observed for tezacaftor and ivacaftor. Elevated bilirubin and transaminase levels in subjects with moderate hepatic impairment exposed to Trikafta were indicative of a potential for Trikafta to cause liver injury in susceptible patients (as observed in international post-marketing data). More conservative dosage reduction recommendations (i.e., not based solely on pharmacokinetic measurements) compared to Symdeko, including a recommendation to not use in patients with severe hepatic impairment, reflect concerns over risk of liver injury.

Overall, the recommended dosage adjustments included in the Trikafta Product Monograph appropriately mitigate risks associated with the use of Trikafta, and help to maintain an overall positive benefit/risk ratio.

Comparative Bioavailability

The effect of food was evaluated in a Phase I study where healthy subjects were administered two 100 mg elexacaftor/50 mg tezacaftor/75 mg deuterated ivacaftor fixed dose combination tablets under light fat, light calorie fed conditions. Compared to when administered under fasting conditions, the area under the concentration versus time curve to the time of the last quantifiable concentration (AUCT) and the maximum concentration (Cmax) increased by approximately 55% and 126%, respectively, for elexacaftor and by 120% and 299%, respectively, for deuterated ivacaftor. When the same dose was administered under moderate fat, moderate calorie fed conditions, there was a greater effect of food on the rate and extent of absorption when compared to administration under fasting conditions such that elexacaftor and deuterated ivacaftor AUCT and Cmax increased by approximately 108% and 293%, and 226% and 519%, respectively. The AUCT and Cmax for tezacaftor were equivalent when administered under fasting and fed conditions (both meal types).

The clinical pharmacological data support the use of Trikafta for the recommended indication. For further details, please refer to the Trikafta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy and safety of Trikafta for the treatment of cystic fibrosis with at least one F508del mutation were evaluated in three pivotal Phase III trials. Not all F508del heterozygotes have been clinically evaluated with Trikafta.

Trial 1

Trial 1 was a 24-week, randomized, double-blind, placebo-controlled trial in patients who had an F508del mutation on one allele and a minimal function (MF) mutation on the second allele. Cystic fibrosis patients eligible for this study were required to have:

  • Class I mutations that predicted no CFTR protein being produced (including nonsense mutations, canonical splice mutations, and insertion/deletion frameshift mutations both small [≤3 nucleotide] and non-small [>3 nucleotide]), or
  • missense mutations which result in CFTR protein that does not transport chloride and is not responsive to ivacaftor and tezacaftor/ivacaftor in vitro.

The most frequent alleles with minimal function assessed in the study were G542X, W1282X, R553X, and R1162X; 621+1G→T, 1717-1G→A, and 1898+1G→A; 3659delC, and 394delTT; CFTRdele2,3; and N1303K, I507del, G85E, R347P, and R560T.

A total of 403 patients aged 12 years and older (mean age: 26.2 years) were randomized to receive Trikafta or placebo. Patients had a percent predicted forced expiratory volume in 1 second (ppFEV1) at screening between 40% to 90%. The mean ppFEV1 at baseline was 61.4% (range: 32.3%, 97.1%).

The primary endpoint was the mean absolute change in ppFEV1 from baseline through Week 24. Treatment with Trikafta compared to placebo resulted in a statistically significant improvement in ppFEV1 of 14.3 percentage points (95% confidence interval [CI]: 12.7, 15.8; p <0.0001). Mean improvement in ppFEV1 was observed at the first assessment on Day 15 and sustained through the 24-week treatment period. Improvements in ppFEV1 were observed regardless of age, baseline ppFEV1, sex, and geographic region. A total of 18 patients receiving Trikafta had a ppFEV1 <40% at baseline. The efficacy and safety in this subgroup were comparable to those observed in the overall population.

Trial 2

Trial 2 was a 4-week, randomized, double-blind, active-controlled study in patients homozygous for the F508del mutation.

A total of 107 patients aged 12 years and older (mean age: 28.4 years) received a tezacaftor/ivacaftor and ivacaftor regimen (tezacaftor/ivacaftor) during a 4-week open-label run-in period and were then randomized to receive Trikafta or tezacaftor/ivacaftor during a 4-week double-blind treatment period. Patients had a ppFEV1 at screening between 40% to 90%. The mean ppFEV1 at baseline, following the tezacaftor/ivacaftor run-in period was 60.9% (range: 35.0%, 89.0%).

The primary endpoint was the mean absolute change in ppFEV1 from baseline at Week 4 of the double-blind treatment period. Treatment with Trikafta compared to the regimen of tezacaftor/ivacaftor resulted in a statistically significant improvement in ppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; p <0.0001). These improvements in ppFEV1 were observed regardless of age, gender, baseline ppFEV1, and geographic region.

Trial 3

Trial 3 was an 8-week, randomized, double-blind, active-controlled study in patients who were heterozygous for the F508del mutation (F) and who had a mutation on the second allele with a gating defect (Gating) or residual CFTR activity (RF). The most frequent alleles with gating defect assessed in the study were G551D, R117H and the most frequent alleles with residual CFTR activity were 3849+10kbC>T, 2789+5G>A, A455E, 3272-26A>G, D1152H, P67L, and L206W.

Patients aged 12 years and older with a ppFEV1 between 40% to 90% at screening received either ivacaftor (F/Gating) or tezacaftor/ivacaftor (F/RF) during a 4-week open label run-in period. Patients with the F/R117H genotype received ivacaftor during the run-in period. A total of 258 patients were then randomized to receive Trikafta or remained on the CFTR modulator therapy received during the run-in period. The mean age at baseline following the run-in period was 37.7 years. The mean ppFEV1 at baseline was 67.6% (range: 29.7%, 113.5%).

Following the 4-week tezacaftor/ivacaftor or ivacaftor run-in period, the primary endpoint for Trial 3 was the within group mean absolute change in ppFEV1 from baseline through Week 8. A statistically significant improvement of 3.7 percentage points (95% CI: 2.8, 4.6; P<0.0001) in ppFEV1 from baseline was demonstrated for this endpoint in the Trikafta-treated group. Overall improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 geographic region, and genotype groups (F/Gating or F/RF).

Indication

The New Drug Submission for Trikafta was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Overall Analysis of Efficacy

Uncertainties with Trikafta surround the clinical relevance of lung function with regard to the contribution of elexacaftor in the fixed-dose combination in patients with “residual function” and “gating” mutations studied in Trial 3. Theoretically, the difference observed with Trikafta should be in addition to the treatment differences noted with Kalydeco (gating) and Symdeko (residual function) respectively. Furthermore, the long-term efficacy of Trikafta was not properly confirmed due to the short duration of two of the pivotal trials (8 weeks for Trial 3 and 4 weeks for Trial 2). Ongoing long-term studies with patients rolled over from both studies should help confirm the long-term efficacy in the near future.

Taking into consideration severity of cystic fibrosis, the current lack of treatment in Canada for a proportion of the proposed mutations (cystic fibrosis patients with minimal function mutations), the larger overall demonstrated efficacy in lung function compared to previously approved CFTR modulators, and the reported safety of this product (described below), Trikafta was authorized for use in the indicated population.

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

Clinical Safety

The clinical safety of Trikafta was evaluated based on data from 768 patients from the three Phase III pivotal clinical trials described in the Clinical Efficacy section. In these trials, a total of 389 patients aged 12 years or older received at least one dose of Trikafta.

In Trial 1, adverse drug reactions that occurred in >5% of Trikafta-treated patients at a frequency >1% higher that placebo were: upper respiratory tract infection (16% versus [vs.] 12%), influenza (7% vs. 1%), headache (17% vs. 15%), nasal congestion (9% vs. 7%), rhinorrhea (8% vs. 3%), sinusitis (5% vs. 4%), rhinitis (7% vs. 5%), diarrhea (13% vs. 7%), abdominal pain (14% vs. 9%), rash (10% vs. 5%), increased alanine aminotransferase (10% vs. 3%), increased aspartate aminotransferase (9% vs. 2%), increased blood creatinine phosphokinase (9% vs. 4%), and increased blood bilirubin (5% vs. 1%). The proportion of patients who discontinued study drug prematurely due to adverse events was 1% for Trikafta-treated patients and 0% for placebo-treated patients.

In Trial 1, serious adverse drug reactions that occurred more frequently in Trikafta-treated patients compared to placebo were rash (1.5% vs. 0.5%) and influenza (1.5% vs. 0.0%). The most common (≥10%) adverse drug reactions in Trikafta-treated patients were headache, diarrhea and upper respiratory tract infection.

In Trial 1, the incidence of rash events (e.g., rash, rash pruritic) was 10.4% in Trikafta- and 5.0% in placebo-treated patients. The rash events were generally mild to moderate in severity. The incidence of rash events by patient sex was 4.8% in males and 16.3% in females in Trikafta-treated patients and 3.8% in males and 6.3% in females in placebo-treated patients. In patients treated with Trikafta, the incidence of rash events was 20.5% in females taking a hormonal contraceptive and 13.6% in females not taking a hormonal contraceptive. A role for hormonal contraceptives in the occurrence of rash cannot be excluded. Patients should refer to the Trikafta Product Monograph for instructions on what to do should a rash develop while taking Trikafta and hormonal contraceptives.

With the exception of sex differences in rash, the safety profile of Trikafta was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV1 (ppFEV1), and geographic regions. The safety profile of Trikafta from the Trials 2 and 3 were consistent with the safety profile observed in Trial 1.

At the recommended therapeutic dose, there is the potential for serious hepatic adverse reactions. To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment have been recommended. Dosing is also to be interrupted with elevated liver function tests and reduced when co-administered with a CYP3A inhibitor. Caution is recommended in patients with severe renal impairment. Co-administration of Trikafta with a strong CYP3A inducer is not recommended. Patients should be monitored by a practitioner for liver function and for cases of non-congenital lens opacities (cataracts) when taking Trikafta.

Overall Analysis of Safety

Trikafta displayed a safety profile generally similar in adverse reactions compared to previously approved CFTR modulators (i.e., Kalydeco and Symdeko); however, post-market data indicate a potential for drug-induced liver failure in patients with pre-existing cirrhosis and portal hypertension. Appropriate warnings and precautions are in place in several sections of the approved Trikafta Product Monograph to address the potential for liver injury.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical review focused on studies conducted with the elexacaftor component of Trikafta alone or in combination with tezacaftor and ivacaftor. Tezacaftor and ivacaftor are currently authorized by Health Canada. Studies included primary, secondary, and safety pharmacology studies, pharmacokinetics studies, and toxicology studies. The results of the non-clinical studies as well as the potential risks to humans have been included in the Trikafta Product Monograph. In view of the intended use of Trikafta, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

In vitro studies demonstrated that elexacaftor is a corrector of mutant CFTR protein and binds to a separate site on the CFTR protein than tezacaftor. The combination of elexacaftor and tezacaftor increased the processing and trafficking of F508del-CFTR more than each molecule alone. Ivacaftor is likely needed to potentiate the defective channel gating of CFTR once it is at the cell surface. At the proposed clinical daily dose of 200 mg, elexacaftor and M23-elexacaftor have the potential to inhibit OATP1B1 and OATP1B3, in addition to known inhibition by tezacaftor and ivacaftor.

Elexacaftor was associated with lower male and female fertility, male copulation, and female conception indices in male rats at 75 mg/kg/day (6 times the maximum recommended human dose [MRHD] based on summed AUCs of elexacaftor and its metabolite) and in female rats at 35 mg/kg/day (7 times the MRHD based on summed AUCs of elexacaftor and its metabolite).

The No Observed Adverse Effect Level (NOAEL) for fertility findings was 55 mg/kg/day (2 times the MRHD based on summed AUCs of elexacaftor and its metabolite) in male rats and 25 mg/kg/day (4 times the MRHD based on summed AUCs of elexacaftor and its metabolite) in female rats.

Elexacaftor-related adverse effects on the male reproductive organ were noted in rat and dog toxicology studies. In rats, at doses exceeding the maximum tolerated dose, degeneration and atrophy of seminiferous tubules were correlated to oligo-/aspermia and cellular debris in epididymides. In dog testes, minimal or mild, bilateral degeneration/atrophy of the seminiferous tubules was present in males administered 14 mg/kg/day elexacaftor (14 times the MRHD based on summed AUCs of elexacaftor and its metabolite) that did not resolve during the recovery period, however without further sequelae. The human relevance of these findings is unknown.

Elexacaftor was not teratogenic in rats at 40 mg/kg/day and at 125 mg/kg/day in rabbits (approximately 9 and 4 times, respectively, the MRHD based on summed AUCs of elexacaftor and its metabolites [for rat] and AUC of elexacaftor [for rabbit]) with developmental findings being limited to lower mean fetal body weight at ≥25 mg/kg/day.

Similar to Symdeko (ivacaftor and tezacaftor), elexacaftor crossed the placenta and was excreted in the milk of rats.

Elexacaftor was shown to be non-carcinogenic in a 6-month study in Tg.rasH2 mice.

Overall, adequate safety margins were obtained for elexacaftor in all species based on NOAEL exposures that exceeded the human exposures at the recommended clinical dose. The overall benefit-to-risk ratio is positive.

Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of elexacaftor, tezacaftor, and ivacaftor to assess the potential for additive and/or synergistic toxicity did not produce any unexpected toxicities or interactions.

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

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Trikafta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at or below 30 ºC.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Trikafta is of human or animal origin.

 

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