Summary Basis of Decision for Symdeko
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Symdeko is located below.
Recent Activity for Symdeko
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.
Post-Authorization Activity Table (PAAT) for Symdeko
Updated:
The following table describes post-authorization activity for Symdeko, a product which contains the medicinal ingredients 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 Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02478080 - Tezacaftor 100 mg/ ivacaftor 150 mg tablets and ivacaftor 150 mg tablets, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02478080) market notification | Not applicable | Date of first sale:2018-06-28 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 211292 | 2017-11-17 | Issued NOC2018-06-27 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Symdeko
Date SBD issued: 2018-09-06
The following information relates to the new drug submission for Symdeko.
Tezacaftor/ivacaftor and ivacaftor
Tezacaftor 100 mg / ivacaftor 150 mg tablets and ivacaftor 150 mg tablets, oral
Drug Identification Number (DIN):
- 02478080
Vertex Pharmaceuticals Inc.orporated
New Drug Submission Control Number: 211292
On June 27, 2018, Health Canada issued a Notice of Compliance to Vertex Pharmaceuticals Incorporated for the drug product Symdeko.
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 benefit-harm-uncertainty profile of Symdeko is favourable for the treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.
1 What was approved?
Symdeko is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and potentiator. It was authorized for the treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.
Symdeko has not been studied in pediatric patients younger than 12 years of age. Therefore, Health Canada has not authorized an indication for use in this age group.
Clinical trials of Symdeko did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.
Symdeko is contraindicated in patients who are hypersensitive to tezacaftor, ivacaftor or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Symdeko 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.
Symdeko consists of tezacaftor 100 mg / ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablets. Non-medicinal ingredients in the tezacaftor/ivacaftor tablet include: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, HPMC/hypromellose 2910, hydroxypropyl cellulose, iron oxide yellow, talc, and titanium dioxide. The ivacaftor tablet contains the following non-medicinal ingredients: croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide, carnauba wax, FD&C Blue No. 2, polyethylene glycol 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 Symdeko Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Symdeko approved?
Health Canada considers that the benefit-harm-uncertainty profile of Symdeko is favourable for the treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.
Cystic fibrosis is an autosomal recessive disease with serious, chronically debilitating morbidities and high premature mortality. It is caused by mutations in the CFTR gene that lead to absent or defective CFTR protein. The CFTR protein is a chloride ion channel that is normally present at the cell surface of epithelial cells, where it transports chloride and contributes to salt, fluid, and pH balance in multiple organs. In people with cystic fibrosis, the loss of chloride transport due to defects in the CFTR protein results in the accumulation of thick mucus in the airways of the lungs, loss of exocrine pancreatic function, impaired intestinal absorption, reproductive dysfunction, and elevated sweat chloride concentration. Lung disease is the primary cause of morbidity and mortality in cystic fibrosis. Patients with cystic fibrosis typically experience a progressive loss of lung function ultimately resulting in respiratory failure and death.
The disease affects approximately 70,000 individuals worldwide. In 2011, 114 individuals were diagnosed with cystic fibrosis in Canada while the national prevalence was approximately 3,900 cases. The predicted median age of survival of individuals born today with cystic fibrosis is 48.5 years, while the actual median age at death reported in Canada is 34 years. There is currently no cure for cystic fibrosis. Most treatments are aimed at alleviating the symptoms caused by the decreased CFTR function.
One therapeutic strategy to treat cystic fibrosis is to enhance chloride transport by increasing the amount and function of CFTR at the cell surface using small-molecule CFTR modulators called CFTR correctors and CFTR potentiators. In Canada, a CFTR potentiator Kalydeco (ivacaftor) has been approved for the treatment of cystic fibrosis in patients who have one mutation in the CFTR gene that is responsive to ivacaftor. In addition, a CFTR corrector-potentiator combination Orkambi (lumacaftor/ivacaftor) is approved for the treatment of cystic fibrosis in patients who are homozygous for F508del mutation (the most common mutation in cystic fibrosis patients).
Symdeko is another CFTR corrector-potentiator combination. It contains tezacaftor, a new molecular entity, and ivacaftor. Tezacaftor facilitates the cellular processing and trafficking of normal CFTR and multiple mutant CFTR forms. This increases the amount of CFTR protein at the cell surface and results in increased chloride transport. Ivacaftor increases chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein. Thus, the combination of tezacaftor (a CFTR corrector) and ivacaftor (a CFTR potentiator) increases both the amount and function of CFTR, leading to a greater increase in chloride transport than either agent alone.
Symdeko has been shown to be efficacious in cystic fibrosis patients who are homozygous for the F508del mutation and those who are heterozygous for the F508del mutation and a second mutation responsive to tezacaftor/ivacaftor. The market authorization was based on efficacy data derived from two randomized, double-blind, placebo-controlled, Phase III clinical trials (Trial 1, with a parallel-group design, and Trial 2, with a crossover design). Trial 1 included 504 patients who were homozygous for the F508del mutation. The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV1) through Week 24. There was a statistically significant improvement in ppFEV1 throughout the 24-week treatment period with Symdeko. Trial 2 included 244 patients who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor. The primary efficacy endpoint was the mean absolute change from study baseline in ppFEV1 averaged at Weeks 4 and 8 of treatment. Treatment with Symdeko resulted in a statistically significant improvement in ppFEV1.
The safety of Symdeko was evaluated on the basis of data pooled from three double-blind, placebo-controlled, Phase III clinical trials. Eligible patients were also able to participate in an open-label extension safety study. A total of 496 patients with cystic fibrosis, aged 12 years and older, received at least one dose of Symdeko. The most common adverse drug reactions experienced by patients who received Symdeko in the pooled trials were headache (14%) and nasopharyngitis (12%). Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in Symdeko-treated patients compared to placebo included distal intestinal obstruction syndrome (3 [0.6%] in Symdeko-treated subjects vs. none in placebo-treated patients). The proportion of patients who discontinued trial drug prematurely due to adverse events was 1.6% for Symdeko-treated patients and 2.0% for placebo-treated patients.
Symdeko displayed a safety profile generally similar in adverse reactions to previously approved CFTR modulators. However, unlike Orkambi, there were no observed respiratory symptom-related adverse events when starting Symdeko. In addition, there were fewer drug interactions, particularly with hormonal contraceptives, and fewer cardiovascular adverse events.
At the recommended therapeutic dose, there exists a potential for hepatic adverse reactions, with an increase in liver enzymes. The Warnings and Precautions section of the Symdeko Product Monograph specifies that the dosing of Symdeko should be interrupted in the event of significant elevations of transaminases. Assessments of transaminases are recommended for all patients prior to initiating Symdeko, every three months during the first year of treatment, and annually thereafter. Recommendations for dosage adjustment in patients with hepatic impairment are included in the Symdeko Product Monograph.
Tezacaftor and ivacaftor are substrates of cytochrome P450 (CYP) 3A enzymes. Therefore, co-administration of Symdeko with strong CYP3A inducers is not recommended as the concomitant use of CYP3A inducers may reduce the exposure to Symdeko and potentially result in the reduction of Symdeko efficacy. In addition, the dose of Symdeko should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors. These drug interactions have been highlighted in the Warnings and Precautions section of the Symdeko Product Monograph.
Cases of non-congenital lens opacities have been reported in pediatric patients treated with Symdeko, as well as with ivacaftor monotherapy. Consequently, baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with Symdeko.
Additionally, caution is recommended while using Symdeko in patients with severe renal impairment (creatinine clearance ≤30 mL/min) or end-stage renal disease.
A Risk Management Plan (RMP) for Symdeko was submitted by Vertex Pharmaceuticals 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 Symdeko Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Symdeko was accepted.
Based on the non-clinical data and clinical studies, Symdeko has an acceptable safety profile for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring.
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 Symdeko?
The drug submission for Symdeko was granted a Priority Review status in accordance with the Priority Review Policy. Symdeko is intended for the treatment of a serious, life-threatening and severely debilitating disease. Substantial evidence of clinical effectiveness has been presented that Symdeko provides:
- effective treatment of a disease for which no drug is presently marketed in Canada (cystic fibrosis with residual function mutations other than Kalydeco-responsive mutations); and
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit-risk profile is improved over existing therapies for cystic fibrosis, a disease that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Symdeko
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-08-23 |
| Request for priority status | |
| Filed: | 2017-09-21 |
| Approval issued by Director, Bureau of Medical Sciences: | 2017-10-18 |
| Submission filed: | 2017-11-17 |
| Screening | |
| Screening Deficiency Notice issued: | 2017-12-12 |
| Response filed: | 2017-12-21 |
| Screening Acceptance Letter issued: | 2017-12-29 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2018-06-22 |
| Quality Evaluation complete: | 2018-06-27 |
| Clinical Evaluation complete: | 2018-06-22 |
| Review of Risk Management Plan complete: | 2018-05-18 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-06-26 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-06-27 |
The Canadian regulatory decision on the non-clinical and clinical review of Symdeko was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions 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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Symdeko contains two medicinal ingredients, tezacaftor and ivacaftor. Tezacaftor is a new molecular entity. Ivacaftor has already been approved in Canada as a monoproduct Kalydeco, and in combination with lumacaftor (Orkambi).
Tezacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector that facilitates the processing and trafficking of mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein. For ivacaftor to function, CFTR protein must be present at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by tezacaftor, leading to a greater enhancement of chloride transport than either agent alone. The combined effect of tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increases in chloride transport.
The pharmacokinetic properties of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with cystic fibrosis. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with cystic fibrosis, plasma concentrations of tezacaftor and ivacaftor reach a steady state within 8 days and within 3 to 5 days, respectively, after starting treatment. Upon dosing tezacaftor/ivacaftor to a steady state, the accumulation ratio is approximately 1.6 for tezacaftor and 2.6 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner, with increasing doses from 10 mg to 150 mg once daily.
The clinical pharmacology data support the use of Symdeko for the recommended indication.
For further details, please refer to the Symdeko Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Symdeko in patients with cystic fibrosis was evaluated in two Phase III, randomized, double-blind, placebo-controlled trials (Trial 1 and Trial 2).
Trial 1 was of 24-week duration. A total of 504 patients aged 12 years and older (mean age 26.3 years), who were homozygous for the F508del mutation in the CFTR gene, were randomized in a ratio of 1:1 (248 Symdeko, 256 placebo). At screening, patients had a percent predicted forced expiratory volume in one second (ppFEV1) between 40% and 90%. The mean ppFEV1 at baseline was 60% (range: 27.8% to 96.2%).
The primary efficacy endpoint was change in lung function as determined by absolute change from baseline in ppFEV1 through Week 24. Key secondary efficacy variables included relative change from baseline in ppFEV1 through Week 24, number of pulmonary exacerbations from baseline through Week 24, absolute change in body mass index from baseline at Week 24, and absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score (a measure of respiratory symptoms relevant to patients with cystic fibrosis, such as cough, sputum production, and difficulty breathing) from baseline through Week 24. A pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) as a result of 4 or more of 12 prespecified sinopulmonary signs/symptoms.
In Trial 1, treatment with Symdeko resulted in a statistically significant improvement in ppFEV1. These changes persisted throughout the 24-week period. The treatment difference between Symdeko and placebo for the primary endpoint was 4 percentage points. Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1, colonization with Pseudomonas, concomitant use of standard of care medications for cystic fibrosis, and geographic region. With regard to the key secondary endpoints, patients treated with Symdeko demonstrated statistically significant improvements in relative change in ppFEV1 and number of pulmonary exacerbations.
Trial 2 was a 2-period, 3-treatment, 8-week crossover trial. A total of 244 patients aged 12 years and older (mean age 34.8 years), who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor, were randomized to and received sequences of treatment that included Symdeko, ivacaftor, and placebo. In the 244 patients enrolled, the following CFTR mutations were represented: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, E831X, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T. Patients had a ppFEV1 at screening between 40% and 90%. The mean ppFEV1 at baseline was 62.3% (range: 34.6% to 93.5%). Of the 244 patients included in the efficacy analysis, 146 patients had a splice mutation and 98 patients had a missense mutation as the second allele. A total of 161 patients received Symdeko, 156 patients received ivacaftor, and 161 patients received placebo.
The primary efficacy endpoint was the mean absolute change from study baseline in ppFEV1 averaged at Weeks 4 and 8 of treatment. The key secondary efficacy endpoint was absolute change in the CFQ-R Respiratory Domain Score from study baseline averaged at Weeks 4 and 8 of treatment.
In Trial 2, treatment with Symdeko resulted in a statistically significant improvement in ppFEV1. The treatment difference between Symdeko and placebo treated patients for the primary efficacy endpoint was 6.8 percentage points. In addition, the treatment difference between ivacaftor- and placebo-treated patients was 4.7 percentage points, and reached 2.1 percentage points between Symdeko- and ivacaftor-treated patients. Improvements in ppFEV1 were observed regardless of age, disease severity, sex, mutation class, colonization with Pseudomonas, concomitant use of standard of care medications for cystic fibrosis, and geographic region. With regard to the key secondary endpoint, patients treated with Symdeko demonstrated statistically significant improvements in the CFQ-R Respiratory Domain Score in comparison to placebo-treated patients only.
Overall, the efficacy results of Symdeko in the two pivotal Phase III studies provided evidence of clinically relevant lung function improvement compared to placebo in the studied population.
Indication
The New Drug Submission for Symdeko was filed by the sponsor with the following indication:
- Symdeko (tezacaftor/ivacaftor) is indicated for the treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
To ensure safe and effective use of the product, Health Canada defined the target patient population in accordance with the submitted clinical evidence and approved the following indication:
- Symdeko (tezacaftor/ivacaftor and ivacaftor) is indicated for the treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.
For more information, refer to the Symdeko Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The evaluation of the safety profile of Symdeko was based on pooled data from three double-blind, placebo-controlled, Phase III clinical trials (2 parallel-group trials of 12-and 24-week duration and one crossover design trial of 8-week duration). A total of 496 patients with cystic fibrosis, aged 12 years and older, received at least one dose of Symdeko. Eligible patients were also able to participate in an open-label extension safety study, projected to last up to 96 weeks. The 12-week parallel arm study was terminated following a planned interim analysis since the prespecified futility criteria had been met.
In the pooled Phase III trials, the proportion of patients who discontinued trial drug prematurely due to adverse events was 1.6% for Symdeko-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in Symdeko-treated patients compared to placebo included distal intestinal obstruction syndrome (3 [0.6%] in Symdeko-treated subjects vs. none in placebo-treated patients). The most common adverse drug reactions experienced by patients who received Symdeko were headache (14%) and nasopharyngitis (12%).
The safety profile of Symdeko was generally similar across all subgroups of patients, including when analyzed by age, sex, baseline ppFEV1, and geographic regions.
Two electrocardiogram (ECG) assessment studies with tezacaftor or ivacaftor, respectively, were conducted in healthy subjects. There was no evidence of any meaningful effect on the QT interval (corrected according to Fridericia, QTcF), the QRS duration, the PR interval or heart rate.
There exists a potential for hepatic adverse reactions, with an increase in liver enzymes, at the recommended therapeutic dose of Symdeko. Accordingly, assessments of transaminases are recommended for all patients prior to initiating Symdeko, every three months during the first year of treatment, and annually thereafter. Recommendations for dosage adjustment based on the severity of hepatic impairment are included in the Symdeko Product Monograph.
Given that tezacaftor and ivacaftor are substrates of cytochrome P450 (CYP) 3A enzymes, co-administration of Symdeko with strong CYP3A inducers is not recommended. In addition, the dose of Symdeko should be adjusted when used concomitantly with strong or moderate CYP3A inhibitors. These drug interactions have been addressed in the Warnings and Precautions section of the Symdeko Product Monograph.
In pediatric patients treated with Symdeko, as well as with ivacaftor monotherapy, cases of non-congenital lens opacities have been reported. Consequently, baseline and follow-up ophthalmological examinations are recommended in pediatric patients who are starting treatment with Symdeko.
Additionally, caution is recommended while using Symdeko in patients with severe renal impairment (creatinine clearance ≤30 mL/min) or end-stage renal disease.
Appropriate warnings and precautions are included in the Symdeko Product Monograph to address the identified safety concerns.
For more information, refer to the Symdeko Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Symdeko contains two medicinal ingredients, tezacaftor and ivacaftor. While tezacaftor is a new molecular entity, ivacaftor has been approved in Canada as a monoproduct Kalydeco, and in combination with lumacaftor (Orkambi).
The non-clinical programme for Symdeko included a complete programme for tezacaftor, a complete programme for ivacaftor (which had been carried out in support of the approved new drug submission for Kalydeco), and a programme for the tezacaftor/ivacaftor combination that consisted of primary pharmacology and general toxicology studies of up to 3-month duration, conducted in rats.
The non-clinical development of tezacaftor was supported by a comprehensive programme of primary, secondary, and safety pharmacology studies; absorption, distribution, metabolism, and excretion studies; and toxicology studies. The safety pharmacology and toxicology studies were generally compliant with current scientific and regulatory guidelines and considered sufficient to support the use of tezacaftor in Symdeko for the specified indication in cystic fibrosis patients.
Primary pharmacodynamic studies demonstrated that tezacaftor is a broad-acting cystic fibrosis transmembrane conductance regulator (CFTR) corrector that facilitates the cellular processing and trafficking of normal and multiple mutant CFTR forms. This increases the amount of CFTR protein at the cell surface and results in increased chloride transport. The CFTR protein delivered to the cell surface by tezacaftor can be potentiated by ivacaftor to further increase chloride transport.
Metabolism, followed by biliary excretion of metabolites, is the primary route of tezacaftor elimination in rats and dogs. Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 are the main CYP isoforms involved in tezacaftor metabolism. Tezacaftor is a substrate for the uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) and efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The pharmacologically active major human metabolite of tezacaftor, M1, is a substrate for P-gp. A major disproportionate human metabolite, M2 (significantly less pharmacologically active than tezacaftor or M1) may also be a substrate for P-gp. Tezacaftor and its metabolites are not likely to be significant inducers or inhibitors of CYP enzymes in patients.
There were no significant toxicological findings in a standard battery of in vitro tests and single oral dose safety pharmacology studies of tezacaftor.
Principal clinical and pathological findings in repeated oral dose toxicology studies were not considered adverse. These included the slowly reversible finding of dilated lymphatic terminals in the villi of the small intestine in all studies in rats and dogs. The underlying mechanism of this effect is unknown. Notably, a clinical endoscopy safety study did not find signs of intestinal lymphangiectasia in treated subjects.
Studies of the tezacaftor/ivacaftor combination, despite limitations in study design, did not indicate any potential new or enhanced toxicities. Tezacaftor was not genotoxic and carcinogenic in rats or transgenic mice. It did not affect male or female rat fertility. When given during organogenesis, tezacaftor did not cause teratogenicity or adverse developmental effects at oral doses up to 100 mg/kg/day in rats and 25 mg/kg/day in rabbits, which produced maternal exposures up to 3 and 0.2 times, respectively, the exposure at the maximum recommended human dose (MRHD), based on summed area under the curve (AUC) for tezacaftor and M1 metabolite (tezacaftor + M1). Lower fetal body weights were observed in rabbits given a maternal toxic dose of 50 mg/kg/day with exposures approximately 1 time the exposure at the MRHD (tezacaftor + M1). In a prenatal and postnatal development study in pregnant rats, tezacaftor had no adverse effects on pups at exposures up to approximately 1 time the exposure at the MRHD (tezacaftor + M1) at a maternal dose of 25 mg/kg/day. Decreased fetal body weights, early developmental delays, and potentially longer estrus cycle duration and reduced fertility occurred at a maternally toxic dose of 50 mg/kg/day that produced exposures approximately 2 times the exposure at the MRHD (tezacaftor + M1).
The M2 metabolite of tezacaftor was not mutagenic in vitro and did not affect embryo-fetal development in pregnant rabbits.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Symdeko Product Monograph. In view of the intended use of Symdeko, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Symdeko 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 Symdeko 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 drug product should be stored at or below 30ºC.
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.
One excipient used in the formulation of Symdeko is of human or animal origin. The excipient is lactose monohydrate which is present in the ivacaftor tablet. The lactose monohydrate is manufactured in compliance with the European Medicines Agency Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Products. Certification letters attesting to these claims were provided by the sponsor.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SYMDEKO | 02478080 | VERTEX PHARMACEUTICALS (CANADA) INCORPORATED | IVACAFTOR 150 MG IVACAFTOR 150 MG TEZACAFTOR 100 MG |