Summary Basis of Decision for Orkambi

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 Orkambi is located below.

Recent Activity for Orkambi

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. 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.

Post-Authorization Activity Table (PAAT) for Orkambi

Updated: 2025-02-05

The following table describes post-authorization activity for Orkambi a product which contains the medicinal ingredients lumacaftor 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 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.

Drug Identification Number (DIN):

DIN 02451379 – 200 mg lumacaftor and 125 mg ivacaftor, tablets, oral administration
DIN 02463040 – 100 mg lumacaftor and 125 mg ivacaftor, tablets, oral administration
DIN 02483831 – 100 mg lumacaftor and 125 mg ivacaftor, granules, oral administration
DIN 02483858 – 150 mg lumacaftor and 188 mg ivacaftor, granules, oral administration
DIN 024837087 – 75 mg lumacaftor and 94 mg ivacaftor, granules, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02537087) market notification Not applicable Date of first sale 2024-04-14 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 264825 2022-06-06 Issued NOC 2023-04-06 Submission filed as a Level I – Supplement to add a new strength of lumacaftor/ivacaftor granules (75 mg/94 mg) and expand the indication for the treatment of cystic fibrosis (CF) in patients 1 to less than 2 years of age who are homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02537087) was issued for the new strength. A Regulatory Decision Summary was published.
SNDS # 248898 2021-02-01 Issued NOC
2021-09-03

Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product (granules). Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 235872 2020-02-07 Issued NOC
2020-10-08

Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product (tablets). Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued.
Drug product (DINs 02483831, 02483858) market notification Not applicable Date of first sale 2018-12-14

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 215032 2018-04-04 Issued NOC 2018-12-11

Submission filed as a Level I – Supplement to add a new indication and new dosage forms (granules, 100 mg lumacaftor and 125 mg ivacaftor, and 150 mg lumacaftor and 188 mg ivacaftor). The indication authorized was for the treatment of cystic fibrosis (CF) in children 2 through 5 years of age who are homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene. Two new DINs (02483831, 02483858) were issued. A Regulatory Decision Summary was published.
NC # 207127 2017-06-30 Issued NOL
2017-10-17

Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph (PM) with clinical trial results and new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections and to Part III: Patient Medication Information of the Product Monograph. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 205066 2017-04-27 Cancellation Letter Received
2017-06-19

Submission filed as a Level II (90 day) Notifiable Change to update the Product Monograph. The sponsor cancelled the submission before it was reviewed.
Drug product (DIN 02463040) market notification Not applicable Date of first sale 2017-05-03

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 198036 2016-09-12 Issued NOC
2017-04-18

Submission filed as a Level I – Supplement to add a new indication and new strength (100 mg lumacaftor and 125 mg ivacaftor). The indication authorized was for the treatment of cystic fibrosis (CF) in children 6 through 11 years of age who are homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene. A new DIN (02463040) was issued for the new strength. A Regulatory Decision Summary was published.
Drug product (DIN 02451379) market notification Not applicable Date of first sale 2016-01-27 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 181715 2015-01-30 Issued NOC
2016-01-26		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Orkambi

Date SBD issued: 2016-03-29

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

Lumacaftor and ivacaftor
200 mg lumacaftor and 125 mg ivacaftor, tablets,, oral

Drug Identification Number (DIN):

  • 02451379

Vertex Pharmaceuticals Canada Inc.orporated

New Drug Submission Control Number: 181715

 

On January 26, 2016, Health Canada issued a Notice of Compliance to Vertex Pharmaceuticals (Canada) Incorporated for the drug product Orkambi.

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/risk profile of Orkambi is favourable for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

1 What was approved?

 

Orkambi, a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and potentiator, was authorized for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The efficacy and safety of Orkambi have not been established in patients with CF other than those homozygous for the F508del mutation.

The safety and efficacy of Orkambi in patients age 65 years or older have not been evaluated.

The safety and efficacy of Orkambi in patients younger than age 12 years have not been established.

Orkambi is contraindicated for patients who are hypersensitive to the active substances within this drug or to any ingredient in the formulation or component of the container. Orkambi was approved for use under the conditions stated in the Orkambi Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Orkambi (200 mg lumacaftor and 125 mg ivacaftor) is presented as tablets. In addition to the medicinal ingredient, the tablets contain microcrystalline cellulose, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, povidone, and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains 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 Orkambi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Orkambi approved?

 

Health Canada considers that the benefit/risk profile of Orkambi is favourable for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic fibrosis (CF) is a chronically debilitating, autosomal recessive disease associated with serious morbidity and a high rate of premature mortality. Approximately 70,000 individuals are affected worldwide, including approximately 4,000 individuals in Canada. The incidence and prevalence of CF varies between racial groups and is considerably more common in the Caucasian populations of North America and Europe than in Asian and African populations.

Cystic fibrosis (CF) is caused by mutations in the CFTR gene that result in the absent or deficient function of the CFTR protein at the cell surface. The CFTR protein is an epithelial chloride channel responsible for aiding in the regulation of salt and water absorption and secretion; the protein is located in the apical membrane of epithelial cells in multiple organs, including lungs, pancreas, intestinal tract, biliary tract, and sweat gland. The failure to regulate chloride transport in those organs results in the multi-system pathology associated with CF.

Lung disease is the primary cause of morbidity and mortality in CF patients. Dysfunction in the CFTR protein in the lungs leads to obstruction of airways with thick mucus, chronic bacterial infection and inflammatory responses that are all thought to play a role in causing irreversible structural changes. Patients with CF typically experience a progressive loss of lung function ultimately resulting in respiratory failure and death. The forced expiratory volume in one second (FEV1) is the best predictor of survival in CF patients. The decline of FEV1 correlates with the number of pulmonary exacerbations per year.

Despite currently available therapies, patients with CF have accelerated lung function decline with age. The predicted median age of survival of individuals born today with CF is 48.5 years, while the actual median age at death reported in Canada is 34 years.

There is currently no cure for CF. Available treatments are aimed at treating the symptoms caused by the decreased CFTR function, such as controlling airway infection and inflammation, mobilizing secretions to reduce airway obstruction, and correcting nutritional deficits. Pharmacologic treatments used in CF patients include dornase alpha (recombinant human deoxyribonuclease [DNase]), inhaled antibiotics and pancreatic enzyme supplements. Brochodilators, oral antibiotics, ibuprofen, and inhaled corticosteroids are also routinely prescribed but are not specifically indicated for patients with CF.

The F508del-CFTR mutation has been characterized as “severe” based upon the F508del-CFTR homozygote clinical phenotype which is characterized by an early onset of clinical manifestations, a high incidence of pancreatic insufficiency, colonization with Pseudomonas aeruginosa, a more rapid rate of lung function decline, and shorter life expectancy. These patients demonstrate progression of disease with advancing age and have a decreased life expectancy.

Orkambi consists of a combination of lumacaftor and ivacaftor. Lumacaftor is part of a new class of drugs known as CFTR correctors which improve the function of the CFTR protein. This is the second molecule that targets the underlying biochemical defect causing CF. Ivacaftor, a CFTR potentiator, is already approved in Canada under the brand name Kalydeco for treatment of CF caused by eleven gating mutations. The efficacy and safety of Orkambi have not been established in patients with CF other than those homozygous for the F508del mutation.

Orkambi has been shown to be efficacious in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. Individuals who are homozygous for the F508del-CFTR mutation have little-to-no CFTR function on both alleles. The market authorization was based on two randomized, double‑blind, placebo‑controlled Phase III clinical trials that evaluated the efficacy and safety of Orkambi in CF patients homozygous for the F508del mutation in the CFTR gene. In the two trials combined, 1,108 clinically stable patients with CF were randomized and received at least 1 dose of study drug. Patients in both trials were randomized 1:1:1 to receive lumacaftor 600 mg once daily/ivacaftor 250 mg every 12 hours (q12h); or Orkambi (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h); or placebo. Patients took the study drug with fat‑containing food for 24 weeks in addition to their prescribed CF therapies (for example [e.g.], bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from these trials were eligible to roll over into an uncontrolled extension study.

The primary efficacy endpoint in both studies was improvement in lung function as determined by the absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV1) at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24.

In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 was 2.6 percentage points in Trial 1 (p = 0.0003) and 3.0 percentage points in Trial 2 (p <0.0001) for the proposed dosage. These changes persisted throughout the 24‑week treatment period. Improvements in ppFEV1 were observed regardless of age, disease severity, sex, and geographic region.

In clinical studies, Orkambi was generally well‑tolerated. The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for Orkambi-treated patients and 2% for placebo-treated patients. The most common adverse reactions experienced by patients who received Orkambi in the pooled, placebo‑controlled, Phase III trials were dyspnea (13%), nasopharyngitis (13%), nausea (13%), diarrhea (12%), and upper respiratory tract infection (10%). Serious adverse reactions, whether considered drug‑related or not by the investigators, that occurred in patients treated with Orkambi included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients. At the recommended therapeutic dose, there is the potential for hepatic, respiratory, menstrual and cardiovascular adverse reactions.

To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment are recommended. Dosing is also to be interrupted with elevated liver function tests and temporarily reduced when co-administering with a cytochrome P450 (CYP)3A inhibitor. Patients should be monitored by a practitioner for liver function, blood pressure and respiratory events when taking Orkambi.

A Notice of Non-Compliance (NON) was originally issued due to disagreement between the Sponsor and Health Canada regarding the inclusion of text in the Product Monograph pertaining to cardiovascular events (that is [i.e.] increases in blood pressure and decreases in heart rate) which Health Canada deemed necessary for proper labelling of Orkambi. Following discussion, the Sponsor complied with Health Canada’s requests and appropriate wording regarding cardiovascular events was included in the following sections of the Product Monograph: Warnings and Precautions, Adverse Events, Action and Clinical Pharmacology.

A Risk Management Plan (RMP) for Orkambi 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.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Orkambi therapy are considered to outweigh the potential risks. Considering the severity of the disease and the current lack of treatment in the intended patient population, the benefit/risk ratio of Orkambi is favorable for the recommended indication and the intended population of CF patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. Orkambi has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Orkambi Product Monograph 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 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 Orkambi?

 

The drug submission for Orkambi was reviewed under the Priority Review Policy. Patients with cystic fibrosis (CF) who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene demonstrate clinical phenotype which is characterized by an early onset of clinical manifestations, a high incidence of pancreatic insufficiency, colonization with Pseudomonas aeruginosa, a more rapid rate of lung function decline, and shorter life expectancy. These patients demonstrate progression of disease with advancing age and have a decreased life expectancy. Given that patients with CF who are homozygous for the F508del-CFTR mutation have a high unmet medical need and that none of the currently approved treatments for this population treat the underlying cause of CF, there is a substantial need to improve the treatment and outlook for these patients.

Kayldeco (ivacaftor) is currently the only approved therapy that targets the molecular defects underlying the pathophysiology of CF. Kalydeco is also the only approved therapy for CF that has evaluated safety and efficacy in small subsets of patients with CF based on their genetic profile; however, it is only approved for use in patients with selected CFTR mutations (class III or gating “mutations”) for which the monotherapy potentiator treatment is effective.

Orkambi demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for CF in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene, a condition that is not adequately managed by a drug marketed in Canada and as such, Priority Review status was granted.

A Notice of Non-Compliance (NON) was issued on September 22, 2015 due disagreement between the Sponsor and Health Canada regarding the inclusion of text in the Product Monograph pertaining to cardiovascular events (including increases in blood pressure and decreases in heart rate) that Health Canada deemed necessary for proper labelling of Orkambi. An initial Response to the NON was submitted on October 26, 2015, and following further discussions, the Sponsor complied with Health Canada’s requests to include appropriate wording in the Product Monograph. As a result, discussion regarding cardiovascular events was added to the following sections of the Product Monograph: Warnings and Precautions, Adverse Events, and Action and Clinical Pharmacology.

 

Submission Milestones: Orkambi

Submission Milestone Date
Pre-submission meeting: 2014-10-02
Request for priority status  
Filed: 2014-12-11
Approval issued by Director, Bureau Cardiology, Allergy and Neurological Sciences: 2015-01-12
Submission filed: 2015-01-30
Screening 1  
Screening Acceptance Letter issued: 2015-03-06
Review 1  
Biopharmaceutics Evaluation complete: 2015-07-20
Quality Evaluation complete: 2015-09-02
Clinical Evaluation complete: 2015-09-22
Labelling Review complete: 2015-08-22
Notice of Non-Compliance (NON) / issued by Director General (safety issues): 2015-09-22
Response filed: 2015-10-26
Screening 2  
Screening Acceptance Letter issued: 2015-10-28
Review 2  
Clinical Evaluation complete: 2016-01-21
Labelling Review complete: 2016-01-21
Notice of Compliance issued by Director General: 2016-01-26

 

The Canadian regulatory decision on the non-clinical and clinical review of Orkambi was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were 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.

 

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

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Orkambi 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 (CF) is a multi-system disease, primarily affecting the lungs and digestive system. It is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that result in absent or deficient function of the CFTR protein at the cell surface. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding by causing a defect in cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective channel gating) compared to wild‑type CFTR protein.

Orkambi is a CFTR corrector and potentiator composed of two medicinal ingredients, lumacaftor and ivacaftor. Lumacaftor is a CFTR corrector that is believed to improve the conformational stability of the F508del-CFTR protein, resulting in increased processing and trafficking of mature F508del-CFTR protein to the cell surface, where it exhibits improved chloride channel function compared to uncorrected F508del-CFTR. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. The combination of a CFTR corrector and potentiator is a novel approach to enhance the amount and function of the defective CFTR protein in patients with CF who have the F508del-CFTR mutation.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Orkambi for the recommended indication.

Lumacaftor has been evaluated in 17 clinical studies which examined lumacaftor monotherapy and/or lumacaftor in combination with ivacaftor in healthy volunteers or in patients with CF possessing the F508del mutation, the most common mutation in the CFTR gene.

Following administration of a double dose of the 200 mg/125 mg (lumacaftor/ivacaftor) fixed-dose combination tablets under high-fat, high-calorie fed conditions, the area under the concentration time curve (AUCT) and the maximum concentration (Cmax) of lumacaftor increased by 1.6 fold and 2.2 fold, respectively when compared to the same dose under fasting conditions. Likewise, the AUCT and Cmax of ivacaftor increased by 2.6 fold and 3.7 fold, respectively.

The exposure (AUC) of lumacaftor was approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor was similar between healthy adult volunteers and patients with CF. Steady-state plasma concentrations of lumacaftor and ivacaftor in healthy volunteers were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor decreased with time due to the cytochrome P450 (CYP)3A induction effect of lumacaftor.

Special Populations

A dose reduction to two tablets in the morning plus one tablet in the evening is recommended for patients with moderate hepatic impairment (Child-Pugh B). The combination therapy has not been studied in patients with severe hepatic impairment (Child-Pugh C); however, exposure is expected to be higher than in patients with moderate hepatic impairment. These patients should be closely monitored and the dose should be reduced at least 50% to one tablet twice per day.

Patients with severe renal impairment or end-stage renal disease may have reduced metabolic capacities. As a result, caution is recommended when administering lumacaftor/ivacaftor combination therapy to patients with severe renal impairment (creatinine clearance ≤30 mL/min) or with end-stage renal disease.

Pharmacodynamic studies with Orkambi revealed increases in blood pressure and decreases in heart rate. Caution should be observed in patients with pre-existing hypertension, a low heart rate at baseline (<60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular block, ischemic heart disease, or congestive heart failure. Concomitant medications that result in a decrease in heart rate should be avoided if possible during treatment with Orkambi.

Drug-Drug Interaction

Drug-drug interaction studies have shown that lumacaftor, a strong inducer of CYP3A, decreases the exposure of ivacaftor and its metabolite, M1. In addition, the exposure of several other substrates of CYP3A may be affected thus leading to reduced efficacy. These include sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index such as midazolam, triazolam, cyclosporine, everolimus, sirolimus, and tacrolimus.

When initiating lumacaftor/ivacaftor combination therapy while taking a strong CYP3A inhibitor, an initial dose adjustment to one tablet once daily should be used for the first week of treatment, followed by the full dose.

Concomitant use of strong CYP3A inducers is not expected to impact lumacaftor exposure, but is expected to decrease the ivacaftor exposure. Therefore, coadministration of lumacaftor/ivacaftor combination therapy is not recommended with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort.

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

Clinical Efficacy

The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled Phase III clinical trials (Trial 1 and 2). A total of 1,122 patients were enrolled in these two studies (559 patients in Trial 1 and 563 patients in Trial 2), of whom 1,108 patients (549 patients in Trial 1 and 559 patients in Trial 2) received at least one dose of study drug. Of the 1,108 patients, 49% were female and 99% were Caucasian.

Patients in both trials were randomized 1:1:1 to receive lumacaftor 600 mg once daily (qd)/ivacaftor 250 mg every 12 hours (q12h; total number [n] = 369); Orkambi (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; n = 369); or placebo (n = 370). Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (for example [e.g.], bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from these trials were eligible to roll over into an uncontrolled extension study.

Trial 1 consisted of 549 patients with CF aged 12 years and older (mean age 25.1 years) with percent predicted forced expiratory volume in one second (ppFEV1) at screening between 40-90 (mean ppFEV1 60.7 at baseline [range: 31.1 to 94.0]). Trial 2 consisted of 559 patients with CF aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40-90 (mean ppFEV1 60.5 at baseline [range: 31.3 to 99.8]).

For both trials, all patients were tested for the CF genotype at screening; eligible patients had the F508del mutation on both alleles. Patients with a history of colonization with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had three or more abnormal liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [AP], gamma-glutamyl transferase [GGT] ≥3x the upper limit of normal [ULN] or total bilirubin ≥2x the ULN) were excluded.

The primary efficacy endpoint for both studies was improvement in lung function as determined by the absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24.

A total of 348 patients in the lumacaftor 600 mg qd/ivacaftor 250 mg q12h group, 344 patients in the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h (Orkambi) group, and 362 patients in the placebo group completed dosing through Week 24.

In both trials, treatment with Orkambi resulted in a statistically significant improvement in ppFEV1. The treatment difference between Orkambi and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points in Trial 1 (p = 0.0003) and 3.0 percentage points in Trial 2 (p <0.0001) for the proposed dosage. These changes persisted throughout the 24-week treatment period. Improvements in ppFEV1 were observed regardless of age, disease severity, sex, and geographic region.

Secondary efficacy endpoints included relative change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in body mass index (BMI) at Week 24; absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ‑R) Respiratory Domain at Week 24. The CFQ-R is a disease specific, patient reported, health related quality of life measure for CF consisting of generic and CF specific scales. The respiratory domain of the CFQ-R was used as an assessment tool for clinically relevant respiratory symptoms such as cough, wheeze, congestion, sputum production, and difficulty breathing. The proportion of patients achieving ≥5% relative change from baseline in ppFEV1 using the average of Week 16 and Week 24 was also assessed in both trials along with the number of pulmonary exacerbations through Week 24. For the purposes of these trials, a pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.

In both studies, patients treated with Orkambi demonstrated statistically significant improvements in relative change in ppFEV1 and absolute change in BMI (in Trial 2 only).

Indication

The indication sought by the sponsor was as follows:

Orkambi (lumacaftor/ivacaftor) is indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

(See Clinical Trials and Warnings and Precautions for information on use in patients who are heterozygous for the F508del mutation.)

Geriatrics (>65 years of age):
The safety and efficacy of Orkambi in patients age 65 years or older have not been evaluated.

Pediatrics (<12 years of age):
The safety and efficacy of Orkambi in patients younger than age 12 years have not been established.

To ensure the safe and effective use of the product, Health Canada recommended the following indication:

Orkambi (lumacaftor/ivacaftor) is indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Limitations of Use
The efficacy and safety of Orkambi have not been established in patients with CF other than those homozygous for the F508del mutation.

Geriatrics (>65 years of age):
The safety and efficacy of Orkambi in patients age 65 years or older have not been evaluated.

Pediatrics (<12 years of age):
The safety and efficacy of Orkambi in patients younger than age 12 years have not been established.

Overall Analysis of Efficacy

The clinical program addressed the treatment of the F508del mutation. The small nature of the program was due to the limited number of patients in the target population. Analysis in two pivotal clinical studies along with supporting data showed a moderate positive effect on lung function in patients ≥12 years of age that was relatively rapid (after two weeks) and sustained for at least 24 weeks (length of exposure). Since respiratory failure is the main cause of premature mortality in CF patients, administration of Orkambi has the potential to modify the natural history of the disease.

While the treatment difference observed in ppFEV1 was a modest 3%, the average rate of lung function decline across the CF population is estimated at 1 percentage point to 3 percentage points per year. As lung function (FEV1) is linked to mortality, even a stabilization of lung function, an improvement in the rate of decline of lung function, or a marginal improvement in lung function may be considered clinically relevant. Secondly, a range of responses amongst patients were seen with approximately 25% showing at least a 5% absolute improvement in ppFEV1 and 13% of patients showing greater than 10% improvement.

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

Clinical Safety

The safety profile of Orkambi is based on the pooled data from 1,108 patients with CF aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who received at least 1 dose of study drug in two double-blind, placebo-controlled, Phase III clinical trials, each with 24 weeks of treatment (Trials 1 and 2 - described in the Clinical Efficacy section). Supportive data from the interim results of a long-term, roll-over study were also evaluated.

The proportion of patients who prematurely discontinued study drug in the pivotal trials due to adverse events was 5% for Orkambi-treated patients and 2% for placebo-treated patients. The most common adverse reactions experienced by patients who received Orkambi in the pooled, placebo‑controlled, Phase III trials were dyspnea (13%), nasopharyngitis (13%), nausea (13%), diarrhea (12%), and upper respiratory tract infection (10%). Serious adverse reactions, whether considered drug-related by the investigators or not, that occurred in patients treated with Orkambi included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients.

At the recommended therapeutic dose, there is the potential for hepatic, respiratory, menstrual and cardiovascular adverse reactions. In particular, an increase in liver function enzymes was noted especially amongst individuals with previous liver disease. To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment are recommended. Dosing is also to be interrupted with elevated liver function tests and temporarily reduced when co-administering with a CYP3A inhibitor, as is detailed in the Product Monograph.

The incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was also more common in patients treated with Orkambi. Furthermore, patients who were taking hormonal contraceptives demonstrated an increased incidence of menstrual abnormality events (amenorrhea, dysmenorrhea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhea, and polymenorrhea). Finally, patients were found to have increased blood pressure and a decreased heart rate. Patients should be monitored by a practitioner for liver function, blood pressure, and respiratory events when taking Orkambi.

Supportive Studies

The interim results of Trial 105, a non-pivotal, long-term rollover trial of the pivotal trials 1 and 2 and one other trial were submitted in support of Orkambi. This trial was ongoing at the time of review. The objective was to evaluate the long-term safety and tolerability of Orkambi in CF patients homozygous (Part A) or heterozygous (Part B) for the F508del mutation. Only data from Part A were reviewed as Part B was not relevant for this submission. The uncontrolled safety data did not identify any new safety issues compared to the data emanating from placebo-controlled Phase II and III trials; however, unlike the previous trials, one death was reported during Trial 105 in a patient who developed a pulmonary exacerbation. Causality cannot be assessed based on the available information.

Overall Analysis of Safety

Orkambi was generally well tolerated in the intended population, displaying a similar safety profile to previously studied CF target populations; however, at the recommended therapeutic dose, there is the potential for serious hepatic, respiratory, and cardiovascular adverse reactions. To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment are recommended. Dosing is also to be interrupted with elevated liver function tests and temporarily reduced when co-administering with a CYP3A inhibitor.

As mentioned above, pharmacodynamic studies with Orkambi revealed increases in blood pressure and decreases in heart rate. Caution should be observed in patients with pre-existing hypertension, a low heart rate at baseline, a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular block, ischemic heart disease, or congestive heart failure. Concomitant medications that result in a decrease in heart rate should be avoided if possible during treatment with lumacaftor/ivacaftor. These findings were proposed in the Product Monograph; however, the Sponsor was reluctant to include any text related to cardiovascular events, which led to a Notice of Non-Compliance (NON) being issued.

Following discussion, the Sponsor complied with Health Canada’s requests and appropriate wording regarding cardiovascular events was included in the following sections of the Product Monograph: Warnings and Precautions, Adverse Events, Action and Clinical Pharmacology.

Appropriate warnings and precautions are in place in the approved Orkambi Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The clinical development for Orkambi was supported by a comprehensive program of toxicity studies conducted for lumacaftor alone as a similar set of studies were previously completed for ivacaftor during the clinical development of Kalydeco.

Key findings of the pivotal toxicity studies conducted included noteworthy findings in rats. These findings consisted of minimal hepatic centrilobular hypertrophy that was considered an adaptive or compensatory response to the observed CYP induction in this species and splenic extramedullary hematopoiesis. The no-observed-adverse-effect level (NOAEL) in rats was established at 1,000 mg/kg/day in males and females based on results from the 6-month repeat-dose toxicity study. In dogs, central nervous system (CNS)-related clinical signs were noted in a few moribund animals administered a high dose of 1,000 mg/kg/day (exceeding the maximum tolerated dose [MTD]) in a 3-month toxicity study. Similar findings were not observed in other studies including a 12-month chronic toxicity study conducted in dogs at doses of up to 500 mg/kg/day (NOAEL). Fecal alterations such as unformed, watery, or discolored stool with mucus were also a consistent finding in dogs. In rats and dogs, body weight changes (decreased body weights in rats and body weight loss in dogs) and decreases in erythrocytic parameters that were considered regenerative in rats and non-regenerative in dogs occurred.

Lumacaftor is not considered genotoxic based on the results of the genetic toxicity studies. It was also concluded that lumacaftor was non-carcinogenic in the 2-year rodent bioassay conducted at doses up to 1,000 mg/kg/day in rats and in a short-term alternative 26-week Tg-rasH2 transgenic mouse (carrying the three copies of human prototype c-Ha-ras oncogenes) carcinogenicity assay conducted at doses up to 2,000 mg/kg/day. Lumacaftor was not associated with any adverse effects in developmental and reproductive toxicity studies, including male or female fertility, embryo-fetal survival, teratogenicity, or post-natal development and sexual maturation.

Repeat-dose toxicity studies, involving co-administration of lumacaftor and ivacaftor were conducted in rats for up to 3 months and in dogs for up to 1 month duration. In rats, minimal to moderate focal necrosis and/or erosions of glandular mucosa and minimal to moderate squamous epithelial cystic degeneration were observed microscopically. These microscopic changes were observed at all dose levels tested and were attributed to local irritant effects of lumacaftor and ivacaftor at high concentrations.

In dogs, a higher incidence of cardiovascular findings was noted than was previously noted in other studies conducted for ivacaftor alone. These findings included PR prolongation, atrioventricular (AV) block, and supraventricular premature complexes (SVPC) runs. In addition, decreases in testes, prostrate, and epididymis weights with correlating microscopic changes in these tissues were also observed in dogs administered the high dose combination of 600/60 mg/kg/day (lumacaftor/ivacaftor). These changes represented a slight retardation of sexual maturation and were likely associated with decreased body weight gain that occurred in these animals.

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

For more information, refer to the Orkambi 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 Orkambi 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 24 months when stored at or below 30ºC is acceptable.

Proposed limits of drug-related impurities are considered adequately qualified (that is, 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.

 

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