Summary Basis of Decision for Repatha

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 Repatha is located below.

Recent Activity for Repatha

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 Repatha

Updated:

2019-04-03

The following table describes post-authorization activity for Repatha, a product which contains the medicinal ingredient evolocumab. 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 02446057 - 140 mg/mL, evolocumab, solution, subcutaneous
  • DIN 02459779 - 120 mg/mL, evolocumab, solution, subcutaneous

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
SNDS # 2155772018-04-19Issued NOC
2018-11-29		Submission filed as a Level I - Supplement to add an alternate manufacturing process for the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 2089042017-08-30Issued NOC
2018-08-10		Submission filed as a Level I - Supplement to expand the indication to include adult patients with hyperlipidemia, as an adjunct to diet, alone or in combination with other lipid-lowering therapies, to reduce low density lipoprotein cholesterol (LDL-C). Regulatory Decision Summary published.
SNDS # 2070382017-06-28Issued NOC
2018-06-05		Submission filed as a Level I - Supplement for new indication: as an adjunct to diet and standard of care therapy (including moderate- to high-intensity statin therapy alone or in combination with other lipid-lowering therapy) to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adult patients with atherosclerotic cardiovascular disease. Regulatory Decision Summary published.
SNDS # 2135372018-02-08Issued NOC
2018-07-05		Submission filed as a Level I - Supplement to add an alternate manufacturing site for the production of the drug product. The information was reviewed and considered acceptable. An NOC was issued.
NC # 2151572018-04-04Cancellation Letter Received
2018-04-16		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The changes exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor, so as to be filed as an SNDS.
NC # 2145942018-03-16Issued NOL
2018-04-06		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information and revise the instructions for use. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2049532017-04-24Issued NOL
2017-05-05		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02459779) market notificationNot applicableDate of first sale:
2017-04-04		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 2004942016-11-22Issued NOL
2017-01-12		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1891772015-11-05Issued NOC
2016-12-15		Submission filed as a Level I - Supplement to seek approval of a new injection presentation and a new strength of Repatha in a 120 mg/mL Automated Mini-Doser (AMD) for self-administration in patients with hyperlipidemia who require additional lowering of low density lipoprotein (LDL-C). Data were presented that demonstrated comparability of the new device and strength compared to the currently-approved injection presentation, the 140 mg/mL autoinjector/pen. Overall, based on the data provided, the benefit-risk profile of the 120 mg/mL AMD for Repatha in the treatment of patients with primary hypercholesterolemia is favourable. The SNDS also sought approval for a new manufacturing facility for the drug product. The data were reviewed and considered acceptable, and an NOC was issued. A new DIN (02459779) was issued for the new strength.
SNDS # 1918362016-02-01Issued NOC
2016-09-20		Submission filed as a Level I - Supplement for the approval of an alternate manufacturing site of the drug product. 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.
NC # 1933742016-03-14Issued NOL
2016-06-29		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to add instructions to support proper drug administration with the Repatha SureClick Autoinjector. As a result of the NC, modifications were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02446057) market notificationNot applicableDate of first sale:
2015-09-28		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations
NDS # 1782342014-09-25Issued NOC
2015-09-10		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Repatha

Date SBD issued: 2016-01-29

The following information relates to the new drug submission for Repatha.

Evolocumab, 140 mg/mL, solution, subcutaneous

Drug Identification Number (DIN):

  • 02446057

Amgen Canada Inc.

New Drug Submission Control Number: 178234

On September 10, 2015, Health Canada issued a Notice of Compliance to Amgen Canada Inc. for the drug product, Repatha.

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 Repatha is favourable for the following indications:

Primary Hyperlipidemia

Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

The effect of Repatha on cardiovascular morbidity and mortality has not been determined.

Homozygous Familial Hypercholesterolemia

Repatha is indicated as an adjunct to diet and other LDL-lowering therapies [for example (e.g.), statins, ezetimibe, LDL apheresis] in adult patients and adolescent patients aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

1 What was approved?

Repatha, an anti-Proprotein Convertase Subtilisin/Kexin Type 9 (anti-PCSK9) monoclonal antibody, is a fully human monoclonal antibody of the immunoglobulin G2 (IgG2) subclass.

Repatha is authorized for the following indications:

Primary Hyperlipidemia

Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

The effect of Repatha on cardiovascular morbidity and mortality has not been determined.

Homozygous Familial Hypercholesterolemia

Repatha is indicated as an adjunct to diet and other LDL-lowering therapies [for example (e.g.), statins, ezetimibe, LDL apheresis] in adult patients and adolescent patients aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

In clinical studies conducted to evaluate Repatha, a total of 6,026 patients were enrolled of which 1,779 (30%) were ≥65 years of age, while 223 (4%) were ≥75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients, but data are limited in patients over 75 years of age.

Repatha has not been studied in pediatric patients <18 years of age with primary hyperlipidemia.

Repatha has not been studied in pediatric patients <12 years of age with homozygous familial hypercholesterolemia.

Repatha is contraindicated for patients who are hypersensitive to Repatha or to any ingredient in the formulation or component of the container. For patients treated with lipid lowering therapies such as a statin or other lipid lowering therapies that are used in combination with Repatha, consult the Contraindications section of the Product Monographs for those medications. Repatha was approved for use under the conditions stated in the Repatha Product Monograph, taking into consideration the identified potential risks associated with the administration of this drug product. As a first-in-class non-statin drug, the safety database for Repatha is considered relatively deficient in long-term, placebo-controlled data relevant to the target population, with limited ability to detect less common adverse events that may arise with longer exposure times.

Repatha (140 mg/mL evolocumab) is presented as a solution for subcutaneous injection and supplied as a pre-filled, single-use autoinjector. The autoinjector is a spring-operated device that contains a pre-filled syringe containing a single dose of Repatha. In addition to the medicinal ingredient, evolocumab, the solution also contains proline, glacial acetic acid, Polysorbate 80, water for injection, and sodium hydroxide.

Repatha is intended for patient self-administration after proper training. Administration should be performed by an individual who has been trained to administer the product.

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 Repatha Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Repatha approved?

Health Canada considers that the benefit/risk profile of Repatha is favourable for the following indications:

Primary Hyperlipidemia

Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

The effect of Repatha on cardiovascular morbidity and mortality has not been determined.

Homozygous Familial Hypercholesterolemia

Repatha is indicated as an adjunct to diet and other LDL-lowering therapies [for example (e.g.), statins, ezetimibe, LDL apheresis] in adult patients and adolescent patients aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

Hyperlipidemia is a heterogeneous group of disorders characterized by excess lipids [that is (i.e.), cholesterol, phospholipids, triglycerides] in the bloodstream. Primary hyperlipidemia is usually due to genetic causes (monogenetic or polygenetic) and environmental factors (diet and lifestyle). Familial hypercholesterolemia, an autosomal co-dominant genetic disorder, is the most common form of familial hyperlipidemia and is characterized by very high plasma levels of low density lipoprotein cholesterol (LDL-C) and the development of premature cardiovascular disease. Familial hypercholesterolemia is the most common genetic disorder leading to premature cardiovascular disease and death; left untreated, men develop cardiovascular disease in the third to fourth decade of life and women ten years later, on average.

Inheritance of familial hypercholesterolemia (FH) is autosomal co-dominant (requiring only one abnormal copy of an FH gene). If a child inherits an FH gene from one of their parents then, because the gene is dominant, the child will have the disorder. When a child inherits an FH gene from only one parent, meaning they have one FH gene and one normal gene, this is referred to as heterozygous familial hypercholesterolemia (HeFH). When a child inherits an FH gene from both parents, meaning they have two FH genes, this is referred to as homozygous familial hypercholesterolemia (HoFH). Heterozygous familial hypercholesterolemia is a more common genetic disorder than HoFH, which is rare.

Approximately 83,500 Canadians are estimated to have familial hypercholesterolemia (most undiagnosed). Early treatment can normalize life expectancy. Statins are the cornerstone of treatment for primary hyperlipidemia, with established cardiovascular benefit. Low density lipoprotein-cholesterol (LDL-C) lowering is also the primary treatment target in familial hypercholesterolemia patients. When patients fail to reach target LDL-C despite high intensity statin therapy, or when statins are poorly tolerated (up to 10% of patients), other LDL-lowering agents include ezetimibe and bile acid resins In HoFH with refractory LDL-C elevation despite maximally tolerated medical therapy, weekly LDL apheresis is effective but not widely available.

A large, statistically significant reduction in LDL-C levels was demonstrated (in the RUTHERFORD-2 and TESLA B studies) for treatment with Repatha as compared with placebo, in patients with HeFH and HoFH who were unable to achieve target LDL despite maximally tolerated statin therapy (with or without additional lipid-lowering therapies). A large, statistically significant reduction in LDL-C levels was also demonstrated (in the LAPLACE-2 and DESCARTES studies), for treatment with Repatha as compared with placebo, in the subgroup of patients with primary hyperlipidemia who also had established cardiovascular disease and who were unable to achieve target LDL despite maximally tolerated statin therapy. Based on the results from the DESCARTES study (a 52-week, double-blinded, randomized, placebo-controlled clinical study), it is expected that the treatment effect would persist for 52 weeks. Patients with HeFH and HoFH and patients with primary hyperlipidemia and established cardiovascular disease are at high risk of cardiovascular events, and those who are unable to achieve target LDL with statin therapy are considered to represent an unmet need. The effect of Repatha on cardiovascular morbidity and mortality has not been determined.

The long-term safety database for Repatha is based primarily on the DESCARTES study. Most patients (64.5%) in this study were at low or moderate cardiovascular risk, in contrast with the high cardiovascular risk target population for which Repatha is indicated. Other studies (including RUTHERFORD-2, LAPLACE-2, and TESLA B) contributing to the integrated analysis of safety were twelve weeks long. Two open-label extension studies are ongoing. While Repatha was generally well-tolerated, the Repatha submission was considered relatively deficient in long-term safety data relevant to the target population, with limited ability to detect less common adverse events that may arise with longer exposure times.

To ensure that the benefits of Repatha therapy continue to outweigh potential risks, Health Canada has required several post-approval activities be carried out. These include submitting the results of a large, ongoing event-driven cardiovascular outcomes trial (CVOT) in subjects with high baseline cardiovascular risk.

A Risk Management Plan (RMP) for Repatha was submitted by Amgen Canada Inc. 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Repatha has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Repatha therapy are considered to outweigh the risks in the approved target population. Repatha has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues will be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Repatha Product Monograph to address 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 Repatha?

Submission Milestones: Repatha

Submission MilestoneDate
Pre-submission meetings:2014-02-12
Submission filed:2014-09-25
Screening
Screening Acceptance Letter issued:2014-11-14
Review
On-Site Evaluation:
Quality Evaluation complete:2015-09-09
Clinical Evaluation complete:2015-09-10
Labelling Review complete:2015-08-28
Device review complete:2015-04-21
Notice of Compliance (NOC) issued by Director General:2015-09-10

The Canadian regulatory decision on the non-clinical and clinical review of Repatha was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and 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?

As part of the marketing authorization for Repatha, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  1. To submit to Health Canada, in accordance with Canadian Regulations, all serious adverse events (including cardiovascular events, pancreatitis, liver disorders, new onset diabetes, neurocognitive events, allergic reaction, severe renal impairment, malignancies, etc.) that occurred in all clinical studies with Repatha.
  2. To submit to Health Canada a Notifiable Change (NC). This will include a safety update report 90 days after the issuance of the Notice of Compliance (NOC) for Repatha.
  3. To provide Health Canada with Repatha Medical Educational materials for review prior to the launch of the product.
  4. To provide Health Canada with all reports/correspondence pertaining to post-approval commitments made to the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This will include reports on the ongoing cardiovascular outcomes trial (CVOT).
  5. To provide Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies.
  6. To provide Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRERs) for Repatha every six months.
  7. To include Canadian patients in the planned Registry for pregnancies committed to the FDA and provide, as appropriate, Health Canada with regular safety updates from this study.

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

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 Repatha 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

Repatha (evolocumab) is a fully human monoclonal immunoglobulin G2 (IgG2) that binds to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Repatha binds selectively and with high affinity to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR) on the liver cell surface. The inhibition of PCSK9 by Repatha leads to increased LDLR expression and subsequent decreased circulating concentrations of low density lipoprotein cholesterol (LDL-C).

The clinical pharmacokinetic and pharmacodynamic properties of evolocumab were investigated in healthy volunteers, volunteers with hepatic impairment, and in patients with hyperlipidemia through data collected by rich sampling in five Phase I studies and by sparse or limited sampling in fifteen Phase II/III efficacy/safety studies. Potential covariates effects [for example (e.g.) gender, age, race, and body weight] on evolocumab pharmacokinetics were evaluated by population modeling analysis based on a pooled database containing 3,414 patients with hyperlipidemia (mostly with non-familial hypercholesterolemia, about 9% with heterozygous familial hypercholesterolemia). In addition, two bioequivalence studies were conducted to bridge major changes in manufacturing processes and formulations during clinical development of evolocumab.

Following a single subcutaneous dose of 140 mg or 420 mg, median peak serum concentrations (Cmax) were attained in 3 to 4 days. The mean (± standard deviation) steady-state volume of distribution and systemic clearance were estimated to be 3.3 ± 0.5 L and 12 ± 2 mL/hr, respectively. Absolute bioavailability was estimated 72% and the estimated half-life was 11 to 17 days according to population pharmacokinetic analysis. In a parallel-group study [number of patients (n) = 24], the exposure to evolocumab was found to be approximately 40% to 50% lower in patients with mild or moderate hepatic impairment compared with healthy volunteers following a single subcutaneous dose at 140 mg.

The pharmacodynamic response, measured by percent reduction from baseline in LDL-C and free PCSK9 levels, increased in a dose-related manner after evolocumab subcutaneous administration. Following a single subcutaneous administration of evolocumab 140 mg or 420 mg in healthy volunteers, the maximum suppression of free PCSK9 occurred by 4 hours followed by a reduction in LDL-C with subsequent returns to baseline. In patients with hyperlipidemia following repeated subcutaneous doses at 140 mg once every two weeks or 420 mg once a month, maximal LDL-C reduction (about 55% to 75% from baseline, respectively) was observed at one week or two weeks following administration, respectively, and maintained during long-term treatment (up to 124 weeks in study duration). The LDL-C lowering effect was found to be similar between patients with mild or moderate hepatic impairment and healthy volunteers.

Population pharmacokinetic analysis identified that body weight and statin use had covariate effect for the exposure of evolocumab pharmacokinetics, that is (i.e.), evolocumab exposure was decreased with increasing body weight and treatment with various statins was associated with lower evolocumab exposure. However, the LDL-C lowering effect was apparently not significantly affected by body weight or the use of statins following evolocumab subcutaneous administration at 140 mg once every two weeks or 420 mg once a month. Overall, the pharmacokinetic/pharmacodynamic data suggest that there were no clinically meaningful covariates effects of age, sex, race, weight, and statin use on LDL-C reduction that were significant enough to warrant dose adjustment for either evolocumab dosing regimen.

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

Clinical Efficacy

Heterozygous Familial Hypercholesterolemia
RUTHERFORD-2

RUTHERFORD-2 was an international, multicentre, double-blind, randomized, placebo-controlled, 12-week pivotal Phase III study of Repatha in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies (most commonly ezetimibe). The primary objective of this study was to evaluate the effect of 12 weeks of Repatha administered subcutaneously (SC) once every two weeks (Q2W) or once monthly (QM) compared with placebo, on the percent change from baseline in LDL-C.

To participate in the study, patients were required to have been on a stable, maximally tolerated dose of an approved statin for at least 4 weeks before LDL-C screening, with a fasting LDL-C concentration ≥2.6 mmol/L. Stable dosing of other allowed lipid-lowering drugs and fasting triglycerides ≤4.5 mmol/L were also required.

Heterozygous familial hypercholesterolemia (HeFH) was diagnosed by the Simon Broome criteria. In this study, 38% of patients had clinical atherosclerotic cardiovascular disease. The mean age at baseline was 51 years (range, 19 to 79 years), 15% of the patients were ≥65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black. Mean baseline LDL-C concentration was 3.9 mmol/L and 4.1 mmol/L in the placebo and Repatha groups, respectively. Statin treatment (most commonly rosuvastatin and atorvastatin) was high-intensity for 76% of patients, moderate intensity for 22% of patients, and 2% were treated with a low-intensity statin dose.

Prior to randomization, subjects entered a 6-week screening period to determine eligibility. During screening, patients were trained to self-administer placebo, to confirm the tolerability of SC administration. All subjects received placebo SC that corresponded to the QM dose volume (3.0 mL) using 3 consecutively administered autoinjector/pens. After the 6-week screening period, eligible patients were randomized to receive SC injections of Repatha 140 mg once every two weeks (Q2W), 420 mg once monthly (QM), or placebo (140 mg once every two weeks or 420 mg once monthly).

There were two co-primary efficacy endpoints: percent change from baseline in LDL-C at Week 12 (first co-primary endpoint) and mean percent change from baseline in LDL-C at Weeks 10 and 12 (second co-primary endpoint).

Results from the analyses of both co-primary endpoints were statistically significant for both doses of Repatha as compared with placebo. The differences between Repatha and placebo groups in mean percent change in LDL-C at Week 12 were −61% [95% confidence interval (CI): −67%, −55%, p<0.0001] and −60% (95% CI: −68%, −53%, p<0.0001) for the 140 mg Q2W and 420 mg QM dosages, respectively.

A large number of co-secondary endpoints were analysed for both dosing regimens at both Week 12 and the mean of Weeks 10 and 12. These endpoints included percent change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and total cholesterol/HDL-C ratio.

Favourable and statistically significant changes were also achieved for all secondary endpoints in patients treated with Repatha, as compared with placebo, at both doses. The overall difference between Repatha and placebo in mean percent change in non-HDL-C from baseline to Week 12 was −55% (95% CI: −60%, −49%) and −55% (95% CI: −62%, −48%) for the 140 mg Q2Wand 420 mg QM dosages, respectively. The difference in ApoB was −49% (95% CI: −55%, −44%) and −49% (95% CI: −56%, −43%) for the 140 mg Q2Wand 420 mg QM dosages, respectively. The difference in total cholesterol was −41% (95% CI: −45%, −36%) and −40% (95% CI: −46%, −34%) for the 140 mg Q2Wand 420 mg QM dosages, respectively.

Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
LAPLACE-2

LAPLACE-2 was an international, multicentre, double-blind, randomized, double-dummy, placebo- and ezetimibe-controlled, 12-week pivotal Phase III study. The primary objective of this study was to evaluate the effect of 12 weeks of Repatha administered SC Q2W and QM when used in combination with a statin, compared with placebo, on percent change from baseline in LDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia.

Prior to randomization, patients entered a screening period to determine eligibility. During screening, SC administration of placebo was performed to confirm tolerability of SC administration prior to randomization. After the screening period, a total of 2,067 patients were first randomized to1 of 5 open-label statin cohorts (atorvastatin 10 mg or 80 mg, rosuvastatin 5 mg or 40 mg, or simvastatin 40 mg) for a 4-week lipid stabilization period followed by random assignment to SC injections of Repatha 140 mg Q2W, Repatha 420 mg QM, or placebo.

The study included 296 (14.3%) patients with a history of clinical atherosclerotic cardiovascular disease (ASCVD) who received Repatha or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 45% were ≥65 years old, 33% were women, 98% were White, 2% were Black, <1% were Asian, and 5% were Hispanic or Latino. After four weeks of statin therapy, the mean baseline LDL-C was measured as 2.8 mmol/L. Clinical ASCVD includes acute coronary syndromes, history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin.

The primary efficacy endpoint was the percent change from baseline in LDL-C at Week 12 (first co-primary endpoint) and mean percent change from baseline in LDL-C at Weeks 10 and 12 (second co-primary endpoint).

In subgroup analysis of patients with atherosclerotic cardiovascular disease who were on maximum-dose statin therapy, the overall difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was −74% (95% CI: −84%, −64%, p<0.0001) and −63% (95% CI: −76%, −50%, p<0.0001) for the 140 mg Q2W and 420 mg QM dosages, respectively.

Repatha also reduced non-HDL-C, ApoB, and total cholesterol.

DESCARTES

DESCARTES was an international, multicentre, double-blind, randomized, placebo-controlled, 52-week non-pivotal Phase III study. The primary objective of the study was to evaluate the effect of 52 weeks of SC Repatha QM, compared with placebo, on percent change from baseline in LDL-C when added to background lipid-lowering therapy.

The study included 139 patients with a history of clinical ASCVD who were assigned to background lipid lowering therapy based on underlying cardiovascular risk. Patients who did not reach the target LDL-C goal on atorvastatin 80 mg also received ezetimibe 10 mg and thus had LDL-C levels more refractory to treatment.

After stabilization on background therapy, patients were randomly assigned to the addition of placebo or Repatha 420 mg administered SC QM. Among these patients, the mean age at baseline was 59 years (range, 35 to 75 years), 25% were ≥65 years, 40% were women, 80% were White, 3% were Black, 5% were Asian, and <1% were Hispanic or Latino. After stabilization on the assigned background therapy, the mean baseline LDL-C was measured as 2.7 mmol/L.

The study's primary endpoint was the percent change from baseline in ultracentrifugation LDL-C at Week 52.

In patients with atherosclerotic cardiovascular disease on maximum-dose atorvastatin therapy with or without ezetimibe, the overall difference between Repatha 420 mg QM and placebo in mean percent change in ultracentrifugation LDL-C from baseline to Week 52 was −57% (95% CI: −61%, −46%; p <0.0001).

Other benefits of Repatha therapy include a reduction in non-HDL-C, ApoB, and total cholesterol.

Homozygous Familial Hypercholesterolemia
TESLA Part B

TESLA Part B was a multicentre, double-blind, randomized, placebo-controlled, 12-week pivotal Phase III study in 49 Homozygous Familial Hypercholesterolemia (HoFH) patients (not on lipid-apheresis therapy), 33 of whom received Repatha 420 mg QM and 16 of whom received placebo, as an adjunct to other lipid-lowering therapies [for example (e.g.), statins, ezetimibe, bile-acid sequestrants]. The mean age at baseline was 31 years, 49% were female, 90% Caucasian, 4% were Asian, and 6% other. The study included 10 adolescents (ages 13 to 17 years), 7 of whom received Repatha.

The mean LDL-C at baseline was measured as 9.0 mmol/L with all patients on statins and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >12.9 mmol/L together with either xanthoma before ten years of age or evidence of HeFH in both parents. Twenty-four participants (49%) had homozygous genetic defects, 24 participants (49%) had compound heterozygous genetic defects and one had heterozygous genetic defects; overall, the gene affected was the LDLR for 96%. The primary endpoint was percent change from baseline in LDL-C at Week 12.

The mean percent change from baseline in LDL-C was 9.02% in the placebo group versus (vs.) −23.09% in the Repatha group leading to a treatment difference of −32.12% (95% CI: −45.05%, −19.18%; p<0.001). In patients 18 years of age or older, the average percent change from baseline in LDL-C was 6.33% in the placebo group [total number of patients (n) = 12] vs. −24.99% in the Repatha group (n = 24) leading to a treatment difference of −32.92% (95% CI: −47.98%, −17.86%). In adolescent patients (less than 18 years of age), the average percent change from baseline in LDL-C was 5.19% in the placebo group (n = 3) vs. −31.31% in the Repatha group (n = 5) leading to a treatment difference of −26.72% (95% CI: −65.66%, 12.22%).

Key secondary or exploratory endpoints examined during this study included percent change from baseline in non-HDL-C, ApoB, and total cholesterol/HDL-C ratio at Week 12. Repatha reduced elevated non-HDL-C, total cholesterol, and ApoB, compared with placebo, with treatment differences of −30.04% (95% CI: −42.23%, −17.86%), −26.78% (95% CI: −37.68%, −15.88%), and −23.14% (95% CI: −34.83%, −11.45%), respectively.

TAUSSIG

TAUSSIG is an ongoing multicentre, open-label 5-year extension non-pivotal Phase II/III study which is currently evaluating the long-term safety and efficacy of Repatha in patients with severe familial hypercholesterolemia (FH), including HoFH, who were treated with Repatha as an adjunct to other lipid lowering therapies. Patients in this study were termed "severe" as they had higher baseline LDL-C and PCSK9 levels as well as a higher patient incidence of coronary disease than the HeFH patients in the RUTHERFORD studies.

A total of 96 HoFH patients (65 non-apheresis and 31 apheresis) enrolled in TAUSSIG. All patients in the study were initially treated with Repatha 420 mg QM except for those receiving apheresis at enrollment, who began with Repatha 420 mg Q2W. Dose frequency in non-apheresis patients could be titrated up to 420 mg Q2W based on LDL-C response and PCSK9 levels. Of the 65 non-apheresis HoFH patients in TAUSSIG (who started on the 420 mg QM), 30 patients up-titrated to the 420 mg Q2W group, with 25 of the 30 patients having received ≥12 weeks of both doses.

The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration >13.0 mmol/L together with either xanthoma before ten years of age or evidence of HeFH in both parents. The statistical analysis of efficacy data from this study is descriptive in nature, and no hypotheses were tested.

Mean percent changes in LDL-C from baseline at Week 12 were −22% in non-apheresis patients (n = 46), −17% in apheresis patients (n = 24), and −13% in adolescent patients. For 25 non-apheresis patients who received Repatha 420 mg QM for at least 12 weeks followed by Repatha 420 mg Q2W for at least 12 weeks in the study, mean percent changes from baseline in LDL-C were −15% at Week 12 QM treatment and 21% at Week 12 of Q2W treatment.

Changes in other lipid parameters (total cholesterol, ApoB, and non-HDL-C) also demonstrate a sustained effect of long-term Repatha administration.

Supportive Studies

Non-pivotal study RUTHERFORD-1 (n = 168) was a Phase II study similar in design to RUTHERFORD-2, except that different dosing regimens were assessed [350 mg once every four weeks (Q4W) and 420 mg Q4W]; an earlier drug formulation of evolocumab (the medicinal ingredient in Repatha) was used and was provided as a vial and syringe for onsite administration by study personnel.

Results from this study showed that a statistically significant difference in percent change from baseline at Week 12 in LDL-C compared to placebo was achieved at both doses, but was greatest at the higher dose of evolocumab (420 mg Q4W). In the evolocumab 350 mg Q4Wgroup and the 450 mg Q4Wgroup, treatment differences were −43.8% (95% CI: −51.6%, −36.1%; p<0.001) and −56.4% (95% CI: −64.1%, −48.7%; p<0.001), respectively.

The analysis of safety for RUTHERFORD-1 was generally similar to RUTHERFORD-2, and did not raise any additional safety concerns.

Overall Analysis of Efficacy

Across all clinical trials, treatment with Repatha as adjunct to maximally tolerated statins with or without other lipid lowering therapies (e.g. ezetimibe) demonstrated a robust reduction in LDL-C. The reduction in LDL-C as a surrogate marker for cardiovascular risk reduction has been used for several lipid lowering drugs to support market authorization in Canada. The validity of a reduction of LDL-C as surrogate for reduced cardiovascular risk has been established for statins in several cardiovascular outcomes trials (CVOTs) but is questionable for other lipid lowering drugs. For Repatha, as first in class, non-statin drug, a CVOT was requested as part of the post-marketing commitments to demonstrate the benefit of Repatha treatment.

Indications

During the original filing of this New Drug Submission (NDS), the indications proposed by Amgen were:

Primary Hyperlipidemia and Mixed Dyslipidemia

Repatha is indicated in adults with primary hyperlipidemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), TC/high density lipoprotein cholesterol (HDL-C), ApoB/apolipoprotein Al (ApoAI), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG) and lipoprotein(a) [Lp(a)], and to increase HDL-C and ApoAI:

  • in combination with a statin or statin with other lipid lowering therapies (e.g., ezetimibe); or
  • alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant; or
  • alone or in combination with other lipid-lowering therapies in patients for whom a statin is not considered clinically appropriate.
Homozygous Familial Hypercholesterolemia

Repatha is indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, TC, ApoB, and non-HDL-C in combination with other lipid lowering therapies (e.g., statins, low-density lipoprotein (LDL) apheresis).

Following review of the submission, it was determined that the indications for non-familial hyperlipidemia and mixed dyslipidemia could not be granted as proposed, taking into account the unknown effect of Repatha on cardiovascular morbidity and mortality, as well as the limitations of the long-term safety database for this new first-in-class product. Since the Repatha NDS did not include pivotal studies to evaluate treatment in HeFH patients with statin intolerance or for whom a statin was not considered clinically appropriate, the HeFH indication was restricted to the therapeutic setting defined by the pivotal study, RUTHERFORD-2 (e.g. in combination treatment with maximally tolerated statin treatment, when additional LDL-C lowering is required). The primary hyperlipidemia indication was further revised to include patients with cardiovascular disease, based on the beneficial results of pivotal study subgroup analyses. The indication for HoFH was revised for consistency with the primary hyperlipidemia indication.

Health Canada authorized Repatha for the following indications:

Primary Hyperlipidemia

Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).

The effect of Repatha on cardiovascular morbidity and mortality has not been determined.

Homozygous Familial Hypercholesterolemia

Repatha is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in adult patients and adolescent patients aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

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

Clinical Safety

The safety of Repatha was primarily established in the clinical studies previously described in the Clinical Efficacy section. During the course of the developmental program, the safety of Repatha was evaluated in approximately 6,700 patients with primary hyperlipidemia and mixed dyslipidemia; 4,971 patients received Repatha, representing 4,242 patient-years of exposure of Repatha at doses of 140 mg Q2W and 420 mg QM.

Heterozygous Familial Hypercholesterolemia
RUTHERFORD-2

In the RUTHERFORD-2 study, treatment emergent adverse events (TEAEs) were reported by a total 56.4% of patients in the Repatha treatment groups (140 mg Q2W, 420 mg QM) versus (vs.) 48.6% of patients in the placebo treatment groups and were generally mild in severity. Adverse events (AEs) moderate in severity were reported by a total of 15.5% of patients in the Repatha treatment groups vs. 13.8% of patients in the placebo treatment groups. Severe AEs were reported in 2.7% of patients vs. 2.8% of patients, respectively. A total of three patients (one Repatha-treated patient, two placebo-treated patients) reported life threatening AEs (0.5% and 1.8%, respectively). Some imbalance was evident between dosing arms in the Repatha and control groups. In the Repatha treatment groups, patients in the 140 mg Q2Wdosing arm reported mild, moderate, and severe AEs more commonly than patients in the 420 mg QM dosing arm, whereas in the placebo groups, these AEs were more common in the 420 mg QM dosing arm.

Adverse events reported in >2% of patients who received Repatha were nasopharyngitis (8.6% Repatha vs. 4.6% placebo), headache (4.1% vs. 3.7%), contusion (4.1% vs. 0.9%), back pain (3.6% vs. 0.9%), nausea (3.6% vs. 0.9%), arthralgia (3.6% vs. 1.8%), upper respiratory tract infection (3.2% vs. 2.8%), influenza (3.2% vs. 0), myalgia (2.7% vs. 0), and pain in extremity (2.3% vs. 2.8%).

Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
LAPLACE-2

LAPLACE-2 evaluated the safety, tolerability, and efficacy of Repatha on LDL-C in combination with statin therapy in patients with primary hypercholesterolemia and mixed dyslipidemia.

The incidence of AEs was similar between treatment groups and was 36.3% for the overall Repatha treatment group (36.4% Repatha 140 mg Q2W, 36.3% Repatha 420 mg QM) and 39.2% for the overall placebo treatment group (39.1% placebo 140 mg Q2W, 39.4% placebo 420 mg QM).

Twenty-one patients (1.9%) in the Repatha treatment group and twelve patients (2.2%) in the placebo treatment group reported AEs that led to discontinuation of Repatha and the patient incidence was similar across treatment groups.

Twenty-three patients (2.1%) in the Repatha treatment group and thirteen patients (2.3%) in the placebo treatment group reported serious AEs.

There was one fatal TEAE (acute myocardial infarction); the event occurred in the placebo treatment group.

The most commonly reported (≥1% of patients in any treatment group) AEs include: back pain (1.8% Repatha vs. 2.5% placebo), headache (1.7% vs. 2.7%), arthralgia (1.7% vs. 1.6%), myalgia (1.1% vs. 2.0%), and diarrhea (1.1% vs. 1.6%).

Device related AEs were reported in a total of eleven patients (1.0%) in the Repatha treatment group and six patients (1.1%) in the placebo treatment group. Device related AEs which occurred in >1 patient in any group were consistent with injection site reactions and included injection site hemorrhage [three patients (0.3%) in the Repatha treatment group] and injection site bruising [two patients (0.4%) in the Repatha treatment group and two patients (0.4%) in the placebo treatment group].

All device related AEs were mild [common terminology criteria for adverse events (CTCAE) grade 1] in severity with the exception of one event of grade 2 fatigue. The grade 2 fatigue event (Repatha 140 mg once every two weeks) was considered to be related to the device and Repatha and led to the discontinuation of Repatha treatment. No device related event was a serious AE.

(Note: Safety description is for the whole study population)

DESCARTES

In the DESCARTES study (52 weeks), the overall incidence of TEAEs appeared comparable between the Repatha QM and placebo QM treatment groups (74.8% and 74.2%, respectively). Serious AEs were reported in 5.5% of patients in the Repatha QM treatment group and 4.3% of patients in the placebo QM treatment group.

Treatment emergent adverse events leading to discontinuation of treatment were reported in 2.2% and 1.0% of patients in the Repatha QM and placebo QM treatment groups, respectively.

Two fatal AEs were reported in the Repatha QM treatment group during the study treatment period. A third fatal AE occurred 21 days after the end-of-study (49 days after the last dose of Repatha QM was administered). These deaths were positively adjudicated events determined by an independent Clinical Events Committee. The majority of AEs were mild (CTCAE grade 1) to moderate (CTCAE grade 2) in severity; ≥ grade 3 AEs were reported by 7.8% and 5.0% of patients in the Repatha QM and placebo QM treatment groups, respectively; and ≥ grade 4 AEs were reported by 1.0% and 0% of patients in the Repatha QM and placebo QM treatment groups, respectively.

Adverse events (AEs) of special interest in this submission were adverse events associated with other lipid lowering therapies [that is (i.e.), diabetes, liver, and muscle events], those associated with other injectable protein therapies (i.e., hypersensitivity events, injection site reactions), and those theoretically associated with PCSK9 inhibition/LDL receptor up-regulation (i.e., hepatitis C events). These AEs were evaluated using Standardised Medical Dictionary for Regulatory Activities (MedDRA) Queries or Amgen search strategies. Adverse events of special interest were reported in 80 patients (13.4%) in the Repatha QM treatment group vs. 35 patients (11.6%) in the placebo treatment group. These AEs included diabetes mellitus reported in 4 patients (0.7%) vs. 1 patient (0.3%), dermatitis and eczema reported in 18 patients (3.0%) vs. 6 patients (2.0%), injection site reactions reported in 34 patients (5.7%) vs. 15 patients (5.0%), and muscle pains reported in 24 patients (4.0%) vs. 9 patients (3.0%).

(Note: Safety description is for the whole study population)

Homozygous Familial Hypercholesterolemia
TESLA Part B

Treatment emergent adverse events (TEAEs) were reported for twelve patients (36.4%) in the Repatha treatment group and ten patients (62.5%) in the placebo treatment group. Adverse events (AEs) reported for more than one patient in either treatment group were as follows: upper respiratory tract infection (9.1% Repatha vs. 6.3% placebo), influenza (9.1% vs. 0.0%), gastroenteritis (6.1% vs. 0.0%), nasopharyngitis (6.1% vs. 0.0%), and nausea (0.0% vs. 12.5%). All events were CTCAE grade 1 to 2 (mild to moderate) in severity. No patients discontinued Repatha due to an AE. There were no serious AEs and no deaths reported in this study.

In the subgroup of adolescent patients (ages 13-17 years) (n = 10), TEAEs were reported for three of seven patients (42.9%) in the Repatha treatment group and two of three patients (66.7%) in the placebo treatment group. No AE was reported for more than one adolescent patient in either treatment group.

A total of 14 patients (nine Repatha, five placebo) used the autoinjector at least once and a total of 104 autoinjectors were used (69 Repatha, 35 placebo). A device related TEAE was reported for one patient in the placebo treatment group who had an event of medical device site reaction (CTCAE grade 1) on day one.

Based on the review of pre-specified AEs of interest associated with other lipid lowering therapies (i.e., diabetes events, liver events, muscle events), those associated with other injectable protein therapies (i.e., hypersensitivity events, injection site reactions), and those that could theoretically be associated with PCSK9 inhibition/LDLR up-regulation (i.e., hepatitis C events), the overall safety assessment of Repatha was considered favourable when used as indicated.

TAUSSIG

In the TAUSSIG study, AEs were reported in 53 patients (55.2%). Serious AEs were reported in 4 of 28 apheresis patients (14.3%) who did not switch from their initial dose of Repatha 420 mg Q2W, 6 of 47 patients (12.8%) in the Repatha 420 mg QM and Q2W switch group, and none in 25 non-apheresis patients who did not switch from their initial dose of Repatha 420 mg QM.

One HoFH patient (2.4%) discontinued study treatment due to an AE of rash. The rash improved after Repatha withdrawal, although intermittent flares without Repatha exposure continued to occur. The investigator deemed that there was a reasonable possibility that the AE of severe skin rash was related to Repatha. As of the April 1, 2014 data cut-off date, Repatha had not been restarted.

As of the April 1, 2014 data cut-off date, the total exposure to Repatha in the TAUSSIG study was 68.8 patient-years, including 51.5 patient-years in patients with HoFH (38.6 patient-years in non-apheresis patients with HoFH and 12.9 patient-years in apheresis patients with HoFH) and 17.3 patient-years in patients with severe familial hyperlipidemia (FH).

The HoFH Interim Analysis Set included all patients who received at least one dose of Repatha and either met clinical criteria of HoFH or who had supportive genetic information. The Severe FH Interim Analysis Set included all patients who received at least one dose of Repatha and were not included in the HoFH Interim Analysis Set. The Interim Analysis Set included all patients enrolled in this study at the time of the data cut-off date who received at least one dose of Repatha; this analysis set included patients with either HoFH or severe FH.

At least one TEAE was reported for 88 patients (44.4%) in the Interim Analysis Set, including 53 patients (55.2%) with HoFH and 35 patients (34.3%) with severe FH.

The most frequently reported AEs were nasopharyngitis (6.6%), headache (4.0%), influenza (3.5%), and injection site erythema (3.0%). The most frequently reported AEs in the HoFH Interim Analysis Set and in the Severe FH Interim Analysis Set were similar to those in the Interim Analysis Set.

Infections and Infestations were reported for 17.7% of patients in the Interim Analysis Set, including 22.9% of patients in the HoFH Interim Analysis Set and 12.7% of patients in the Severe FH Interim Analysis Set, which was likely related to the observed differences in Repatha exposure as of the data cut-off date. General Disorders and Administration Site Conditions were reported for 12.1% of patients (12.5% in the HoFH Interim Analysis Set, 11.8% in the Sever FH Interim Analysis Set).

The majority of AEs were CTCAE grade 1 or 2. Adverse events of CTCAE grade 3 were reported for ten patients (5.1%) overall, including 8 patients with HoFH and two patients with severe FH; no patient had a CTCAE grade ≥4 AE.

Two patients (1.0%) (one with HoFH and one with severe FH) discontinued Repatha due to a TEAE; neither was a serious AE. One event (rash) was considered related to Repatha by the investigator. This patient did not have evidence of anti-evolocumab (the medicinal ingredient in Repatha) antibodies reported at baseline or during the study.

Integrated Safety Summary

In an integrated analysis of eleven 12-week studies (four Phase II studies and seven Phase III studies, excluding the DESCARTES study), AEs were reported in 1,151 patients (44.2%) in the Repatha 140 mg Q2W treatment group or the Repatha 420 mg QM treatment group (n = 2,602) vs. 529 patients (43.2%) in the placebo treatment groups (n = 1,224).

Non adjudicated cardiac disorders (AEs of special interest) were reported in 48 Repatha-treated patients (1.8%) vs. 18 placebo-treated patients (1.5%). Musculoskeletal and connective tissue disorders were reported in 306 Repatha-treated patients (11.8%) vs. 119 placebo-treated patients (9.7%).

Serious AEs were reported in 62 Repatha-treated patients (2.4%) vs. 23 placebo-treated patients (1.9%). Non adjudicated serious cardiac disorders were reported in 15 Repatha-treated patients (0.6%) vs. two placebo-treated patients (0.2%), pancreatitis was reported in two Repatha-treated patients (0.1%) vs. zero placebo treated-patients, and renal and urinary disorders were reported in three Repatha-treated patients (0.1%) vs. zero placebo-treated patients.

Safety Extension Studies

Patients completing the Phase II and III studies (including the pivotal studies and other studies in the submission) could enrol in the open-label extension Studies 110 and 138, respectively. For the first year of both extension studies, patients were randomized (2:1) to either standard of care + Repatha (140 mg Q2W or 420 mg QM) or standard of care only. After the first year, all patients received Repatha treatment.The anticipated duration of Study 110 is 5 years; 976 patients have received Repatha for ≥12 months as of the cut-off date April 1, 2014. The anticipated duration of Study 138 is two years.

In the integrated analysis of the Year 1 period for both standard of care-controlled studies, AEs were reported in 1,708 patients (60.3%) in the standard of care + Repatha treatment group vs. 781 (55.0%) in the standard of care treatment group. Serious AEs were reported in 153 patients (5.4%) vs. 82 patients (5.8%).

Adverse events of special interest associated with other lipid lowering therapies (i.e., diabetes, liver, and muscle events), those associated with other injectable protein therapies (i.e., hypersensitivity events, injection site reactions), and those theoretically associated with PCSK9 inhibition/LDL receptor up-regulation (i.e., hepatitis C events) were evaluated.

Adverse events of special interest included diabetes mellitus reported in 29 patients (1.0%) vs. 5 patients (0.4%), and hypersensitivity events reported in 124 patients (4.4%) vs. 47 patients (3.3%).

The overall safety presented in the submission and post-approval commitments are acceptable for the approved indications.

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

7.2 Non-Clinical Basis for Decision

Overall, toxicological data was reassuring with respect to safety and pharmacological benefit of combination Repatha/statin therapy. Although no significant adverse effects pertaining to toxicology were observed for the endpoints verified, theoretical concerns include those potentially associated with ultra-low LDL-C and total cholesterol levels attainable with combination therapy (neurocognitive events, alterations in levels of cholesterol derived sterols and immune modulation).

Apart from lipid transport, heterogeneous high density lipoprotein (HDL) particles have been implicated in diverse biological functions, including anti-oxidative, anti-inflammatory, vasodilatory, antithrombotic and cytoprotective properties. A theoretical concern of PCSK9 inhibition is therefore unintentional modulation of HDL mediated biological processes. Changes in HDL-C however, were limited to hamsters in non-clinical studies and subsequently were not observed human clinical studies. The observed high density lipoprotein cholesterol (HDL-C) reductions were consistent with high expression of apolipoprotein E (ApoE) in hamsters, which can bind LDLR on HDL particles.

As Repatha is not expected to interact directly with deoxyribonucleic acid (DNA) or any other chromosomal components, theoretical carcinogenic risk is related to its cholesterol modifying ability including a potential increase of bile acid production, hepatic cholesterol burden and immune modulation (cholesterol mediated clonal expansion or signaling of immune cells). However, no Repatha-related cancer signals were observed in any tissue in a lifetime study conducted in the hamster.

Marked elevated serum alkaline phosphatase activity may indicate, among many other possible clinical conditions, an extra- or intrahepatic obstruction. A concern of PCSK9 inhibition and Repatha therapy is an increased uptake of cholesterol into the liver and subsequent up-regulation of bile acid synthesis. Observed elevations in a 1-month hamster study were minimal however and were not observed in the subsequent 3-month Subcutaneous Extended Pharmacology Study. There was also no increase in intestinal tumors (correlated with high levels of bile acids) in the Subcutaneous Lifetime Pharmacology study in Hamsters.

Repatha was well tolerated as a monotherapy in hamsters and monkeys for three and six months, respectively, or in combination with rosuvastatin in monkeys for three months. The intended pharmacological effect of decreased LDL-C and total cholesterol were observed in these studies and was reversible upon cessation of treatment. Overall, animal studies were reassuring regarding theoretical concerns potentially associated with very low plasma cholesterol levels. Although no embryo-fetal or postnatal toxicity was observed, maternal LDL-C reductions and placental transfer should be considered when assessing the safety of Repatha in pregnant women.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that evolocumab (the medicinal ingredient in Repatha) consistently exhibits the desired characteristic structure.

Potential and known degradation pathways were explored as part of evolocumab characterization in order to ensure that relevant controls and conditions are in place to maintain the stability of the product, and that appropriate tests are developed and incorporated into stability studies.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Repatha is supplied as a 140 mg/mL formulation in a sterile, single-use (1.0 mL fixed dose), preservative-free solution for delivery by subcutaneous injection.

Evolocumab drug substance is expressed in Chinese hamster ovarian cells. The cell culture fluid is harvested by centrifugation and the antibody is purified through a series of chromatography, filtration, and viral inactivation steps. The drug substance is formulated, filtered, and stored frozen.

The commercial drug product manufacturing process includes thawing the frozen drug substance, formulation (pooling and mixing), sterile filtration, and filling into the final container under aseptic processing conditions.

The drug substance manufacturing process has been adequately validated and the drug substance has been appropriately characterized. The proposed commercial drug substance has been demonstrated to be comparable to the drug substance used in the clinical and pre-clinical testing.

The drug product manufacturing process has been adequately validated and data has been provided to demonstrate the comparability of the proposed commercial drug product to drug product used in the pre-clinical and clinical studies.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Each lot of Repatha drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the drug product specifications, demonstrating consistency in manufacturing of the product.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf-life at 2°C to 8°C for Repatha is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

On-Site Evaluations (OSEs) of the facilities involved in the manufacture and testing of evolocumab and Repatha were not warranted since the facilities were recently evaluated and in good standing.

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

Adventitious Agents Safety Evaluation

An assessment of risk for transmissible spongiform encephalopathy (TSE) transmission was performed on all raw materials used to produce evolocumab, from the transfection of the cell line through fill and finish of the drug product. Additionally, in order to minimize the risk, the evolocumab manufacturing process uses no excipients, cell culture media components, or purification resins of animal origin. In addition, materials not directly used in the process, but which may come into contact with the product during manufacture or primary packaging (e.g., tubing, cryovials), were identified and assessed for bovine spongiform encephalopathy (BSE)/TSE transmission risk. For those materials manufactured using animal tallow derivatives, the processing conditions meet the "rigorous processes" criteria defined in the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3).

The Repatha manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

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