Summary Basis of Decision for Praluent

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 Praluent is located below.

Recent Activity for Praluent

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 Praluent

Updated: 2023-12-04

The following table describes post-authorization activity for Praluent, a product which contains the medicinal ingredient alirocumab. 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 AnchorGuidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number(s) (DINs):

  • DIN 02453819 - 75 mg/mL, alirocumab, solution, pre-filled pen, subcutaneous injection
  • DIN 02453754 - 75 mg/mL, alirocumab, solution, pre-filled syringe, subcutaneous injection
  • DIN 02453835 - 150 mg/mL, alirocumab, solution, pre-filled pen, subcutaneous injection
  • DIN 02453762 - 150 mg/mL, alirocumab, solution, pre-filled syringe, subcutaneous injection

Post-Authorization Activity Table (PAAT) 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 261559

2022-02-16

Issued NOC 2023-02-17

Submission filed as a Level I – Supplement to update the PM with safety data from study R727-CL-1532, a clinical trial that evaluated the effect of Praluent on neurocognitive endpoints in patients with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia at high or very high cardiovascular risk, and with safety data related to very low levels of LDL-C in Praluent-treated patients based on the observational drug utilization study OBS14697. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.

SNDS # 248948

2021-01-29

Issued NOC 2022-01-12

Submission filed as a Level I – Supplement to update the PM with information pertaining to the use of Praluent in a pediatric homozygous familial hypercholesterolemia population on the basis of clinical study EFC14660. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 255383

2021-07-30

Issued NOL 2021-08-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step. The submission was considered acceptable, and an NOL was issued.

DINs 02453754, 02453762 cancelled post market

Not applicable

Discontinuation date: 2021-03-04

The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.

NC # 245328

2020-10-20

Issued NOL 2021-01-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance manufacturing facility and process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 240667

2020-06-15

Issued NOC 2021-01-25

Submission filed as a Level I – Supplement for the addition of an alternate drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 243766

2020-09-09

Issued NOL 2020-12-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance and drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 241662

2020-07-10

Issued NOL 2020-10-13

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a drug substance testing site. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 231310

2019-09-03

Issued NOL 2019-12-06

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOL was issued.

SNDS # 219669

2018-08-30

Issued NOC 2019-07-31

Submission filed as a Level I – Supplement for the addition of a new indication and the amendment of the initial indication. The indications authorized were:

Prevention of Cardiovascular Events- Praluent is indicated in combination with a maximum tolerated dose of a statin, with or without other lipid lowering therapies, to reduce the risk of myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.

Primary Hyperlipidemia- Praluent is indicated for the reduction of LDL-C in adults with primary hyperlipidemia (heterozygous familial and non-familial):

  • As an adjunct to diet and statin therapy, with or without other lipid-lowering therapies;
  • As an adjunct to diet, as monotherapy or in combination with other non-statin lipid-modifying therapies, in patients for whom a statin is contraindicated.

The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 221576

2018-10-31

Issued NOC 2019-06-04

Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 223690

2019-01-15

Issued NOL

2019-02-20

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.

NC # 218088

2018-07-10

Issued NOL

2018-10-11

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 218963

2018-08-07

Issued NOL

2018-09-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the time out of refrigeration from 24 hours to 30 days. As a result of the NC, modifications were made to the Special Handling Instructions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 218385

2018-07-19

Issued NOL

2018-07-30

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 214313

2018-03-07

Issued NOL

2018-06-08

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 # 211841

2017-12-05

Issued NOC

2018-05-17

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the 75 mg/mL pre-filled syringe. The submission was reviewed and considered acceptable. An NOC was issued.

SNDS # 214447

2018-03-12

Issued NOC

2018-05-15

Submission filed as a Level I – Supplement to update the outer labels for the 75 mg/mL and 150 mg/mL pens. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 211618

2017-11-24

Issued NOL

2018-03-06

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing of the drug substance and drug product to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 206772

2017-06-21

Issued NOL

2017-08-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an additional drug substance manufacturing suite at an approved site. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 196180

2016-06-22

Issued NOC

2017-06-06

Submission filed as a Level I – Supplement to add a less frequent dosing regimen for the same indication as originally approved. Results from a placebo-controlled CHOICE I study demonstrated that in patients with hypercholesterolemia and taking concurrent statin therapy, the 300 mg every 4 week (Q4W) regimen was associated with significant and sustained low-density lipoprotein cholesterol (LDL-C). reduction from baseline compared to placebo. In addition to a slightly higher rate of injection site reactions, the study did not reveal unexpected or new safety signals, compared to the safety profile for Q2W regimen (75 mg or 150 mg) presented in the original NDS. The overall risk-to-benefit profile favours the 300 mg Q4W regimen as an alternative to the current dosing paradigm for patients indicated for alirocumab treatment who prefer less frequent monthly dosing. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 202727

2017-02-09

Issued 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.

NC # 196366

2016/06/29

Issued NOL 2016/10/07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to fulfill several quality-related post-authorization commitments. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DINs 02453754, 02453762) market notification

Not applicable

Date of first sale: 2016/08/13

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

Drug product (DIN 02453819) market notification

Not applicable

Date of first sale: 2016/05/18

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

Drug product (DIN 02453835) market notification

Not applicable

Date of first sale: 2016/04/29

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

NDS # 183116

2015/03/20

Issued NOC 2016/04/11

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Praluent

Date SBD issued: 2016-06-08

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

Alirocumab, 75 mg/mL and 150 mg/mL, solution, subcutaneous injection

Drug Identification Number (DIN):

  • DIN 02453819 - 75 mg/mL solution, pre-filled pen
  • DIN 02453754 - 75 mg/mL solution, pre-filled syringe
  • DIN 02453835 -150 mg/mL solution, pre-filled pen
  • DIN 02453762 - 150 mg/mL solution, pre-filled syringe

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 183116

 

On April 11, 2016, Health Canada issued a Notice of Compliance to Sanofi-aventis Canada Inc. for the drug product Praluent.

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 Praluent is favourable as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults 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 Praluent on cardiovascular morbidity and mortality has not been determined.

 

1 What was approved?

 

Praluent is a fully human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). Praluent was authorized as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults 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 Praluent on cardiovascular morbidity and mortality has not been determined.

In controlled studies, 1,158 patients (34.7 %) treated with Praluent were ≥65 years of age and 241 patients (7.2 %) treated with Praluent 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.

The safety and efficacy in pediatric patients have not been established.

Praluent is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

For contraindications related to concomitant statins or other lipid-modifying therapy, please refer to their current respective prescribing information.

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

Praluent (75 mg/mL and 150 mg/mL alirocumab) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains histidine, polysorbate 20, sucrose, and water for injection.

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

 

2 Why was Praluent approved?

 

Health Canada considers that the benefit/risk profile of Praluent is favourable as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults 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 Praluent on cardiovascular morbidity and mortality has not been determined.

Familial hypercholesterolemia (FH), a genetic disorder characterized by elevated levels of LDL-C and development of premature CVD, is the most common form of familial hyperlipidemia, a genetic disorder characterized by excess lipids (cholesterol, phospholipds, and triglycerides) in the bloodstream.

Inheritance of 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). The prevalence of HeFH in Canada is conservatively estimated at 1:500 (1:270 in French-Canadians). Approximately 83,500 Canadians are estimated to have FH (most undiagnosed); early treatment can normalize life expectancy.

Statins remain the cornerstone of treatment for primary hyperlipidemia, with established cardiovascular benefit. Based on overwhelming evidence from the general population, LDL-C lowering is also the primary treatment target in FH 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, bile acid resins, and niacin. Health Canada also recently approved an anti-proprotein convertase subtilisin kexin type 9 (PCSK9) antibody, Repatha, for reducing LDL-C in patients with heFH or clinical atherosclerotic CVD.

Praluent has been shown to be efficacious in adult patients with HeFH or clinical atherosclerotic CVD, who require additional lowering of LDL-C. The market authorization was based on results from five, placebo-controlled, Phase III studies. Treatment with Praluent demonstrated a large, statistically significant reduction in LDL-C levels compared with placebo, in patients with primary hyperlipidemia (HeFH or clinical atherosclerotic CVD) who were unable to achieve target LDL-C despite maximally tolerated statin therapy at baseline (with or without additional lipid-lowering therapies). In the Praluent group, LDL-C reductions from baseline were observed from Week 4 to Week 52. Other benefits included reductions of elevated non high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and apolipoprotein (Apo B), a main protein constituent of lipoproteins.

The most common adverse events of Praluent included itching, swelling, pain, or bruising where injection was given, nasopharyngitis, and flu. Allergic reactions, such as hypersensitivity vasculitis (a skin rash usually appearing as purple-colored spots on the skin associated with inflammation of small blood vessels) and hypersensitivity reactions were reported with the use of Praluent. Safety issues of interest, which require post-market monitoring and further investigation, are related to neurocognitive adverse events and the long-term effects of very low levels of LDL-C induced by Praluent. To ensure that the benefits of Praluent therapy continue to outweigh potential risks, Health Canada has required several post-approval activities to be carried out. These include submitting the results of the Cardiovascular Outcome Trial (EFC11570). For more information, see What follow-up measures will the company take?

A Risk Management Plan (RMP) for Praluent was submitted by Sanofi-aventis 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 Praluent has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Praluent therapy are considered to outweigh the potential risks. Praluent 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 Praluent 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 Praluent?

 

Submission Milestones: Praluent

Submission Milestone Date
Pre-submission meeting: 2015-02-25
Submission filed: 2015-03-20
Screening 1  
Screening Deficiency Notice issued: 2015-05-15
Response filed: 2015-06-04
Screening 2  
Screening Acceptance Letter issued: 2015-06-16
Review 1  
On-Site Evaluation: 2016-02-01 - 2016-02-05
Quality Evaluation complete: 2016-04-07
Clinical Evaluation complete: 2016-04-05
Labelling Review complete: 2016-04-07
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate 2016-04-11

 

The Canadian regulatory decision on the non-clinical and clinical review of Praluent 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 Praluent, 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) to provide the following:

  • All serious adverse events (including cardiovascular events, liver disorders, new onset diabetes, allergic reaction, neurocognitive events, severe renal impairment, malignancies, etc.) that occurred in all clinical studies with Praluent.
  • The final clinical study report for the completed placebo-controlled studies since the original submission, including the 78-week Phase III studies: Study LTS11717 (LONG TERM), Study EFC12492 (FH I), Study EFC12732 (HIGH FH), Study R727-CL-1112 (FH II).
  • All reports/correspondence pertaining to post-approval commitments made to the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This will also include reports on the ongoing Cardiovascular Outcome study - EFC11570 (OUTCOMES).
  • The interim reports and the final report of the prospective observational study, committed to the FDA, which planned to evaluate fetal, infant, and childhood outcomes of pregnant women exposed to Praluent and their live born offspring. In addition, provide, as appropriate, regular safety updates from this study. This should be indicated in the updated Risk Management Plan (RMP).
  • Praluent Medical Educational materials for review prior to the launch of the product.
  • Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Praluent every 6 months. Include in each PSUR/ PBRER an analysis of all adverse drug events as per the Pharmacovigilance Plan and include safety updates from all ongoing clinical studies with Praluent.
  • An updated Canadian RMP to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies.
    • Propose acceptable risk minimization measures to mitigate potential risk of medication/dispensing errors, in patients exposed to Praluent in the clinical settings.
    • Provide a plan to address and monitor the potential risk of off-label use.
    • Provide relevant safety data in patients infected with human immunodeficiency virus (HIV).

 

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

 

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 Praluent 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

Alirocumab, the active ingredient in Praluent, is a fully human monoclonal antibody (immunoglobulin G1 [IgG1]) that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). Binding of alirocumab to PCSK9 inhibits circulating PCSK9 from binding to the low-density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation therefore increasing number of available LDLR to clear LDL. The result is the lowering of serum low-density lipoprotein cholesterol (LDL-C) levels.

The pharmacokinetic (PK), and pharmacodynamic (PD) properties of alirocumab and their effects on the target (PCSK9) were assessed in ten clinical pharmacology Phase I studies conducted in healthy subjects (including Japanese subjects), special populations (subjects with hepatic impairment) and in patients with familial hypercholesterolemia (FH) and non-FH. The PK of alirocumab and its effects on PCSK9 were also assessed in five Phase II and four Phase III studies conducted in patients with FH, non-FH, and mixed dyslipidemia.

The review of the pharmacokinetic/pharmacodynamics portion was based on the United States Food and Drug Administration (FDA) reports; however, the data submitted have been verified for validation purposes and labelling.

The clinical pharmacological data support the use of Praluent for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Praluent (alirocumab) was investigated in five, double-blind, placebo-controlled, Phase III studies (LONG TERM, COMBO I, FH I, FH II, and HIGH FH) that enrolled 3,499 patients; 36% were patients with heterozygous familial hypercholesterolemia (HeFH) and 54% were non-FH patients who had clinical atherosclerotic cardiovascular disease (CVD). Three of the five studies (FH I, FH II, and HIGH FH) were conducted exclusively in patients with HeFH. All patients took background lipid-modifying therapy (LMT) consisting of a maximum tolerated dose of statin, with or without other LMTs. In the studies that enrolled patients with HeFH, the diagnosis of HeFH was made either by genotyping or clinical criteria (“definite FH” using either the Simon Broome or World Health Organization/Dutch Lipid Network criteria). All studies were at least 52 weeks in duration with the primary efficacy endpoint being the mean percent change in LDL-C from baseline measured at Week 24.

Two studies (LONG TERM and HIGH FH) which involved a total of 2,416 patients, were conducted with a 150 mg every 2 weeks (Q2W) dose only. The other three studies (COMBO I, FH I and FH II) were performed with a dose of 75 mg Q2W, and criteria-based up-titration to 150 mg Q2W at Week 12 in patients who did not achieve their pre-defined target LDL-C based on their level of CVD risk at Week 8.

LONG TERM Study

The LONG TERM study was a multicentre, randomized, double-blind, placebo-controlled, 18-month study which included 2,341 patients (1,553 patients in the Praluent group and 788 patients in the placebo group) with HeFH or non-familial hypercholesterolemia (non-FH) on a maximum tolerated dose of statin, with or without other LMT. Patients received either Praluent at a dose of 150 mg Q2W or placebo in addition to their existing LMT.

The patient population included 17.7% HeFH patients and 68.6% non-FH patients with clinical atherosclerotic CVD. The mean age was 60.5 years (range 18-89), 37.8% were women, 93% were Caucasian, 3% were Black, and 5% were Hispanic/Latino. The mean LDL-C level at baseline was 3.15 mmol/L (122 mg/dL).The proportion of patients who prematurely discontinued the study drug prior to the 24-week endpoint was 8% among those treated with Praluent and 8% among those treated with placebo.

The least-square (LS) means for calculated LDL-C, at Week 24 percent change from baseline, were -57.8% in the Praluent 150 mg Q2W group (number of patients [n] = 1,553) and -0.7% in the placebo group (n = 788). At Week 24, the treatment difference between Praluent and placebo in mean LDL-C percent change was -58.5% (95% confidence interval [CI] -61.1, -55.8).

Subgroup analyses of the primary efficacy endpoint (intent-to-treat [ITT] analysis) showed consistent reductions of calculated LDL-C from baseline to Week 24 with Praluent versus placebo across a range of demographic and baseline characteristics (gender, ethnicity, region, baseline PCSK9 level [total and free], chronic kidney disease [CKD] status, diabetes, baseline calculated LDL-C, and baseline high-density lipoprotein cholesterol [HDL-C]).

Results of the primary analysis, sensitivity analyses, and subgroup analyses for the primary endpoint (percent change from baseline in calculated LDL-C at Week 24) were consistent and the treatment differences were approximately -61% for each analysis. Praluent treatment resulted in statistically and clinically significant reductions in calculated LDL-C compared to placebo in patients with HeFH and non-FH and with very high CVD risk (established coronary heart disease [CHD] or CHD risk equivalents) and who are not adequately controlled with a maximum tolerated stable daily dose of statin, with or without other LMT.

At all time points, Week 12, Week 24, and Week 52, the absolute change from baseline calculated LDL-C (ITT analysis) was greater in the Praluent group versus the placebo group.

Compared with placebo at Week 24 (ITT analysis), Praluent significantly reduced apolipoprotein B (Apo B), non-HDL-C, total cholesterol (Total-C), lipoprotein a (Lp [a]), and triglycerides (TG).

Significant increases in HDL-C and apolipoprotein A-1 (Apo A-1) were also observed at Week 24 (ITT analysis).

Consistent results were observed at Week 12 and Week 52 for both the ITT analysis and the on-treatment analysis.

COMBO I Study

The COMBO I study was a multicentre, randomized, double-blind, placebo-controlled, 52-week study which included 316 patients (209 in the Praluent group and 107 patients in the placebo group) categorized as having a very high CVD risk with hypercholesterolemia on a maximum tolerated dose of statin, with or without other LMT who required additional LDL-C reduction. Patients received either 75 mg Praluent Q2W or placebo in addition to their existing LMT. Dose up-titration of Praluent to 150 mg Q2W occurred at Week 12 in patients with LDL-C ≥1.81 mmol/L (70 mg/dL).

The mean age was 63 years (range: 39-87), 34.2% were women, 82% were Caucasian, 16% were Black, and 11% were Hispanic/Latino. Overall 84% of patients had clinical atherosclerotic CVD. The mean baseline LDL-C was 2.63 mmol/L (102 mg/dL).The dose was up-titrated to 150 mg Q2W in 32 of 191 (16.8%) of patients treated beyond 12 weeks.

The proportion of patients who prematurely discontinued study drug prior to the 24-week endpoint was 11% among those treated with Praluent and 12% among those treated with placebo.

At Week 24, the mean percent change from baseline in LDL-C was -44.2% in the Praluent 75 mg Q2W/up-titrated to 150 mg Q2W group (n = 209) and -1.5% in the placebo group (n = 107). The LS mean difference comparing Praluent to placebo was-42.7% (95% CI -49.9, -35.4).

Subgroup analyses of the primary efficacy endpoint (ITT analysis) showed consistent reduction of calculated LDL-C from baseline to Week 24 with Praluent versus placebo across a range of demographic and baseline characteristics.

Praluent treatment resulted in statistically and clinical significant reductions in calculated LDL-C compared to placebo in patients with non-FH who had a very high CVD risk (established CHD or CHD risk equivalents) and patients who were not adequately controlled with a maximally tolerated stable daily dose of statin, with or without other LMT.

At all timepoints, Week 12, Week 24 and Week 52, the absolute change from baseline in calculated LDL-C (ITT analysis) was greater in the Praluent group versus the placebo group.

Compared with placebo, Praluent significantly reduced Apo B, non-HDL-C, and Total-C at Week 12 and Week 24 following the same trend as was observed for calculated LDL-C.

FH I and FH II Studies

The FH I and FH II studies were multicentre, placebo-controlled, double-blind 18-month studies which, when combined, included 735 patients with HeFH (490 in the Praluent group and 245 patients in the placebo group) who received a maximally tolerated dose of statin, with or without other LMT. The studies were similar in design and eligibility criteria. Patients received either Praluent 75 mg Q2W or placebo in addition to their existing LMT. Dose up-titration of Praluent to 150 mg Q2W occurred at Week 12 in patients with LDL-C ≥1.81 mmol/L (70 mg/dL).

Overall, the mean age was 52 years (range 20-87), 45% were women, 94% were Caucasian, 1% were Black, and 3% were Hispanic/Latino. The proportion of patients in FH I study and in the FH II study with clinical atherosclerotic CVD was 51.2% and 38.3% respectively. The mean baseline LDL-C was 3.74 mmol/L (144.6 mg/dL) in the FH I study and 3.48 mmol/dL (134.4 mg/dL) in FH II study. The dose was up-titrated beyond Week 12 in 135 of the 311 patients (43.4%) in the FH I study and in 61 of the 158 patients (38.6%) in the FH II study.

The proportion of patients who prematurely discontinued the study drug prior to the 24-week endpoint was 6.5% among those treated with Praluent and 5.5% among those treated with placebo in the FH I study; and 4.8% among those treated with Praluent and 2.4% among those treated with placebo in the FH II study .

In the FH I study at Week 24, the LS mean percent change from baseline in calculated LDL-C was -47.2% in the Praluent group, and 9.0% in the placebo group. The mean treatment difference from placebo in LDL-C percent change from baseline was -56.3% (95% CI -61.8, -50.7). At Week 24, the proportion of very high CVD risk patients who reached a calculated LDL-C level of <70 mg/dL (<1.81 mmol/L) or high CVD risk patients who reached a calculated LDL-C level of <100 mg/dL (<2.59 mmol/L) was greater in the Praluent group (72.2%) than in the placebo group (2.4%). Overall, at Week 24, 59.8% of the Praluent patients reached the calculated LDL-C level of <70 mg/dL (<1.81 mmol/L) compared to 0.8% of patients in the placebo group. The primary and key secondary endpoints for efficacy were all met, and a sustained decrease from baseline in LDL-C was evident as early as 4 weeks after onset of treatment. While more than 1/3 of the patients were up-titrated to the higher 150 mg dose after Week 12 based on sub-optimal response at Week 8, the overall Praluent group showed similar efficacy over time.

In the FH II study, a statistically significant decrease from baseline in LDL-C was observed in the Praluent group compared to the placebo group, with an LS mean difference of percent change from baseline of -50.2% (95% CI -57.1, -43.2) at Week 24. At Week 24, the LS mean percent change in LDL-C from baseline was -47.3% in the Praluent group and +2.8% in the placebo group. At Week 12, a statistically significant decrease in LDL-C from baseline was observed in the Praluent group compared with the placebo group. Compared with placebo, Praluent significantly reduced Apo B, non-HDL-C, total-C, and lipoprotein (a) at Week 12 and Week 24.

Patient population, demography, and results were similar in the FH II study to the FH I study. As with FH I, patient compliance and retention was high, and efficacy with respect to LDL-C (the primary endpoint) was observed from as early as 4 weeks after treatment onset. Patients that were up-titrated to 150 mg Q2W dosing at Week 12 due to sub-optimal response by Week 8 tended to have higher baseline LDL-C levels (160 mg/dL) compared to those patients that remained on 75 mg Q2W (118 mg/dL).

HIGH FH Study

The HIGH FH study was a multicentre, randomized, double-blind, placebo-controlled 18-month study that included 107 HeFH patients (72 patients in the Praluent group and 35 patients in the placebo group) on a maximum tolerated dose of statin, with or without other LMTs, and a baseline LDL-C ≥4.14 mmol/L (160 mg/dL). Patients received either Praluent at a dose of 150 mg Q2W or placebo in addition to their existing LMT.

The mean age was 50.6 years (range 18-80), 46.7% were women, 88% were Caucasian, 2% were Black, and 6% were Hispanic/Latino. Overall, 50% of patients had clinical atherosclerotic CVD. Mean baseline LDL-C was 5.08 mmol/L (196.3 mg/dL) in the Praluent group and 5.2 mmol/L (201.0 mg/dL) in the placebo group.

The proportion of patients who discontinued study drug prior to the 24-week endpoint was 10% among those treated with Praluent and 0% among those treated with placebo.

The primary objective for this study was met, given that a statistically significant and clinically meaningful reduction in LDL-C with Praluent as an add-on therapy to a stable maximum tolerated daily statin therapy with or without other LMT in comparison with placebo after 24 weeks of treatment in patients with HeFH was achieved. At Week 24, the mean percent change from baseline in LDL-C was -43.3 % with Praluent and -6.9% with placebo, and the mean treatment difference from placebo in LDL-C percent change from baseline was -36.3% (95% CI -48.5%, -24.2%, p-value ˂0.0001).

Overall Analysis of Efficacy

Treatment with Praluent in all five placebo-controlled studies demonstrated large, statistically significant reductions in LDL-C when compared with placebo in patients with primary hyperlipidemia (HeFH or clinical atherosclerotic CVD) who were unable to achieve target LDL-C despite maximum tolerated statin therapy at baseline (with or without additional lipid-lowering therapies). In the Praluent group, LDL-C reduction from baseline was observed from Week 4 to Week 52. Praluent also reduced levels of non-HDL-C, ApoB and TC.

The efficacy results obtained from the above-mentioned studies have been extensively validated and are based on statistical methods that reflect current thinking on specified topics, and are aligned with other regulators.

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

Clinical Safety

The clinical safety of Praluent administered in conjunction with a statin was primarily evaluated in five placebo-controlled Phase III studies (described in the Clinical Efficacy section) and four placebo-controlled Phase II studies with 2,476 patients treated with 75 mg or 150 mg Praluent Q2W, including 1,999 patients exposed for at least 52 weeks and 639 patients exposed for at least 76 weeks.

The most common adverse reactions were local injection site reactions (including redness, swelling, pain and bruising), upper respiratory tract signs and symptoms, and pruritus (itch). Adverse reactions led to discontinuation of treatment in 5.3% of patients treated with Praluent and 5.1% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with Praluent were allergic reactions (0.6% for Praluent versus 0.4% for placebo) and injection site reactions (0.2% for Praluent versus 0.3% for placebo). Serious adverse events (SAEs) occurred in 13.7% of Praluent and 14.3% of placebo patients.

In an Integrated Safety Summary that analyzed 3,340 patients who were treated with Praluent at a dose of 75 or 150 mg Q2W, treatment-emergent adverse event s (TEAEs) and SAEs were similar between the Praluent and comparator groups with few exceptions. The percentage of SAEs were markedly higher in patients that only received Praluent 150 mg (16.2%) versus patients that received Praluent 75 mg and 150 mg (10.8%), indicating a relationship between a higher dose and SAEs.

Safety issues of interest, which require post-market monitoring and further investigation, are related to neurocognitive adverse events and the long-term effects of very low levels of LDL-C induced by Praluent.

From safety data based on nine placebo-controlled studies (four Phase II studies and five Phase III studies), neurocognitive events were reported in 0.8% of patients treated with Praluent and 0.7% in the placebo group. Confusion or memory impairment were each reported in 0.2% of patients treated with Praluent and in <0.1% (for each) in the placebo group patients. The majority of neurocognitive events were non-serious. The causal relationship between these events and Praluent has not been established.

In a pool of the placebo- and active-controlled studies, 796 of 3,340 patients (23.8%) treated with Praluent had two consecutive values of LDL-C <0.65 mmol/L (25 mg/dL), including 288 patients (8.6%) with two consecutive values of LDL-C <0.39 mmol/L (15 mg/dL). This occurred more often when patients were initiated and maintained on 150 mg Q2W of Praluent regardless of the baseline LDL-C value or the response to treatment. Although adverse consequences of very low LDL-C were not identified in these studies, the long-term effects of very low levels of LDL-C induced by Praluent are unknown.

As with all therapeutic proteins, there is a potential for immunogenicity. In the controlled clinical Phase III studies, 4.8% of the patients treated with Praluent had a treatment-emergent anti-drug antibody (ADA) response as compared to 0.6% in the control group. A total of 1.2% of patients exhibited transient low-titre ADA responses with no neutralizing activity.

In a pooled analysis of the Phase III studies, all-cause mortality was 0.6% (20 of 3,182) of patients in the Praluent group and 0.9% (17 of 1,792) of patients in the control group. The primary cause of death in the majority of these patients was cardiovascular (CV) events.

The impact of Praluent on CV risk has been assessed in the Phase III program and firm conclusions on the effect of Praluent on CV morbidity and mortality could not be drawn from these data. The reduction of CV risk is being assessed in an ongoing 18,000 patient study where the primary endpoint is major CV events (consisting of coronary heart disease (CHD) death, MI, stroke, and unstable angina requiring hospitalization, confirmed by adjudication.In a pre-specified pooled analysis of the Phase III studies, major adverse cardiovascular events were reported in 52 of the 3,182 patients (1.5 per 100 patient-years) in the Praluent group and 33 of the 1,792 patients (1.8 per 100 patient-years) in the control group (placebo or active control).

Overall, the safety profile of Praluent is considered acceptable for the target population to be treated. In order to ensure that this benefit continues to outweigh any risk after authorization, Health Canada has required several post-approval activities to be carried out and a Risk Management Plan. Appropriate warnings and precautions are in place in the approved Praluent Product Monograph to address the identified safety concerns.

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

Indication

During the original filing of this New Drug Submission (NDS), the sponsor proposed the following indication:

  • Praluent (alirocumab) is indicated, as adjunct therapy to diet, for long-term treatment of adult patients with primary hypercholesterolemia (non-familial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes mellitus, to reduce low-density lipoprotein cholesterol (LDL-C).

Health Canada authorized the following indication for Praluent:

  • Praluent (alirocumab) is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults 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 Praluent on cardiovascular morbidity and mortality has not been determined.

In the absence of data from a cardiovascular outcome trial, the indication regarding the use of Praluent as monotherapy in patients who are intolerant to statin cannot be considered. Therefore at this time, the indication had to be narrowed to include only patients on a background of maximum tolerated statin dose. For the same reasons, the indication had to be restricted to patients with heterozygous hypercholesterolemia (who are at high CVD risk) and to patients who already have a clinical atherosclerotic CVD. This approach is in line with the labelling of a similar biologic drug of the same class marketed in Canada, and with the FDA’s labelling for Praluent.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical pharmacology (primary pharmacodynamics and safety), pharmacokinetic and general toxicity studies were conducted in pharmacologically relevant species (rats and monkeys). Subcutaneous (SC) and intravenous (IV) routes of administration were selected to reflect the intended use in human clinical studies. 

No significant adverse effects were observed in rats and monkeys when alirocumab, the active ingredient of Praluent, was administered by SC or IV injection up to dose levels of 75 mg/kg once per week (QW) for 6 months.

There were no additive or synergistic adverse effects when alirocumab was administered in combination with atorvastatin to monkeys up to dose levels of 75 mg/kg QW and 40 mg/kg once per day (QD), respectively, for 3 months. There were no adverse effects on surrogate markers of fertility (for example, estrous cyclicity, testicular volume or sperm parameters) up to doses of 75 mg/kg QW included in a 26-week chronic subcutaneous toxicology study in sexually-mature monkeys. In addition, there were no alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in any rat or monkey toxicology study.

No effects on embryo-fetal development were observed in rats up to doses of 75 mg/kg by SC route on gestational Day 6 and 12. Studies in monkeys showed that alirocumab crossed the placental barrier and was pharmacologically active in infants exposed during organogenesis through parturition. Dose-related decreases in T-cell dependent antibody response to keyhole limpet hemocyanin were observed at doses ≥15 mg/kg QW in offspring of exposed mothers at 4 to 6 months of age, suggesting a suppression of humoral immune response.

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

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

 

 

7.3 Quality Basis for Decision

 

Alirocumab, the active ingredient in Praluent, is a fully human monoclonal antibody (immunoglobulin G1 [IgG1]) that binds PCSK9.

Praluent is a clear, colorless to pale yellow solution, with a pH of about 6.0.

Praluent is supplied as a sterile, preservative-free solution for injection, in a single-use pre-filled pen or single-use pre-filled syringe, with dosage strengths of 75 mg/mL and 150 mg/mL.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that alirocumab consistently exhibits the desired characteristic structure and biological activity.

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.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

Alirocumab is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese Hamster Ovary cell suspension culture.

Alirocumab protein is expressed by the cells and secreted into the culture medium. Each production bioreactor batch is harvested, Protein A affinity purified, virus-inactivated (low pH), clarified by depth filtration, further purified using a series of chromatographic and membrane filtration steps (anion exchange chromatography, hydrophobic interaction chromatography and virus retentive filtration), and formulated

The production of Praluent drug product consists of thawing, pooling, and dilution (only applicable for the manufacturing of alirocumab 75 mg/mL solution for injection) of the drug substance, followed by sterile filtration and aseptic filling of the bulk drug product solution into sterile syringes.

The pre-filled pens are produced by inserting the alirocumab bulk pre-filled syringes into a single-use, disposable autoinjectors.

The drug substance and drug product manufacturing processes have been successfully validated.

In-process control tests for the drug substance and drug product were established, corresponding analytical methods validated, and acceptance criteria justified. The manufacturing process is considered to be adequately controlled within justified limits.

The materials used in the manufacture of the drug substance and drug product are considered to be suitable and/or meet standards appropriate for their intended use.

Overall, the method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

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 Praluent drug product is tested for appearance, content, identity, potency, purity, and impurities. The 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 specifications of the drug product and demonstrate consistency in manufacturing.

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 Praluent is considered acceptable.

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

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance, alirocumab, was not warranted since the facility was recently evaluated in good standing.

An OSE of the facility involved in the manufacture and testing of the drug product, Praluent, was successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

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

Adventitious Agents Safety Evaluation

Extensive testing for endogenous and adventitious viral agents has been conducted for the alirocumab expression cell line, the master cell bank, and the working cell bank to ensure that the cell banks are free of detectable adventitious viral contamination. Testing for virus contamination on cells at the end of production and at the limit of in vitro cell age was also completed during the Phase III clinical manufacturing process to ensure absence of latent viruses.

The alirocumab 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.

 

Report a problem or mistake on this page
Please select all that apply:
Date modified: