Summary Basis of Decision for Leqvio

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 Leqvio is located below.

Recent Activity for Leqvio

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

The following table describes post-authorization activity for Leqvio, a product which contains the medicinal ingredient inclisiran (supplied as inclisiran sodium). 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 and Applications Guidance.

Updated: 2023-08-17

Drug Identification Number (DIN):

DIN 02518376 – 284 mg inclisiran/1.5 mL, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 262760 2022-03-24 Issued NOC 2022-10-26 Submission filed as a Level I – Supplement for the addition of an alternative drug product manufacturing and primary packing site, and a change in part of the primary packaging material not in contact with the finished product formulation. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02518376) market notification Not applicable Date of first sale: 2022-09-26 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 243470 2020-08-31 Issued NOC 2021-07-26 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Leqvio

Date SBD issued: 2021-11-10

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

Inclisiran (supplied as inclisiran sodium)

Drug Identification Number (DIN):

  • DIN 02518376 - 284 mg inclisiran/1.5 mL, solution, subcutaneous administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 243470

 

On July 26, 2021, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Leqvio.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Leqvio is favourable as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) level in adults with the following conditions who are on maximally tolerated dose of a statin, with or without other LDL-C-lowering therapies:

  • Heterozygous familial hypercholesterolemia, or

 

  • Non-familial hypercholesterolemia with atherosclerotic cardiovascular disease.
1 What was approved?

 

Leqvio is a small interfering ribonucleic acid (siRNA) that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. It was authorized as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) level in adults with the following conditions who are on maximally tolerated dose of a statin, with or without other LDL-C-lowering therapies:

  • Heterozygous familial hypercholesterolemia (HeFH), or
  • Non-familial hypercholesterolemia with atherosclerotic cardiovascular disease.

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

Leqvio is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.

No overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients. Of the 1,833 patients treated with inclisiran in the Phase III clinical program, 981 (54%) patients were 65 years of age and older, while 239 (13%) patients were 75 years of age and older. Elderly patients with HeFH were, however, less represented (22% were aged ≥65 years).

Leqvio was approved for use under the conditions stated in its product monograph, taking into consideration the potential risks associated with the administration of this drug product.

Leqvio (284 mg inclisiran/1.5 mL, supplied as inclisiran sodium) is presented as a solution for subcutaneous injection. In addition to the medicinal ingredient, the solution contains phosphoric acid, sodium hydroxide, and water for injection.

Leqvio is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Additionally, as Leqvio is used in combination with a statin, with or without other lipid-lowering therapies, it is recommended to consult the Contraindications section of the product monographs for those medications.

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

 

2 Why was Leqvio approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Leqvio is favourable as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) level in adults with the following conditions who are on maximally tolerated dose of a statin, with or without other LDL-C-lowering therapies:

  • Heterozygous familial hypercholesterolemia (HeFH), or
  • Non-familial hypercholesterolemia (non-FH) with atherosclerotic cardiovascular disease (ASCVD).

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

Hypercholesterolemia is a common type of dyslipidemia characterized by increased levels of LDL-C. Persistently elevated levels of LDL-C can be deleterious to the cardiovascular health. The accumulation of LDL-C on the artery walls can contribute to the initiation and progression of atherosclerotic plaques (chronic inflammatory disorder in the vessel). These plaques can cause narrowing of the arteries, thereby obstructing the blood flow, and can be associated with cardiovascular morbidity (myocardial infarction, stroke, and heart failure) and mortality.

Hypercholesterolemia can be caused by genetic and environmental factors or it can develop secondary to an underlying disease. The most common autosomal codominant disorder that causes elevated LDL-C is HeFH. The risk of ASCVD in patients with familial hypercholesterolemia (FH) is 10- to 20-fold that of a normolipidemic individual. Atherosclerotic cardiovascular disease includes clinical conditions of atherosclerotic origin, such as acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary artery disease documented by angiography, coronary or other arterial revascularization, stroke, transient ischemic attack, documented carotid disease, peripheral artery disease, and abdominal aortic aneurysm.

Approximately 145,000 Canadians are estimated to have FH. Based on data from 2012 to 2013 (the most recent data available from the surveillance system), 1 in 12 Canadian adults 20 years of age and older (about 2.4 million) live with ischemic heart disease. In 2012, heart disease was the second leading cause of death in Canada and the leading cause of death globally.

Statins (3-hydroxy-3-methyl glutaryl-coenzyme A [HMG-CoA] reductase inhibitors) are indicated as standard-of-care therapy, as an adjunct to lifestyle changes, including diet, for the management of dyslipidemia in hyperlipidemic and dyslipidemic conditions. When the response to diet and other non-pharmacological measures alone has been inadequate and patients require additional lowering of LDL-C despite use of standard-of-care therapy, second-line therapy includes ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies, fibrates and bile acid-sequestering resins, and microsomal triglyceride transfer protein inhibitors.

Leqvio is a subcutaneously administered PCSK9 inhibitor, intended to lower LDL-C in patients with hypercholesterolemia. The medicinal ingredient in Leqvio, inclisiran, is a double-stranded small interfering ribonucleic acid (siRNA) that causes the degradation of PCSK9 messenger RNA (mRNA). Inclisiran is conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes and selectively target asialoglycoprotein receptors in the liver. Proprotein convertase subtilisin/kexin type 9 is predominantly produced in the cytoplasm of liver cells by cellular machinery that translates PCSK9 mRNA into proteins. A natural cellular mechanism called RNA interference is responsible for regulating the production of this and other proteins in a highly specific way. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte surface, which generally results in lowering of serum LDL-C levels in the circulation.

The safety and efficacy of Leqvio was primarily supported by three randomized, double-blind, placebo-controlled Phase III trials (ORION-9, ORION-10, and ORION-11) that enrolled 3,655 patients with HeFH (ORION-9), or patients with non-FH with ASCVD or at a high risk to develop these diseases (ORION-10 and ORION-11). In all studies, patients were followed for 18 months, taking a maximally tolerated dose of statins (i.e., a maximum dose of statin that can be taken on a regular basis without intolerable adverse events) with or without other lipid-modifying therapies (such as ezetimibe). The co-primary endpoints in each study were the percentage change in LDL-C from baseline to Day 510 relative to placebo and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 to estimate the integrated effect on LDL-C over time.

Patients were administered subcutaneous injections of Leqvio (284 mg) or placebo on Day 1, Day 90, Day 270, and Day 450. In all pivotal trials, Leqvio was shown to statistically significantly reduce LDL-C levels compared to placebo (p<0.0001). In the ORION-9 study (number of patients [n] = 482), Leqvio led to a significant mean percentage change in LDL-C from baseline to Day 510 of -40% compared to a change of +8% in patients receiving placebo. In the ORION-10 study (n = 1561), Leqvio demonstrated a significant change in LDL-C from baseline to Day 510 of -51% compared to a +1% change in patients receiving placebo. A consistent reduction in LDL-C was also observed in the ORION-11 study (n = 1,617) with the mean percentage change in LDL-C from baseline to Day 510 being -46% in Leqvio-treated patients compared to +4% in placebo-treated patients. The time-adjusted LDL-C changes (ORION-9, ORION-10, and ORION-11) in the Leqvio treatment groups were -38%, -51%, and -46% compared to +6%, +3%, and +3%, respectively, in the placebo groups. The treatment benefit for both co-primary endpoints was consistent across all the different subgroups regardless of baseline patient characteristics, including age, race, gender, region, body mass index, smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status (i.e., diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, and baseline triglycerides. The majority of patients maintained an LDL-C reduction under a Leqvio dosing regimen (every 6 months after initial doses on Day 1 and Day 90).

The overall safety profile of Leqvio is considered favourable for use in the population studied. Leqvio was generally well tolerated. Injection-related reactions were the most commonly reported adverse reactions. In the placebo-controlled studies, adverse reactions at the injection site occurred in 8.2% of Leqvio-treated patients and 1.8% of placebo-treated patients. These adverse reactions were generally mild in severity and resolved over time.

The effect of Leqvio on cardiovascular outcome, such as heart attacks, stroke, or death, is not known. Therefore, Leqvio is an add-on therapy to statins, a therapy with known effect, in reducing the risk of heart attacks and strokes in patients who require LDL-C reduction.

Cautionary statements have been included in the Leqvio Product Monograph to address identified safety issues and uncertainties.

A Risk Management Plan (RMP) for Leqvio was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. 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. Upon review, Health Canada has required additional post-approval activities to be carried in order to ensure that the benefit of Leqvio continues to outweigh any risk after authorization of the drug.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Leqvio Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements. A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Leqvio was accepted.

Overall, the efficacy, safety, and quality data demonstrate that Leqvio has a favourable benefit-risk profile in the target patient population to be treated.

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.

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

 

3 What steps led to the approval of Leqvio?

 

The New Drug Submission for Leqvio was reviewed under the New Active Substance Work Sharing Initiative (NASWSI) of the Australia, Canada, Singapore, Switzerland, and United Kingdom (Access) Consortium, a work-sharing initiative. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

This submission was reviewed jointly. Health Canada completed the clinical data review of Leqvio, while Singapore’s Health Science Authority completed the non-clinical data review and Australia's Therapeutic Goods Administration completed the quality data review. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

 

Submission Milestones: Leqvio

Submission Milestone Date
Pre-submission meeting 2020-06-16
Submission filed 2020-08-31
Screening  
Screening Acceptance Letter issued 2020-09-30
Review  
Review of Risk Management Plan complete 2021-06-20
Biostatistics Evaluation complete 2021-06-21
Labelling Review complete 2021-07-20
Quality Evaluation complete 2021-07-21
Non-Clinical Evaluation complete 2021-07-22
Clinical/Medical Evaluation complete 2021-07-23
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2021-07-26

 

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

 

4 What follow-up measures will the company take?

 

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

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Leqvio 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

The medicinal ingredient in Leqvio, inclisiran, is a double-stranded small interfering ribonucleic acid (siRNA) that causes the degradation of proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA). Inclisiran is conjugated on the sense strand with triantennary N acetylgalactosamine to facilitate uptake by hepatocytes and selectively target asialoglycoprotein receptors in the liver. Proprotein convertase subtilisin/kexin type 9 is predominantly produced in the cytoplasm of liver cells by cellular machinery that translates PCSK9 mRNA into proteins. A natural cellular mechanism called RNA interference is responsible for regulating the production of this and other proteins in a highly specific way. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases low-density lipoprotein cholesterol (LDL-C) receptor recycling and expression on the hepatocyte surface, which generally increases LDL-C uptake and lowers LDL-C levels in the circulation. The mechanism of action of inclisiran also includes long-term intracellular presence in hepatocytes (>42 days in monkeys and >98 days in rats after a single administration), after it is cleared from the plasma, which contributes to its long duration of effect in lowering LDL-C.

The pharmacokinetic and pharmacodynamic properties of inclisiran were assessed in four clinical pharmacology Phase I studies conducted in healthy subjects and subjects with hepatic and renal impairment. The clinical pharmacological program was considered acceptable to support the use of Leqvio for the specified indication. Despite an increase in drug exposure, no dose adjustment is necessary for patients with mild or moderate hepatic or renal impairment. Based on the limited data available, clinically meaningful interactions with atorvastatin, rosuvastatin, or simvastatin are not expected.

The effects of inclisiran on inhibiting PCSK9 and lowering LDL-C were assessed in one Phase II and three Phase III studies described in the Clinical Efficacy section.

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

Clinical Efficacy

The clinical efficacy of Leqvio was investigated in three, double-blind, placebo-controlled, Phase III studies (ORION-9, ORION-10 and ORION-11) that enrolled 3,655 patients with heterozygous familial hypercholesterolemia (HeFH), patients with non-familial hypercholesterolemia with atherosclerotic cardiovascular disease (ASCVD), or ASCVD risk equivalents (defined as type 2 diabetes, HeFH, and a 10-year risk of a cardiovascular event assessed by the Framingham Risk Score or equivalent with a target LDL-C of <2.6 mmol/L) who required additional LDL-C lowering despite the use of maximally tolerated statins or other lipid-lowering therapies.

Patients were administered subcutaneous injections of Leqvio (284 mg) or placebo on Day 1, Day 90, Day 270, and Day 450. The ORION-9 study was conducted exclusively in patients with HeFH. The ORION-10 and ORION-11 studies were conducted in patients with ASCVD and ASCVD risk equivalents (13% of patients were ASCVD risk equivalent). All patients required additional LDL-C lowering despite background lipid-modifying therapy consisting of a maximum tolerated dose of statin (i.e., a maximum dose of statin that can be taken on a regular basis without intolerable adverse events), with or without other lipid-modifying therapies. In the studies that enrolled patients with HeFH, the diagnosis of HeFH was made by either genotyping or clinical criteria (defined as "definite FH" using either the Simon Broome or World Health Organization/Dutch Lipid Network criteria). All studies were at least 18 months (540 days) in duration with the co-primary endpoints in each study being the percentage change in LDL-C from baseline to Day 510 relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 to estimate the integrated effect on LDL-C over time.

In all pivotal studies, Leqvio was shown to statistically significantly reduce LDL-C levels compared to placebo (p<0.0001). In the ORION-9 study (number of patients [n] = 482), the mean percentage change in LDL-C from baseline to Day 510 was -40% in Leqvio-treated patients compared to +8% in placebo-treated patients. In the ORION-10 study (n = 1,561), the mean percentage change in LDL-C from baseline to Day 510 was -51% in Leqvio-treated patients compared to +1% in placebo-treated patients. Similarly, in the ORION-11 study (n = 1,617), the mean percentage change in LDL-C from baseline to Day 510 was -46% in Leqvio-treated patients compared to +4% in placebo-treated patients. This magnitude of effect is considered clinically meaningful. Leqvio was also shown to reduce the levels of PCSK9, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol.

The treatment benefit for both co-primary endpoints was consistent across all the different subgroups analyzed, irrespective of baseline demographics, baseline disease characteristics (including gender, age, body mass index, race, and baseline statin use), comorbidities, and geographic regions.

The efficacy results obtained from these three pivotal studies have been extensively validated and are based on robust statistical methods.

Indication

The New Drug Submission for Leqvio was filed by the sponsor with the following indication:

Hypercholesterolemia

Leqvio is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial), as an adjunct to diet:

  • in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein cholesterol (LDL-C) goals with the tolerated dose of a statin or,
  • alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

Health Canada revised the proposed indication to more accurately represent the patient populations studied in the pivotal trials for which sufficient evidence was provided to demonstrate a positive benefit-risk profile. Accordingly, Health Canada approved the following indication:

Primary hypercholesterolemia

Leqvio is indicated as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) level in adults with the following conditions who are on maximally tolerated dose of a statin, with or without other LDL-C-lowering therapies:

  • Heterozygous familial hypercholesterolemia (HeFH), or
  • Non-familial hypercholesterolemia with atherosclerotic cardiovascular disease

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

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

Clinical Safety

Overall, the drug submission provided clinical data (Phase I, Phase II, and Phase III studies) from 4,330 subjects in the safety population, encompassing 2,450 subjects who received Leqvio at any dose and 2,118 subjects who received Leqvio at the recommended dose of 284 mg. However, the clinical safety of Leqvio administered in conjunction with a statin was primarily evaluated in the three pivotal placebo-controlled Phase III studies (ORION-9, ORION-10, and ORION-11) described in the Clinical Efficacy section, totalling 3,655 subjects (pooled safety population). These 18-month duration studies were nearly identical in design to enable data pooling where appropriate.

Among the 1,833 patients in the pooled safety population who were treated with a dose of 284 mg Leqvio, treatment-emergent adverse events (TEAEs) and serious adverse events were similar compared to the placebo groups, with a few exceptions.

In the pooled safety population, adverse events at the injection site occurred in 8.2% and 1.8% of Leqvio-treated and placebo-treated patients, respectively. The most commonly reported adverse reactions associated with Leqvio in the clinical trials were local injection site reactions (including pain, rash, and bruising). All of these adverse drug reactions were mild or moderate in severity, transient, and resolved without sequelae. Additional TEAEs that occurred more frequently in the Leqvio-treated patients, compared to placebo, were diabetes mellitus, nasopharyngitis, arthralgia, back pain, urinary tract infection, diarrhea, bronchitis, cough, headache, angina pectoris, dizziness, pain in extremity, and dyspnea. Most of the TEAEs were of mild to moderate intensity. Treatment discontinuation due to adverse events occurred in 0.7% (12/1,833) of Leqvio-treated patients and was comparable to the rate of treatment discontinuation in the placebo group. The most commonly reported causes of death were associated with cardiac disorders, which is expected for the studied population.

Additional safety issues identified in the pooled safety population analysis, and considered potential safety risks due to a higher frequency of events observed in patients receiving Leqvio compared to placebo (Leqvio versus [vs.] placebo) included: 1) elevations of serum hepatic transaminases between >1x the upper limit of normal (ULN) and ≤3x the ULN (alanine aminotransferase [ALT]: 19.7% and aspartate aminotransferase [AST]: 17.2% vs. ALT: 13.6% and AST: 11.1%); 2) increase in hemoglobin A1C (18.7% vs. 15.6%) and worsening of glycemic control (25.2% vs. 21.7%); and 3) increase in bronchitis (4.26% vs. 2.74%) or lower respiratory tract infections (1.85% vs. 1.45%).

Approximately 30% of Leqvio-treated patients had an LDL-C of <0.65 mmol/L (25 mg/dL) at least at one time point, and 14% of patients had an LDL-C of <0.65 mmol/L at two consecutive occasions. The safety profile of Leqvio in patients reaching a sustained LDL-C of <0.65 mmol/L compared with the remaining study patients showed a higher incidence of adverse events related to hypersensitivity and new onset/worsening of diabetes. The long-term effects of very low levels of LDL-C induced by Leqvio are unknown.

With all oligonucleotides, there is a potential for immunogenicity. In the controlled clinical Phase III studies, 4.9% of the patients treated with Leqvio had a treatment-emergent anti-drug antibody (ADA) response as compared to 1.8% of patients with confirmed positivity prior to dosing. No clinically significant differences in the clinical safety or pharmacodynamic profiles of Leqvio were observed in the patients who tested positive for ADAs. Efficacy based on reductions in LDL-C was mostly similar in patients with or without ADAs. However, some Leqvio-treated patients with persistent or transient antibodies experienced attenuation in LDL-C efficacy. Attenuation in LDL-C efficacy was also observed in patients with no confirmed positive ADAs. Long-term immunogenicity with subsequent injections is unknown since the observation period was limited to 18 months (four injections) in these studies.

The effect of Leqvio on cardiovascular morbidity and mortality has not yet been determined. Exploratory analysis demonstrated that the incidence of major cardiovascular events (MACE) such as cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, and stroke (ischemic and hemorrhagic) was 7.1% in Leqvio-treated patients compared to 9.4% in placebo-treated patients. Non-fatal myocardial infarction was the driving component of the composite and the incidence of cardiovascular death was numerically higher with Leqvio (18 patients) compared to placebo (15 patients). The reduction of cardiovascular risk is being assessed in an ongoing study of 15,000 patients where the primary endpoint is MACE (consisting of coronary heart disease death, myocardial infarction, fatal or non-fatal ischemic stroke, and urgent coronary revascularization procedure).

The long-term safety, use in pregnancy and breastfeeding, and use in patients with severe hepatic impairment and end stage renal failure were characterized as safety concerns with missing information. Patients with severe renal impairment were an under-represented patient group for which a benefit/risk profile could not be established. Two ongoing studies in patients at high risk of developing cardiovascular disease are investigating long-term safety and tolerability of Leqvio.

In summary, the safety profile of Leqvio is considered acceptable for the target patient population.

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

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Overall, the non-clinical pharmacology (primary pharmacology and safety), pharmacokinetic, and general toxicity data reviewed were reassuring regarding the safety and pharmacological benefit of Leqvio. Studies were conducted in pharmacologically relevant species (rats, rabbits, and monkeys) using subcutaneously administered Leqvio, reflecting the intended route of administration in human clinical studies.

No significant adverse effects were observed in rats, rabbits, and monkeys when Leqvio was administered up to doses of 300 mg/kg once per month for 40 weeks. A common terminal pathology finding across species is the histological presence of basophilic granules in the liver (target organ), the kidney (primary excretion pathway), macrophages, and lymph nodes. These observations are believed to be common to all oligonucleotides (antisense oligonucleotides and small interfering ribonucleic acid), representing histological evidence of intracellular oligonucleotide accumulation, and did not result in adverse events.

Leqvio has a low potential for drug-drug interactions since it is not metabolized by classical pathways (cytochrome P450 enzymes and uridine 5′-diphospho-glucuronosyltransferases), nor does it interact with transporters. When Leqvio (300 mg/kg, every four weeks) was administered concomitantly with atorvastatin (40 mg/kg, then 25 mg/kg, once daily) in monkeys for 85 days, there were no clinical observations attributed to the interaction between Leqvio and atorvastatin.

In a two-year carcinogenicity study in rats subcutaneously administered 250 mg/kg of Leqvio once per month, there was no evidence for carcinogenicity.

Leqvio is present in maternal milk and crosses the placenta, being present in fetal plasma but not detected in the fetal liver. Incomplete ossification was observed in the embryo-fetal development study in rabbits administered 150 mg/kg of Leqvio (equivalent to 16-fold human exposure based on the area under the concentration-time curve). A theoretical concern exists for an effect of Leqvio on reduced bone remodelling, whereby the inhibition of PCSK9 in bone marrow adipocytes and/or bone progenitors leads to an intracellular accumulation of lipids and cellular dysfunction.

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

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

 

 

7.3 Quality Basis for Decision

 

The chemistry and manufacturing information submitted for Leqvio has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC).

Proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.

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

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

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

 

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