Regulatory Decision Summary for Leqvio

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

inclisiran sodium

Therapeutic area:

Lipid Modifying Agents

Type of submission:

New Drug Submission (New Active Substance)

Control number:

243470
What was the purpose of this submission?

This New Drug Submission (NDS) was filed to obtain market authorization for Leqvio (inclisiran sodium) to be used along with lifestyle changes including: diet, and maximally tolerated statin therapy, with or without other lipid lowering therapies, in adults with heterozygous familial hypercholesterolemia; or in adults with non-familial hypercholesterolemia with atherosclerotic cardiovascular disease who need additional lowering of low density lipoprotein cholesterol (LDL-C). 

The sponsor consented to information sharing between Health Canada and Canadian Agency for Drugs and Technologies in Health as part of an aligned review pathway.

This NDS was filed simultaneously with Therapeutic Goods Administration of Australia, Health Canada, and the Singapore Health Sciences Authority via the new active substance work sharing initiative of the Access Consortium. The review was jointly conducted; Health Canada reviewed the Clinical module, the Australian Therapeutic Goods Administration reviewed the Quality module, and Singapore Health Sciences Authority reviewed the Non-clinical module.

Why was the decision issued?

The safety and efficacy of Leqvio were primarily supported by three randomized, double-blind, placebo-controlled trials that enrolled 3,655 patients with heterozygous familial hypercholesterolemia (ORION 9), or patients with non-familial hypercholesterolemia with atherosclerotic heart diseases or at 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. maximum dose of statin that can be taken on a regular basis without intolerable adverse events) with or without other lipid-modifying therapy (such as ezetimibe). There were two primary endpoints used in each pivotal trial. The first co-primary endpoint was the percentage change in LDL-C from baseline to Day 510. The second co-primary endpoint was the average percentage of LDL-C change from baseline to each measure between the 2nd dose and the end of the study, to show consistent effects on LDL-C over time.

Patients were administered subcutaneous injections of Leqvio (284 milligrams) 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-value <0.0001). In ORION 9 (number of subjects [n] = 482), inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by -40% compared to +8% in the placebo group. In ORION 10 (n =1,561), Leqvio demonstrated a significant -51% LDL-C reduction from baseline at day 510 compared to +1% in patients receiving placebo. A consistent reduction in LDL-C was also observed in ORION 11 (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 averaged LDL-C reductions in the Leqvio treatment groups were -38%, -51% and -46% compared to +6%, +3% and +3%, respectively, in the placebo groups in the ORION 9, 10 and 11 studies. 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 (diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, and baseline triglycerides. The majority of patients maintained LDL-C reduction under Leqvio dosing regimen (every 6 months after initial doses at 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, with the most common risk identified being injection-related reactions. In the placebo-controlled studies, adverse reactions at the injection site occurred in 8.2% and 1.8% of Leqvio-treated versus 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 Product Monograph to address safety issues and uncertainties.

A Risk Management Plan (RMP) for Leqvio was submitted. The RMP was 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-authorization activities to be carried out in a revised RMP in order to ensure that the benefit of Leqvio continues to outweigh any risk after authorization.

In conclusion, the data on quality, safety and efficacy demonstrated that Leqvio had a favourable benefit/risk profile in the target patient population to be treated.

Decision issued

Authorized; issued a Notice of Compliance (NOC) in accordance with the Food and Drug Regulations.