Regulatory Decision Summary for Verquvo

This New Drug Submission (NDS) was filed to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Verquvo (vericiguat) to reduce the risk of cardiovascular death and heart failure hospitalization in adults with symptomatic chronic heart failure with reduced ejection fraction (less than 45%) who are stabilized after a recent worsening heart failure event (a hospitalization for heart failure or need for outpatient intravenous diuretics), in combination with other heart failure therapies.

The effect of Verquvo was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase 3 study (VICTORIA). A total of 5,050 adult patients with symptomatic chronic heart failure and reduced ejection fraction (HFrEF) were randomized to receive Verquvo (n = 2,526) or matching placebo (n = 2,524) to background guideline-directed HFrEF therapies following a worsening heart failure event (heart failure hospitalization [HFH] within 6 months before randomization or use of outpatient intravenous [IV] diuretics for hear failure within 3 months before randomization). The starting treatment dose was 2.5 milligrams (mg) once daily to a maximum of 10 mg daily, based on tolerability. The mean duration of treatment was one year (maximum of 2.6 years). The primary endpoint was a composite of death from cardiovascular causes or first hospitalization for heart failure.

The majority of subjects were male (76.1%), of white race (64.1%), and were enrolled within 3 months of a HFH event (67%). The mean age was 67.3 years, and 31% were 75 years of age and older at baseline. The median baseline left ventricular ejection fraction (LVEF) and natriuretic peptides N-terminal proBNP (NT-proBNP) was 30% and 2,816 picograms per milliliter (pg/mL), respectively. Baseline characteristics were generally balanced between the Verquvo and placebo groups.

The efficacy results showed that Verquvo was superior to placebo on the primary composite endpoint by reducing the incidence of cardiovascular (CV) death or HFH, based on a time-to-event analysis (hazard ratio [HR]: 0.90, 95% confidence interval [CI], 0.82-0.98; p = 0.019). The treatment effect was mainly driven by a reduction in HFHs (HR 0.90, 95% CI: 0.81-1.00, p = 0.048). Cardiovascular death also contributed to the treatment effect; however, this difference did not achieve statistical significance (HR 0.93, 95% CI 0.81-1.06, p = 0.269). The treatment effect on the primary composite endpoint was generally consistent across pre-defined subgroups. As an apparent exception, there was an increased risk of CV death (HR 1.16, 95% CI: 0.95, 1.43) and HFH (HR 1.19, 95% CI: 0.9, 1.44) in patients with a markedly elevated serum NT-proBNP levels (greater than 5,314 pg/mL) at baseline that did not appear to be adequately stabilized before Verquvo use. To mitigate the risks in this subgroup, warnings were added to the Product Monograph, including a statement that patients should be stabilized by a healthcare professional who is experienced in the management of heart failure before Verquvo use (particularly high NT-proBNP patients).

Verquvo was generally well-tolerated. The most commonly reported adverse reactions were hypotension (16.4% of patients receiving Verquvo vs. 14.9% of patients receiving placebo), anemia (9.6% of patients receiving Verquvo vs. 7.4% of patients receiving placebo) and dizziness (6.7% of patients receiving Verquvo vs. 6.0% of patients receiving placebo). The most frequently reported adverse reaction leading to discontinuation of treatment was hypotension. The safety concerns and uncertainties were addressed with appropriate risk minimization measures in the Product Monograph as well as pharmacovigilance activities in the Risk Management Plan (RMP). The overall safety profile of Verquvo is considered acceptable under the conditions of use approved.

The information submitted and reviewed with respect to Chemistry and Manufacturing was considered acceptable and in accordance with the Health Canada Guidance Document: Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) requirement.

The RMP submitted for Verquvo was considered to be acceptable to ensure that the benefit of Verquvo continues to outweigh any risk after authorization. The RMP describes known and potential safety issues, presents the monitoring scheme, and describes measures that will minimise risks associated with the product.

The overall benefit-harm-uncertainty profile is favourable for Verquvo for the recommended indication, therefore a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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