Regulatory Decision Summary for Winrevair

This Supplement to a New Drug Submission (SNDS), was filed under the Priority Review of Drug Submissions policy with the purpose of obtaining marketing authorization for an expanded indication for Winrevair (sotatercept) for patients with severe pulmonary arterial hypertension (PAH) World Health Organization (WHO) Group 1 and Functional Class (FC) IV at high risk of mortality.

In this Supplement to a New Drug Submission (SNDS), the sponsor sought to obtain market approval for an expanded indication for Winrevair (sotatercept) to include patients with Pulmonary Arterial Hypertension (PAH) Functional Class IV.

In a Phase 3, randomized, double blind, placebo-controlled trial (ZENITH trial), Winrevair was shown to reduce the risk by 76% for all-cause of death, lung transplantation or PAH worsening-related hospitalization ≥24 hours compared to placebo. Data from the secondary endpoints (e.g., overall survival, transplant-free survival) as well as from functional status (e.g., 6-minute walk distance) and hemodynamic outcomes (e.g., mean pulmonary arterial pressure, and pulmonary vascular resistance) supported the primary endpoint findings. Overall, the efficacy data supported the use of sotatercept in FC IV PAH patients through delay in disease progression, reduce clinical deterioration, and may confer a survival advantage in patients with severe PAH who have limited therapeutic alternatives.

The safety profile of sotatercept was generally acceptable, tolerable, and manageable with dose reductions or delays in drug administration. It was also found to be consistent with the established safety profile of sotatercept as concluded in the previous trials supporting the approval for patients with PAH FC II and III. No new or unexpected safety concerns were identified for sotatercept in the ZENITH trial. The proportion of patients with at least one adverse event (AE) was similar in the sotatercept and placebo groups (98.8% and 96.5%, respectively). However, the proportion of patients with drug-related AEs was higher in the sotatercept group compared with the placebo group (65.1% vs. 32.6%). Drug-related AEs were mostly due to bleeding events with higher incidences observed with sotatercept compared to placebo: gingival bleeding (10.5% vs. 2.3%) and epistaxis (44.2% vs. 9.3%). Although mucosal bleeding events were non-serious and generally mild or moderate in severity, their notable incidence suggests a treatment-related effect and consequently these events were included in the Warnings and Precautions section of the PM.

The totality of evidence from the ZENITH trial supports a favorable benefit-risk profile for the use of sotatercept in combination with standard PAH therapy in patients with severe PAH FC IV at high risk of mortality.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Winrevair for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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