Regulatory Decision Summary for Veklury

The initial conditional authorization of Veklury was based on the efficacy and safety data from the interim analysis of a Phase 3 randomized, double-blind, placebo-controlled clinical trial CO-US-540-5776 (ACTT-1). In this SNDS-C, the final Clinical Study Report (CSR) from this trial was provided. The trial enrolled 1,063 hospitalized patients, including approximately 10% patients with mild-to-moderate disease (defined by saturation of peripheral oxygen (SpO2) >94% and respiratory rate <24 breaths/min without supplemental oxygen) and approximately 90% patients with severe disease (defined by SpO2 ≤94% on room air, or respiratory rate ≥24 breaths/min and requiring supplemental oxygen or ventilatory support). Patients were randomized 1:1 and stratified by baseline disease to receive Veklury (n=541) or placebo (n=521), plus standard of care (SOC). Veklury was administered intravenously at 200 mg on Day 1 day and at 100 mg once daily for up to 9 additional days.

Overall, the final efficacy and safety results from the ACTT-1 study were consistent with the interim results. The primary efficacy endpoint was time to recovery within 29 days after randomization defined as either discharged from hospital (with or without limitations of activity and with or without oxygen requirements) or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery in the overall population was 10 days in the Veklury group and 15 days in the placebo group (recovery rate ratio 1.29; [95% confidence interval (CI) 1.12 to 1.49]; p <0.001). The clinical outcomes differed between patients with mild to moderate and severe disease at enrolment. No difference in time to recovery was observed between the treatment groups for patients with mild to moderate disease; the median time to recovery was 5 days in the Veklury group and 7 days in the placebo group (recovery rate ratio 1.10; [95% CI 0.8 to 1.53]). Among patients with severe disease, the median time to recovery was 11 days in the Veklury group compared to 18 days in the placebo group (recovery rate ratio, 1.31; [95% CI 1.12 to 1.52]; p <0.001). The clinical benefit for patients with severe disease was primarily observed in patients receiving supplemental oxygen. No difference in median time to recovery was observed between the treatment groups for patients who were receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at enrolment; median time to recovery in these patients was 29 days in the Veklury group and 28 days in the placebo group (recovery rate ratio 0.98; [95% CI 0.70 to 1.36]). Veklury had no statistically significant effect on the 29-day mortality rate as compared to placebo (hazard ratio, 0.73; [95% CI 0.52 to 1.03]; p = 0.07).

Veklury was well tolerated in ACTT-1 trial. Adverse events (AEs) were reported in 57% of patients in the Veklury group and 63% of patients in the placebo group. The most common AEs in the Veklury and placebo groups were decreased glomerular filtration rate (11% and 15%, respectively), blood creatinine increased (6.0% and 7%) decreased hemoglobin (9.0% and 12%), anemia and lymphocyte count decreased (each 8.0% and 10%), respiratory failure (7.0% and 12%), pyrexia (7.0% and 7.0%), hyperglycemia (6.0% and 7.0%), increased blood glucose level (7.0% and 5.0%), acute kidney injury (5.0% and 6.0%), alanine transaminase (ALT) increased (2.0% and 5.0%) and aspartate aminotransferase (AST) increased (3.0% and 6.0%).

The incidence of Grade 3 or Grade 4 AE of prothrombin time increased was higher in the Veklury group (9%) as compared to the placebo group (4%). Similarly, the incidence of the AE of international normalized ratio (INR) increased, predominantly Grade1 or Grade 2, was higher in the Veklury group (13%) as compared to the placebo group (5%). There was no difference observed in the incidence of bleeding events between the two groups (2.1% in the Veklury group and 1.9% in the placebo group).

Serious AEs occurred in 25% of patients in the Veklury group and 32% of patients in the placebo group. AEs leading to discontinuation of study treatment were reported in 11% of patients in the Veklury group 15% of patients in the placebo group. There were no treatment-related deaths, as judged by the site investigators.

Limited or no data are available for use of Veklury in renal impairment, hepatic impairment, and pregnancy. In addition, no clinical drug interactions studies were conducted with Veklury. The Veklury Product Monograph includes adequate recommendations to mitigate the risk of using Veklury in these populations.

Based on the data submitted, Health Canada considers that the benefit-harm-uncertainty profile of Veklury in the treatment of COVID-19 in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen remains favourable when used as directed in the Veklury Product Monograph at this time. The conditions related to submission of confirmatory Phase 3 clinical trial evidence were removed from the Notice of Compliance (NOC) for Veklury.