Regulatory Decision Summary for Veklury

The indication for Veklury in the treatment of non-hospitalized adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death, was supported by the efficacy and safety data from a randomized, double-blind, placebo-controlled Phase 3 study GS-US-540-9012. This study included 562 patients with confirmed SARS-CoV-2 infection (symptomatic for COVID-19 for ≤7 days) and at least one risk factor for progression to hospitalization. Risks for disease progression included chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity, immunocompromised state, chronic mild or moderate kidney disease, chronic liver disease, current cancer, sickle cell disease or aged ≥ 60 years. Patients were randomized in a 1:1 manner, stratified by residence in a skilled nursing facility (yes/no), age (< 60 vs ≥ 60 years), and region (US vs ex-US) to receive Veklury (n=279; 200 mg once daily for 1 day followed by 100 mg once daily for 2 days) or placebo (n=283), plus standard of care. At baseline, mean age was 50 years (with 30% of patients aged 60 or older); 52% were male, 80% were White, 8% were Black, and 2% were Asian; 44% were Hispanic or Latino; median body mass index was 30.7 kg/m². Patients in this trial were unvaccinated. The most common comorbidities were diabetes mellitus (62%), obesity (56%), and hypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3, 6) days; median viral load was 6.3 log₁₀ copies/mL at baseline. The baseline demographics and disease characteristics were well balanced across the Veklury and placebo treatment groups.

The primary endpoint was the proportion of patients with COVID-19 related hospitalization (defined as at least 24 hours of acute care) or all-cause mortality through Day 28. Events occurred in 2 (0.7%) patients treated with Veklury compared to 15 (5.3%) patients concurrently randomized to placebo, demonstrating an 87% relative reduction in COVID-19 related hospitalization or all-cause mortality through Day 28 compared to placebo (hazard ratio, 0.134; [95% CI 0.031 to 0.586]; p=0.0076). No deaths were observed through Day 28. Adverse reactions (all grades) were reported in 34 (12%) patients in the Veklury group and 25 (9%) patients in the placebo group. The most common adverse reaction occurring in at least 5% of patients in the Veklury group was nausea (6%). There were no serious adverse reactions or adverse reactions leading to treatment discontinuation in either treatment group.

The pharmacokinetic exposure of remdesivir and its metabolites in non-hospitalized COVID-19 patients was consistent with that of healthy participants administered a 200 mg loading dose on Day 1 followed by 100 mg daily maintenance doses for 5 to 10 days.

Based on the data reviewed above, it is considered that the benefit-risk-uncertainty profile of Veklury is favorable in the treatment of non-hospitalized adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progression to severe COVID-19, including hospitalization or death. The approved updated Product Monograph includes information on recommended use of Veklury in this patient population. Since study GS-US-540-9012 included only 8 pediatric patients (12 years of age and older and weighing at least 40 kg), these patients are not included in the authorized indication for non-hospitalized patients.

Based on the evidence submitted in this SNDS, Health Canada has not been able to determine the benefit of Veklury in the treatment of COVID-19 in hospitalized adults with pneumonia not requiring supplemental oxygen. Specifically, the following was noted:

• The risk of bias could not be excluded in the pivotal Phase 3 study GS-US-540-5774 (Simple Moderate; Part A) due to an open label design of this trial and changes in the primary efficacy endpoint that were made when the trial was already ongoing. In addition, there was no plausible reason why a 10-day course of remdesivir led to worse outcomes than a 5-day course with respect to the primary efficacy endpoint (clinical status assessed by a 7-point ordinal scale on Day 11), taking into account that the median exposure to remdesivir was similar in both treatment groups, i.e. 5 days versus 6 days. Furthermore, remdesivir did not demonstrate a statistically significant effect on other efficacy endpoints such as duration of hospitalization, time to clinical improvement ≥ 2-Points, time to clinical improvement ≥ 1-Point, time to recovery or death.
• In the supportive study GS-US-540-5776 (ACTT-1), the number of patients with COVID-19 pneumonia not requiring supplemental oxygen (mild/moderate disease subgroup; 55 in the remdesivir group and 50 in the placebo group) was too small for a meaningful analysis of efficacy. In addition, in this group of patients, remdesivir did not demonstrate a statistically significant effect on the primary efficacy endpoint of time to recovery (the median time to recovery was 5 days in both remdesivir and placebo groups) or key secondary endpoint of odds of improvement in clinical status on Day 15.

Therefore, the indication in the treatment of COVID-19 in hospitalized adults with pneumonia not requiring supplemental oxygen was not authorized.