Regulatory Decision Summary for Veklury

Veklury contains remdesivir, which is a nucleotide analogue prodrug with in vitro activity against SARS-CoV-2, the coronavirus that causes COVID-19.

Veklury is formulated as 100 mg powder for solution for infusion and 100 mg solution for infusion. The recommended dosing of Veklury is 200 mg on Day 1 and 100 mg per day for up to 9 additional days. Use of Veklury is confined to healthcare facilities in which patients can be monitored closely.

The indication for Veklury is supported primarily by the safety and efficacy data from the interim analysis of a randomized, double-blind, placebo-controlled clinical trial NIAID ACTT-1 (CO-US-540-5776). Additional evidence is from the placebo-controlled China-severe study (GS-US 540-5758), two open-label SIMPLE-studies (GS-US-540-5773 in severe COVID-19 and GS-US-540-5774 in moderate COVID-19) and compassionate use of remdesivir.

The NIAID ACTT-1 trial evaluated Veklury 200 mg once daily for 1 day followed by Veklury 100 mg once daily for up to 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalized adult patients with COVID-19 with evidence of lower respiratory tract involvement. The trial enrolled 1,063 hospitalized patients: 120 (11.3%) patients with mild/moderate disease (defined by SpO2 >94% and respiratory rate <24 breaths/min without supplemental oxygen) and 943 (88.7%) 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, stratified by disease severity at enrolment, to receive Veklury (n = 541) or placebo (n = 522), plus standard of care.

The primary clinical endpoint was time to recovery within 28 days after randomization, defined as either discharged from hospital (with or without limitations of activity and with or without home oxygen requirements) or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. In an analysis performed after all patients had been followed up for 14 days, the median time to recovery in the overall population was 11 days in the Veklury group compared to 15 days in the placebo group (recovery rate ratio 1.32; [95% CI 1.12 to 1.55], p<0.001). The outcome differed between the two strata. In the severe disease stratum time to recovery was 12 days in the Veklury group and 18 days in the placebo group (recovery rate ratio 1.37 [95% CI: 1.15 to 1.63]). For the mild/moderate disease stratum, time to recovery was not different between the two groups (5 days for both, Veklury and placebo). There was no difference in efficacy in patients randomized during the first 10 days after onset of symptoms as compared to those with symptoms for more than 10 days. The clinical benefit of Veklury was most apparent in patients receiving oxygen, but not on ventilation, at Day 1 (rate recovery ratio 1.47 [95% CI 1.17 to 1.84]). For patients who were receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) on Day 1 no difference in recovery rate was observed between the treatment groups (0.95 [95% CI 0.64 to 1.42]). The data for the key secondary endpoint, i.e. mortality at Day 28, were not available at the time of this review.

The placebo-controlled China-severe study was terminated early due to a low enrollment. This study failed to show efficacy of Veklury with respect to time to clinical improvement at Day 14 as well as Day 28 mortality.

The SIMPLE-severe and SIMPLE-moderate studies have important deficiencies in design such as lack of blinding (both studies) and placebo arm (SIMPLE-severe). The SIMPLE-severe study showed no difference in efficacy between Veklury administered for 5 days vs. Veklury administered for 10 days.

No adolescents (12 years of age and older and weighing ≥40 kg) were included in the available clinical trials with Veklury. The indication for this group of patients is supported by a physiologically based pharmacokinetic (PBPK) modelling study that predicted similar disposition of remdesivir and its metabolites in adolescents as compared to adults.

A clinical proof-of-concept for antiviral activity of remdesivir has not been established. The China-severe and SIMPLE-moderate studies investigated SARS-CoV-2 RNA in nasopharyngeal swabs as an additional endpoint, but failed to show any change in patients administered Veklury.

Veklury was generally well tolerated in the clinical trials in patients with COVID-19. The most common adverse reactions were increased transaminases, nausea, headache and rash. Other adverse reactions included infusion-related reactions and hypersensitivity reactions. In the NIAID ACTT-1 study, no increase in serious adverse events or discontinuations due to an adverse event were reported for Veklury as compared to placebo.

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

The Risk Management Plan for Veklury has been submitted and it is considered acceptable. The important identified and potential risks, as well as clinical outcomes in different populations, will be monitored post-market.

The efficacy and safety of Veklury in the treatment of COVID-19 have not been fully characterized at this time because the available clinical trial data are not comprehensive. Specifically, no clinical study report (CSR) was available for any of the COVID-19 clinical trials and the data available from these studies were limited to study protocols and preliminary and/or topline results.

However, given the high unmet medical need and emergency context of the COVID-19 pandemic, Health Canada considered the balance of benefit and harm for Veklury to be positive. A Notice of Compliance with Conditions has been issued for the indication 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. The data provided in the submission have not established the efficacy of Veklury in patients with moderate COVID-19.

The quality of Veklury lots manufactured to date is considered to be suitable for its intended use. However, some uncertainty remains regarding the ability of the control strategy to consistently produce drug substance and drug product of acceptable quality that is comparable to the clinical lots.

The following conditions apply to the Veklury authorization to ensure the continued safety, efficacy and quality of this drug:

• To confirm the safety and efficacy of Veklury in the treatment of COVID-19, the sponsor should provide the final CSRs from studies NIAID ACTT-1, SIMPLE-severe, and SIMPLE-moderate as well as the Integrated Summary of Safety and CSRs from studies in hepatic and renal impairment. In addition, the sponsor should provide reports of post-market safety monitoring activities, including monthly safety reports until the time of submission of the first Periodic Benefit-Risk Evaluation Report (PBRER) or Periodic Safety Update Report (PSUR), reports on all serious adverse drug reactions (ADRs) that occurred in Canada and serious unexpected ADRs that occurred outside of Canada, annual pregnancy safety reports, PBRERs or PSURs every 6 months for the first 2 years of marketing in Canada and any foreign regulatory actions related to the safety of remdesivir.
• The sponsor is required to provide additional quality data related to, but not limited to, the drug substance and drug product manufacturing information and controls.

For more information on Health Canadas decision, please view the Summary Basis of Decision.