Summary Basis of Decision for Veklury

 

Clinical Pharmacology

Limited clinical pharmacology data are available for remdesivir, the medicinal ingredient in Veklury.

The pharmacokinetic properties of remdesivir have only been studied in healthy adult volunteers. Pharmacokinetic data of remdesivir in adult and pediatric patients with coronavirus disease 2019 (COVID-19) are not available.

Following intravenous administration over 30 min, peak plasma concentrations of remdesivir were observed at the end of infusion and declined rapidly thereafter with a half-life of approximately 1 hour.

Remdesivir undergoes rapid hydrolysis by esterases resulting in the formation of the intermediate metabolite GS-704277. Phosphoramidate cleavage followed by phosphorylation forms the active triphosphate GS-443902. Dephosphorylation of all phosphorylated metabolites can result in the formation of nucleoside metabolite GS-441524 that itself is not efficiently re-phosphorylated. Additionally, the human mass balance study indicates presence of a currently unidentified major and possible human-specific metabolite (M27) in plasma.

Following administration of [¹⁴C]-remdesivir, over 92% of the dose was recovered, consisting of approximately 74% in urine and 18% in feces. The majority of the dose recovered in urine was GS-441524 (48.6%), while 10.3% was recovered as remdesivir. These data indicate that renal clearance is the major elimination pathway for GS-441524. The median terminal half-lives of remdesivir, GS-704277, and GS-441524 were approximately 1, approximately 1.3, and 27 hours, respectively.

The effect of intrinsic factors, including the effect of renal and hepatic impairment on the pharmacokinetics of remdesivir, has not been examined. Intra- and inter-subject variability has also not been studied.

In order to define the dosing recommendation for Remdesivir in adolescent patients (12 years of age and older weighing at least 40 kg), the sponsor developed a physiologically based pharmacokinetic model to characterize the pharmacokinetics of remdesivir and the primary circulating nucleoside metabolite, GS-441524, in adults. This model was applied to predict pediatric patient exposure, accounting for age-dependent changes in organ volume or size, enzyme expression, plasma protein binding, blood cell distribution, and organ blood flow. The model predicts that for pediatric patients weighing at least 40 kg, the proposed adult dosage regimen (one loading dose of remdesivir 200 mg intravenously infused over 30 min on day 1, followed by remdesivir 100 mg intravenously infused over 30 min once daily for 9 days) will provide exposures of remdesivir and GS-441524 similar to those observed in healthy adult volunteers.

Drug-drug interaction studies of remdesivir and other concomitantly administered drugs have not been conducted in humans.

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

Clinical Efficacy and Safety

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. No clinical study report was available to Health Canada for any of the clinical trials conducted in COVID-19 patients and the data provided were limited to study protocols and preliminary or topline results.

Additional efficacy and safety data will be assessed when the requested studies are submitted, as part of the conditions under the Notice of Compliance with Conditions (NOC/c) Guidance.

Clinical Efficacy

The efficacy of Veklury in the treatment of COVID-19 is supported primarily by the ongoing, pivotal, Phase III, randomized, double-blind, placebo-controlled, multicentre study (NIAID ACTT-1). In order to expedite the regulatory approval of Veklury, an interim analysis of data from the published study was accepted for review by Health Canada. The complete study report is expected to be available before the end of 2020.

Additional clinical evidence is from the following supportive trials: two open-label SIMPLE-studies, GS-US-540-5773 in patients with severe COVID-19 and GS-US-540-5774 in patients with moderate COVID-19, and the placebo-controlled study GS-US-540-5758 in patients with severe COVID-19.

Study NIAID ACTT-1 (CO-US-540-5776)

The pivotal, Phase III study NIAID ACTT-1 was conducted in hospitalized adult patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and evidence of lower respiratory tract involvement.

The study enrolled 1,063 hospitalized patients: 120 (11.3%) patients with mild/moderate disease (defined by oxygen saturation [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 in a ratio of 1:1 to receive Veklury (number of patients [n] = 541) or placebo (n = 522), plus standard of care. Randomization was stratified by study site and disease severity at enrolment. Veklury was administered intravenously at a dose of 200 mg on day 1 and at a dose of 100 mg once daily for up to 9 additional days. Approximately 33% (180/541) of the patients received a 10-day course of treatment with Veklury.

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. Based on 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% confidence interval [CI] 1.12 to 1.55], p<0.001).

The outcome differed between the two disease strata (mild to moderate disease at baseline and severe disease at baseline). Time to recovery was similar between the two treatment groups in patients with mild to moderate disease at baseline, whereas 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]). The clinical benefit of Veklury was limited to patients with pneumonia who were receiving oxygen at baseline (recovery rate ratio 1.47 [95% CI 1.17 to 1.84]). Veklury did not reduce the time to recovery in patients who were receiving mechanical ventilation or extracorporeal membrane oxygenation at baseline (recovery rate ratio 0.95 [95% CI 0.64 to 1.42]). There was no difference in efficacy in patients randomized during the first 10 days after the onset of symptoms as compared to those with symptoms for more than 10 days. Mortality was numerically lower in the Veklury group than in the placebo group, however, the difference was not statistically significant (hazard ratio for death 0.70 [95% CI 0.47 to 1.04], based on 1,059 patients).

Viral loads were not quantified during the study. A demonstrated correlation between clinical improvement and decreased viral loads would provide definitive evidence about the antiviral activity of Veklury against SARS-CoV-2.

The submission contained incomplete information about the comorbidities of study participants and no information about concomitant medications. Therefore, it is unknown whether potential imbalances in comorbidities or differences in the medications used as standard of care (e.g., corticosteroids) between the two treatment groups may have had an impact on the outcomes during the study.

Study GS-US-540-5758

The GS-US-540-5758 study was an investigator-initiated, Phase III, randomized, placebo-controlled, double-blind trial performed at ten hospitals in Wuhan, China, in patients with severe COVID-19. Patients were randomly assigned (2:1) to receive either Veklury or placebo. Patients in the Veklury group received the drug for up to 10 days. This study was terminated early due to low enrollment of patients and therefore, it was underpowered.

The primary clinical endpoint was time to clinical improvement within 28 days after randomization. The time to clinical improvement in the Veklury group was not significantly different to that of the placebo group. The median time to clinical improvement was 21 days (interquartile range [IQR] 13.0 to 28.0) in the Veklury group vs. 23 days (IQR 15.0 to 28.0) in the placebo group; hazard ratio (HR) 1.23 (95% CI 0.87 to 1.75). The day 28 all-cause mortality was similar between the two groups, i.e., 22 (14%) patients died in the Veklury group vs. 10 (13%) patients in the placebo group; difference 1.1% (95% CI -8.1 to 10.3).

Study GS-US-540-5773 (SIMPLE-severe)

The SIMPLE-severe study is an ongoing Phase III, randomized, open-label, multicentre trial in patients with severe COVID-19 to evaluate the safety and efficacy of Veklury administered for 5 or 10 days. Veklury was administered intravenously at a dose of 200 mg on day 1 followed by 100 mg on subsequent days, for a scheduled course of 5 or 10 days depending on the study group. The most severely ill patients, i.e., patients on mechanical ventilation, were excluded from this study. Only results from an interim analysis from this study were available for review.

The primary endpoint was clinical outcome at day 14. After adjusting for baseline clinical status, participants receiving a 10-day course of Veklury had a similar distribution in clinical status at day 14 as those receiving a 5-day course of Veklury. In addition, day 14 mortality was numerically lower in the 5-day group vs. the 10-day group (8% vs. 11%).

Study GS-US-540-5774 (SIMPLE-moderate)

The SIMPLE-moderate study is an ongoing Phase III, randomized, open-label, multicentre study in patients with moderate COVID-19 to evaluate the safety and efficacy of Veklury administered for 5 or 10 days. Veklury was administered intravenously at a dose of 200 mg on day 1 followed by 100 mg on subsequent days, for a scheduled course of 5 or 10 days depending on the study arm. The control arm received standard of care alone. Only results from an interim analysis from this study were available for review.

The primary efficacy endpoint was clinical status assessed by a 7-point ordinal scale on day 11. A statistically significant improvement in clinical status at day 11 for participants receiving a 5-day course of Veklury compared with those receiving standard of care alone was found (odds ratio 1.65 [95% CI 1.09 to 2.48], p = 0.017) based on the Last Observation Carried Forward (LOCF)-analysis. Based on the Observed Cases (OC)-analysis, as prespecified in the protocol, no difference was seen for either Veklury groups compared to standard of care. Data concerning the length of the hospital stay do not indicate a positive effect of Veklury (5-day course: 8 days, 10-day course: 8 days, standard of care: 7 days). For other efficacy endpoints of interest, at day 11, improvements of two or more points in the clinical ordinal scale were reported in 70.2% of participants who received a 5-day course of Veklury and 65.3% of participants who received a 10-day course of Veklury compared with 60.5% of those who received standard of care alone. Clinical recovery at day 11 was achieved in a numerically greater proportion of patients in the 5-day Veklury group (73.8%) than the 10-day Veklury group (68.4%) and the standard-of-care group (64.0%).

Indication

Only minor editorial changes were made to the initially proposed indication of Veklury. Health Canada approved the following indication:

• Veklury (remdesivir) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen.

For more information, refer to the Veklury Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Veklury is supported primarily by data derived from the ongoing Phase III, randomized, double-blind, placebo-controlled, multicentre study NIAID ACTT-1. Additional safety data stem from the placebo-controlled study GS-US-540-5758 in patients with severe COVID-19 and two open-label SIMPLE-studies, GS-US-540-5773 in patients with severe COVID-19 and GS-US-540-5774 in patients with moderate COVID-19. The studies are described in the Clinical Efficacy section.

In study NIAID ACTT-1, the safety of Veklury was assessed in 531 hospitalized patients with COVID-19. Based on the preliminary dataset, the incidence of adverse events was comparable between the Veklury and the placebo groups. Grade 3 or 4 adverse events occurred in 156 (28.8%) patients in the Veklury group and in 172 (33.0%) patients in the placebo group. The most common adverse events in the Veklury and placebo groups were anemia or decreased hemoglobin (7.9% and 9.0%, respectively), acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (7.4% and 7.3%, respectively), pyrexia (5.0% and 3.3%, respectively), hyperglycemia or increased blood glucose level (4.1% and 3.3%, respectively), and increased aminotransferase levels, including alanine aminotransferase, aspartate aminotransferase, or both (4.1% and 5.9%, respectively).

Serious adverse events occurred in 114 (21.1%) patients in the Veklury group and 141 (27.0%) patients in the placebo group. Four events (two in each treatment group) were considered by site investigators to be related to Veklury or placebo. There were 28 (5.2%) serious adverse events of respiratory failure in the Veklury group and 42 (8.0%) in the placebo group. Thirty-six patients receiving Veklury and 36 patients receiving placebo discontinued treatment before day 10 due to an adverse event or a serious adverse event other than death. There were no treatment-related deaths, as considered by the site investigators.

In the study GS-US-540-5758, adverse events were reported in 102 (66%) of 155 patients in the Veklury group and 50 (64%) of 78 patients in the placebo group. Serious adverse events occurred with a higher frequency in the placebo group compared to the Veklury group. More patients in the Veklury group discontinued study drug due to adverse events compared to the placebo group, i.e., 12% vs. 5%. The most common adverse events leading to study drug discontinuation were secondary infection, respiratory failure/acute respiratory distress syndrome, and cardiopulmonary failure.

In the SIMPLE-severe study (GS-US-540-5773), the frequency and severity of adverse events were higher in the patients receiving a 10-day course of Veklury in comparison to those receiving a 5-day course of Veklury. Elevations of transaminases and renal adverse events were reported with a higher frequency in the 10-day Veklury group compared to the 5-day Veklury group, which could be due to imbalances in some baseline characteristics, underlying disease conditions and/or concomitant medications.

In the SIMPLE-moderate study (GS-US-540-5774), adverse events were reported in 106 (54.9%) of 193 patients receiving Veklury for 10 days, 97 (50.8%) of 191 patients receiving Veklury for 5 days, and 90 (45.0%) of 200 patients receiving standard of care. The overall incidence of grade 3 or higher adverse events, serious adverse events, and deaths were generally comparable between the three groups.

Appropriate warnings and precautions are in place in the approved Veklury Product Monograph to address the identified safety concerns.

For more information, refer to the Veklury Product Monograph, approved by Health Canada and available through the Drug Product Database.