General Information

Veklury (remdesivir) is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor.

Veklury is specifically indicated for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization. Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care. Veklury is also approved in pediatric patients 28 days of age and older weighing at least 3 kilograms (about 7 pounds) with positive results of direct SARS-CoV-2 viral testing, who are: 1) Hospitalized, or 2) not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death.

Veklury is supplied as an injection for intravenous administration. Veklury must be diluted prior to intravenous infusion.

• Testing prior to and during treatment: Perform eGFR, hepatic laboratory, and prothrombin time testing prior to initiating Veklury and during use as clinically appropriate.
• Renal impairment: Veklury is not recommended in individuals with eGFR <30 mL/min.

The recommended dosage for adults and pediatric patients 12 years of age and older and weighing at least 40 kg is a single loading dose of Veklury 200 mg on Day 1 via intravenous infusion followed by once-daily maintenance doses of Veklury 100 mg from Day 2 via intravenous infusion.

The recommended treatment duration for patients not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days.

The recommended total treatment duration for patients requiring invasive mechanical ventilation and/or ECMO is 10 days.

Mechanism of Action

Veklury (remdesivir) is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or cathepsin A, depending upon the cell type. The nucleoside monophosphate is subsequently phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate metabolite (GS-443902). Remdesivir triphosphate (RDV-TP) acts as an analog of adenosine triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination (position i+3) during replication of the viral RNA. In a biochemical assay assessing RDV-TP incorporation by the MERS-CoV RdRp complex, RDV-TP inhibited RNA synthesis with an IC50 value of 0.032 µM. RDV-TP can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as a result of read-through by the viral polymerase that may occur at higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases, including human mitochondrial RNA polymerase.

Side Effects

Hypersensitivity including infusion-related and anaphylactic reactions: Hypersensitivity reactions have been observed during and following administration of Veklury. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent signs and symptoms of hypersensitivity. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of Veklury and initiate appropriate treatment.

Increased risk of transaminase elevations: Transaminase elevations have been observed in healthy volunteers and have also been reported in patients with COVID-19 who received Veklury. These elevations have also been reported as a clinical feature of COVID-19. Perform hepatic laboratory testing in all patients. Consider discontinuing Veklury if ALT levels increase to >10x ULN. Discontinue Veklury if ALT elevation is accompanied by signs or symptoms of liver inflammation.

Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine: Coadministration of Veklury with chloroquine phosphate or hydroxychloroquine sulfate is not recommended due to antagonism observed in cell culture, which may lead to a decrease in antiviral activity of Veklury.

The most commons adverse reactions associated with the use of Veklury included the following:

• nausea
• ALT increased
• AST increased

Clinical Trial Results

The FDA approval of Veklury for COVOD-19 was based on three randomized controlled trials: ACTT-1, SIMPLE-Severe and SIMPLE-Moderate.

ACTT-1

The global, randomized, double-blind, placebo-controlled, Phase 3 ACTT-1 trial, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), evaluated the efficacy and safety of a 10-day treatment course of Veklury versus placebo in 1,063 hospitalized adult patients with confirmed SARS-CoV-2 infection and mild, moderate or severe COVID-19 who also were receiving treatment with standard of care.

The primary outcome measure of ACTT-1 was time to recovery within 29 days after randomization. Recovery was defined as discharged from the hospital without limitations on activities, discharged from the hospital with limitations on activities and/or requiring home oxygen, or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care.

Veklury significantly improved time to recovery as compared to placebo by five days in the overall study population (10 vs. 15 days) and seven days in patients who required oxygen support at baseline (11 vs. 18 days). As a secondary endpoint, Veklury also reduced disease progression in patients needing oxygen, resulting in a significantly lower incidence of new mechanical ventilation or ECMO (13% vs. 23%). In the overall patient population, there was a trend toward reduced mortality with Veklury compared with placebo at Day 29 (11.4% vs. 15.2%).

SIMPLE Trials: 

The two open-label Phase 3 SIMPLE trials were conducted in countries with a high prevalence of COVID-19 infections and included U.S. trial sites that serve diverse communities.

SIMPLE-Severe was a randomized, open-label multi-center study that evaluated the efficacy and safety of five-day and 10-day dosing durations of Veklury plus standard of care in 397 hospitalized adult patients with severe COVID-19. Severe COVID-19 was defined as patients with confirmed SARS-CoV-2 infection, an SpO2 of ≤94% on room air, and radiological evidence of pneumonia. The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale. Treatment with Veklury was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment. Subjects receiving a 5-day course of Veklury had similar clinical status at Day 14 as those receiving a 10-day course. There were no statistically significant differences in recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between-group differences at baseline. All-cause mortality at Day 28 was 12% vs 14% in the 5- and 10-day treatment groups, respectively.

SIMPLE-Moderate was a randomized, controlled, open-label multi-center study that evaluated the efficacy and safety of five-day and 10-day dosing durations of Veklury plus standard of care compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19. Moderate COVID-19 was defined as confirmed SARS-CoV-2 infection, SpO2 >94% and radiological evidence of pneumonia. The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale. Overall, the odds of improvement in the ordinal scale were higher in the 5-day Veklury group at Day 11 when compared to those receiving only standard of care. The odds of improvement in clinical status with the 10-day treatment group when compared to those receiving only standard of care were not statistically significant. All-cause mortality at Day 28 was ≤2% in all treatment groups.