Veklury® (remdesivir)

Use With Hydroxychloroquine for the Treatment of COVID-19

This document is in response to your request for information regarding Veklury® (remdesivir [RDV]) and use with hydroxychloroquine (HCQ) for the treatment of COVID-19.

This response was developed according to principles of evidence-based medicine and contains data from Phase 3 clinical studies.

Some data may be outside of the US FDA-approved Prescribing Information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi

Summary

Product Labeling1

Warnings and Precautions

Risk of reduced antiviral activity when coadministered with chloroquine phosphate or hydroxychloroquine sulfate: Coadministration of RDV and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on data from cell culture experiments demonstrating a potential antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of RDV.

Drug Interactions

Due to potential antagonism based on data from cell culture experiments, concomitant use of RDV with chloroquine phosphate or hydroxychloroquine sulfate is not recommended.

Antiviral Activity

RDV EC50 values for SARS-CoV-2 in A549-hACE2 cells were not different when combined with chloroquine phosphate or hydroxychloroquine sulfate at concentrations up to 2.5 μM. In a separate study, the antiviral activity of RDV was antagonized by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher RDV EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate or hydroxychloroquine sulfate reduced formation of RDV triphosphate in A549-hACE2, HEp-2, and normal human bronchial epithelial cells.

Phase 3 Clinical Studies

In the SIMPLE study of RDV in participants with severe COVID-19, those in the RDV + HCQ group (n=160) were less likely to experience clinical improvement and recovery than those in the RDV alone (n=237) group (Table 2).2

• Mortality rates were not increased in the RDV + HCQ group relative to those observed in the RDV alone group (Table 2).2
• A higher proportion of AEs was observed in participants in the RDV + HCQ group than the RDV alone group, and significantly more Grade ≥3 and RDV-related Grade ≥3 AEs were observed in the RDV + HCQ group than the RDV alone group (Table 3).2

In the SIMPLE study of RDV in participants with moderate COVID-19, the rate of recovery was not significantly different between participants in the RDV alone (n=274) and RDV + HCQ (n=110) groups or between those in the SOC alone (n=107) and SOC + HCQ (n=93) groups (Table 5).3

• Participants in the RDV alone group had significantly fewer treatment-emergent toxicities than those in the RDV + HCQ group, and similar rates of AEs and treatment-emergent toxicities were reported in the SOC alone and SOC + HCQ groups (Table 6).3

Clinical Data from Phase 3 Studies

SIMPLE Study in Severe COVID-19

Study Design, Baseline Demographics and Participant Disposition

A phase 3, randomized, two-part (Part A and Part B), open-label study (NCT04292899, EudraCT 2020-000841-15) evaluated RDV in participants with severe of COVID‑19 (SARS-CoV-2 confirmed by reverse transcriptase-PCR, peripheral oxygen saturation ≤94% on room air, radiographic evidence of pulmonary infiltrates, and CrCl ≥50 mL/min).4,5 An analysis of data from Part A of the study assessed the clinical outcomes and safety of concomitant use of RDV (5-day or 10-day RDV dosing regimens, in addition to SOC) and HCQ, which included treatment for ≥1 day with HCQ, HCQ sulfate, chloroquine, or aminoquinolines within 2 days before RDV initiation or anytime thereafter.2

Part A enrolled participants who were not mechanically ventilated between March 6 and March 26, 2020, and those who met all eligibility criteria were randomly assigned in a 1:1 ratio to receive RDV 200 mg IV loading dose on Day 1, followed by RDV 100 mg/day IV on Days 2-5 or Days 2-10 with SOC therapy.4

Table 1. Select Baseline Demographics and Disease Characteristics2

aP=0.02 vs RDV alone. bP=0.016 vs RDV alone. cP=0.033 vs RDV alone.

Sixty-two percent of participants initiated HCQ within 2 days prior to starting RDV, and 16% initiated HCQ on the same day they started RDV. The remaining participants had initial exposure to HCQ up to Day 14 after they started RDV.

Results2

Participants in the RDV + HCQ group were less likely to experience clinical improvement (≥2-point improvement in ordinal score) than those in the RDV alone group (Table 2). Participants in the RDV + HCQ group were less likely to experience recovery (improvement from a baseline ordinal score of 2 to 5 to a score of 6 or 7 or improvement from a baseline score of 6 to a score of 7) than those in the RDV alone group. The median times to clinical improvement and recovery were longer in the RDV + HCQ group than the RDV alone group. Mortality rates were not increased in the RDV + HCQ group relative to those observed in the RDV alone group.

Table 2. Participant Outcomes2

aClinical improvement was defined as ≥2-point improvement in ordinal score and/or live discharge from hospital.

bRecovery was defined as an improvement from a baseline ordinal score of 2 to 5 to a score of 6 or 7 or an improvement from a baseline score of 6 to a score of 7.

Safety2

A higher proportion of AEs was observed in participants in the RDV + HCQ group than the RDV alone group (P=0.34). After adjustment for baseline covariates, significantly more Grade ≥3 and RDV-related Grade ≥3 AEs were observed in the RDV + HCQ group than the RDV alone group (P=0.045 and P=0.007, respectively).

Table 3. Safety Outcomes2

aP=0.045. bP=0.007.

SIMPLE Study in Moderate COVID-19

Study Design, Baseline Demographics and Patient Disposition

A phase 3, two-part (Parts A and B), open-label study (NCT04292730 and EudraCT 2020-000842-32) evaluated the efficacy of two RDV regimens compared with SOC in participants with moderate COVID-19.6 An analysis of data from Part A of the study assessed the clinical outcomes and safety of concomitant use of RDV and HCQ, which included treatment with HCQ, HCQ sulfate, chloroquine, or aminoquinolines.3

Part A was conducted between March 15 and April 18, 2020, and consisted of 584 participants who received SOC therapy according to local guidelines either alone or with a 5- or 10-day course of RDV (loading dose of RDV 200 mg IV on Day 1, followed by RDV 100 mg/day IV on either Days 2-5 or Days 2-10). RDV was infused over 30 to 60 minutes.6

Table 4. Select Baseline Demographics and Disease Characteristics3

Within the RDV + HCQ group, 72 participants discontinued HCQ before RDV treatment started, 33 participants discontinued HCQ after RDV treatment started (range: 1-13 days), and 5 participants were receiving ongoing HCQ at the time of analysis. Within the SOC + HCQ group, 87 participants continued HCQ after randomization, of whom 70 had discontinued HCQ (range: 2-17 days) and 17 continued to receive HCQ at the time of analysis.

Results3

After adjustment for baseline covariates, the rate of recovery was not significantly different between participants in the RDV alone and RDV + HCQ groups (recovery rate ratio: 0.88 [95% CI: 0.68–1.14) or between participants in the SOC alone and SOC + HCQ groups (recovery rate ratio: 1.13 [95% CI: 0.82–1.56]). Similar observations were noted for both comparisons regarding the rate of ≥2-point improvements in ordinal scores.

Table 5. Recovery Outcomes3

Safety3

Participants in the RDV alone group had significantly fewer treatment-emergent toxicities than those in the RDV + HCQ group, and similar rates of AEs and treatment-emergent toxicities were reported in the SOC alone and SOC + HCQ groups.

Table 6. Safety Outcomes3

Abbreviation: NE=not evaluable due to low numbers of AEs.

aP-values were calculated in a logistic regression model that adjusted for clinical status (high- or low-flow O2 vs room air), age (<65 vs ≥65 years), sex, race, and ethnicity.

References

1. VEKLURY®, Gilead Sciences Inc. Veklury® (remdesivir) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA. Revised June 2024.
2. Diaz G, Cattelan AM, Balani B, et al. Association Between Concomitant Hydroxychloroquine Use and Safety and Efficacy of Remdesivir in Severe COVID-19 Patients [Poster 11781]. Paper presented at: Virtual COVID-19 Conference; 10-11 July, 2020.
3. Arribas JR, Sanyal AJ, Viladomiu AS, et al. Impact of Concomitant Hydroxychloroquine Use on Safety and Efficacy of Remdesivir in Moderate COVID-19 Patients [Poster 557]. Paper presented at: IDWeek Virtual; 21-25 October, 2020.
4. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Eng J Med. 2020:1-11.
5. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 [Protocol]. N Eng J Med. 2020.
6. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(11):1048-1057. https://jamanetwork.com/journals/jama/fullarticle/2769871

Abbreviations

AE=adverse event
ECMO=extracorporeal membrane oxygenation
HCQ= hydroxychloroquine
HR=hazard ratio
IMV=invasive mechanical ventilation
NIPPV=noninvasive positive pressure ventilation
O2=oxygen
PCR=polymerase chain reaction;
RDV=remdesivir
SOC=standard of care

Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Veklury US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/covid-19/veklury/veklury_pi

Follow Up

For any additional questions, please contact Gilead Medical Information at:

☎1‐866‐MEDI‐GSI (1‐866‐633‐4474) or   www.askgileadmedical.com

Adverse Event Reporting

Please report all adverse events to:

Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
 www.gilead.com/utility/contact/report-an-adverse-event

FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or   www.accessdata.fda.gov/scripts/medwatch

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