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A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in December 2019 as the cause of a respiratory illness designated as coronavirus disease 2019, or Covid-19. Several therapeutic agents have been evaluated for the treatment of Covid-19, but none has yet been shown to be efficacious. Remdesivir (GS-5734), is an inhibitor of the viral RNA-dependent, RNA polymerase. The virus uses this enzyme to assemble chains of RNA (its genetic material) piece by piece. Remdesivir being a nucleoside analog, gets picked up by the viral RNA polymerase, instead of the original nucleoside. Thus the RNA assembly line gets jammed. Despite a powerful proofreading function of the virus, it is unable to undo the damage, and gradually the replication comes to a stop. So remdesivir is basically faking the virus into thinking that it’s a building block of viral genetic material.

When tested in infected cells in the lab, remdesivir stops replication in a number of viruses, including hepatitis, Ebola and other human coronaviruses, such as SARS and MERS. In nonhuman primate studies, remdesivir initiated 12 hours after inoculation with MERS-CoV, reduced lung virus levels and lung damage.

Remdesivir is currently approved in Japan as a treatment for patients with COVID-19. Outside of Japan, remdesivir is an investigational, unapproved drug. The U.S. Food and Drug Administration (FDA) granted remdesivir an Emergency Use Authorization (May 01, 2020) for the treatment of hospitalized patients with severe COVID-19. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO). It is authorized for adult or pediatric patients who are admitted to a hospital and for whom use of an IV agent is clinically appropriate. The authorization is temporary and does not take the place of the formal new drug application submission, review and approval process. The authorization can be terminated or revoked sooner. India will start clinical trials on the effectiveness of Remdesivir against Covid-19 as part of the World Health Organization solidarity trial, under a fast tracked study.

Gilead Sciences, Inc. (Nasdaq: GILD), the company that manufactures remdesivir, initiated two randomized, open-label, multi-center Phase 3 clinical trials for remdesivir, the SIMPLE studies, in countries with a high prevalence of COVID-19 infections. The studies were conducted at more than 180 trial sites around the world, including sites in the United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, the Netherlands, Singapore, Spain, Sweden, Switzerland, Taiwan and the United Kingdom.

The first SIMPLE trial is evaluating the safety and efficacy of 5-day and 10-day dosing durations of remdesivir, administered intravenously, in hospitalized patients with severe manifestations of COVID-19. The initial phase of the study randomized 397 patients in a 1:1 ratio to receive either a 5-day or a 10-day treatment course of remdesivir in addition to standard of care. The full data were published in The New England Journal of Medicine on May 27. At baseline, patients who were randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P=0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P=0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).

The authors concluded that in patients with severe Covid-19, not requiring mechanical ventilation, the trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. An expansion phase of the study was added to enroll up to 5,600 additional patients, including those on mechanical ventilation.

The second SIMPLE trial is evaluating the safety and efficacy of 5-day and 10-day dosing durations of remdesivir administered intravenously in hospitalized patients with moderate manifestations of COVID-19, compared with standard of care. In the initial phase of this study, 600 hospitalized patients with confirmed COVID-19 infection and evidence of pneumonia without reduced oxygen levels were randomized (1:1:1) to receive open-label remdesivir for 5 or 10 days or standard of care alone. The primary endpoint was the clinical status, as assessed by a 7-point ordinal score at Day 11. It ranged from hospital discharge to increasing levels of oxygen and ventilatory support to death. The secondary study objective was the rate of adverse events in each remdesivir treatment group compared with standard of care.

The initial topline results from the open label Phase 3 SIMPLE trial in hospitalized patients with moderate COVID-19 pneumonia were announced in a press release on June 01, 2020. The study demonstrated that patients in the 5-day remdesivir treatment group were 65 percent more likely to have clinical improvement at Day 11 compared with those in the standard of care group (OR 1.65 [95% CI 1.09-2.48]; p=0.017). The odds of improvement in clinical status with the 10-day treatment course of remdesivir versus standard of care were also favorable, trending toward but not reaching statistical significance. No new safety issues were identified with remdesivir in either treatment group. Remdesivir was generally well-tolerated in both the 5-day and 10-day treatment groups. The most common adverse events occurring in more than 5 percent of patients in both treatment groups were nausea, diarrhea and headache.

An expansion phase of the second SIMPLE trial will be evaluating 1,000 additional patients for the safety and efficacy of 5-day and 10-day dosing durations of remdesivir administered intravenously in hospitalized patients with moderate manifestations of COVID-19, compared with standard of care. The results from the expansion phase are expected in the coming months.

Preliminary results of the first stage of the Adaptive Covid-19 Treatment Trial (ACTT-1), conducted by National Institute of Allergy and Infectious Diseases (NIAID), USA, was published in The New England Journal of Medicine (May 20, 2020). This is a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. There were 60 trial sites and 13 subsites in the United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1). A total of 1063 patients participated in the trial. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) indicated that those who received remdesivir had a median recovery time of 11 days, as compared with 15 days in those who received placebo. The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo. Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization .

The authors concluded that remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection.

Summary:

The scientific community is encouraged by the moderate benefits shown by remdesivir thus far. A lot of questions remain unanswered-Does the efficacy of the drug depend on severity of illness? Is it more effective if given earlier? It is well known that the benefit of any antiviral is more when given early in infection, to stop viral replication. A classic example of this is Tamiflu, which is more effective in the first few days of the flu. Similarly, remdesivir may have more impact when administered early in the course of COVID-19. This is important not only from a public health standpoint – the sooner the viral load is reduced, the less the chances of transmission to others – but also because of the inflammatory complications that arise later in the disease. When patients reach the second stage of COVID-19, the inflammatory response causes serious lung damage. At this stage antivirals alone may not be enough.

Although it is thought that remdesivir reduces the viral load in patients, even that cannot be confirmed without further adequate data. So more time is needed to look at the available data critically and expand on the knowledge base with ongoing clinical trials. This does not mean that remdesivir usage needs to be stopped, but it does mean that before opening the floodgates, a more detailed understanding of the drug and its effects in patients with differing severity of the disease, is required.

References:

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2. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020;3(4):e208857-e208857.
3. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222-222.
4. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-271.
5. de Wit E, Rasmussen AL, Falzarano D, et al. Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 2013;110:16598-16603.
6. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020;117:6771-6776.
7. John H. Beigel, Kay M. Tomashek, Lori E. Dodd, Aneesh K. Mehta, Barry S. Zingman, Andre C. Kalil, Elizabeth Hohmann, Helen Y. Chu, Annie Luetkemeyer, Susan Kline, Diego Lopez de Castilla, Robert W. Finberg, et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. May 22, 2020 DOI: 10.1056/NEJMoa2007764