key: cord-254452-gqqdx2r5
authors: Singh, Awadhesh Kumar; Singh, Akriti; Singh, Ritu; Misra, Anoop
title: Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies
date: 2020-05-12
journal: Diabetes Metab Syndr
DOI: 10.1016/j.dsx.2020.05.018
sha: 
doc_id: 254452
cord_uid: gqqdx2r5

BACKGROUND & AIMS: Remdesivir is a broad spectrum anti-viral drug that has shown to inhibit SARS-CoV-2, in vitro and in vivo. In absence of any effective treatment for SARS-CoV-2 infection (COVID-19), remdesivir has been tried for a compassionate use in severe COVID-19. Newer randomized controlled studies that have recently become available, showed a mixed result. We aimed to systematically search the literature to understand the pharmacology and clinical effects of remdesivir in patients with COVID-19. METHODS: We systematically searched the PubMed, ClinicalTrial.Org and MedRxiv database up till May 5, 2020 using specific key words such as “Remdesivir” or ‘GS-5734″ AND “COVID-19” or “SARS-CoV-2” and retrieved all the article published in English language, that have reported the pharmacology and the clinical outcomes of remdesivir in patients with COVID-19. RESULTS: Initial compassionate use of remdesivir has shown a fairly good result, but difficult to quantify, in the absence of control arm. While the very first double-blind, placebo-controlled, randomized trial conducted in Wuhan, did not find any significant benefit compared to the control, the preliminary result of another similar multi-country trial has shown a significant faster time to recovery but without any difference in mortality. CONCLUSIONS: Remdesivir has shown a mixed result in patients with COVID-19 with an acceptable side effect. However, jury is still out while awaiting the results from the forthcoming trials.

In vivo efficacy against EBOV in non-human primates led to its inclusion in clinical studies for the treatment of acute Ebola virus disease (EVD). It should be noted however, that the efficacy in vitro or in animal studies does not inevitably predict outcomes in humans. Interestingly, in a randomized controlled trial (RCT) named The Pamoja Tulinde Maisha (PALM, NCT03719586) conducted in 681 patients of acute EBV, remdesivir was found to be less effective than other monoclonal antibodies, while the mortality was 53% (significantly worse) with remdesivir, compared to 35% with the most active antibody MAB114. Authors alluded these differences due to more sicker patients in the remdesivir arm [5] .

Another double-blind phase II RCT study named Partnership for Research on Ebola Virus in Liberia IV (PREVAIL IV, NCT02818582) conducted in chronic carriers of EVD (n=38) has been recently completed, although the full results are still not available in literature [6] .

With regards to the coronaviruses, remdesivir has been shown to inhibit all the animal and human coronaviruses in vitro including MERS-CoV and SARS-CoV-1 [2, 7, 8] . It has shown antiviral effect and clinical benefit in animal models of SARS-CoV-1 and MERS-CoV infections [2, [9] [10] [11] . Interestingly, remdesivir was found to be superior to combined interferon beta plus lopinavir-ritonavir regime in the murine models of MERS-CoV infections [9] .

Fortunately, remdesivir effectively inhibited SARS-CoV-2 infected Vero cells in vitro study [12] . Early administration of remdesivir showed a significant reduction in viral load in bronchoalveolar lavage compared to the vehicle and also decreased the pulmonary infiltrates in SARS-CoV-2 infection of rhesus macaque model. Thus, it demonstrated both antiviral as well as the clinical effects [13] . Moreover, remdesivir was found to be a potent inhibitor of SARS-CoV-2 replication in human nasal and bronchial airway epithelial cells [14] . These outcomes encouraged its use in patients with SARS-CoV-2 infection (COVID-19), in the absence of any effective treatment.

A preliminary report (April 29, 2020) from an interim analysis of an ongoing double-blind randomized controlled trial (RCT) recently suggested that remdesivir had a 31% faster time to recovery, compared to the placebo (p<0.001), in patients with COVID-19 [15] . United State Food Drug Administration (US FDA) urgently gave the Emergency Use Authorization (EUA) permission for remdesivir in COVID-19 on May 1, 2020. The current EUA have permitted the use of remdesivir only to treat adults and children with suspected or laboratory confirmed COVID-19 and severe disease defined as SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) in an in-patient hospital setting [16] . Historically, this would be the third time USFDA has given any drug to have a EUA in human, in the absence of approved indication, pending the results from a large robust trial. Interestingly, earlier on March 30, 2020, FDA also gave EUA to chloroquine and hydroxychloroquine in the treatment of COVID-19, in the absence of approved indication [17] . In the past, an investigational neuraminidase inhibitor -peramivir was given EUA by the FDA Nevertheless, this prompted us to conduct a systematic search of remdesivir to understand its pharmacology, safety and efficacy in patients with COVID-19.

We systematically searched the PubMed, ClinicalTrial.Org and MedRxiv database up till May 5, 2020 using the several specific key words "Remdesivir" or "GS-5734" AND "COVID-19" or "SARS-COV-2" etc. and retrieved all the articles published in English language that reported pharmacology and any clinical outcome with the remdesivir in patients with COVID-19. In addition, we also searched the ClinicalTrial.Org for the ongoing trials with remdesivir in COVID-19.

We compiled all the data chronologically and narrated the past, present and future of remdesivir in the context of COVID-19.

Remdesivir is the most promising repurposed candidate drug that has shown a consistent inhibitory effect both in vitro and in vivo against SARS-CoV-1, MERS-CoV and SARS-CoV-2. The overview of all the randomized trials that have been completed or currently ongoing with the remdesivir in COVID-19 are compiled in table 1.

The "compassionate use" of remdesivir and purported benefit in patients with COVID-19 have been reported in some of the case series, over the last couple of months. The first high-profile single case report from Washington, USA that was published in New England Journal of Medicine (NEJM) got attention about remdesivir [18] . This patient received the first dose of remdesivir on hospital Day 7 (illness Day 11) on a compassionate ground, when progressively found to develop severe pneumonia (clinically and chest X-ray-wise), despite receiving parenteral vancomycin (Day 6 only) and cefepime (Day 6 and 7). Interestingly, the patient recovered significantly on hospital Day 8 (illness Day 12) clinically, with no requirement of supplemental oxygen (SpO2 improved to 96% from 94% on an ambient air). Unfortunately, no further details of remdesivir with regards to the dose and duration were made available. Another case series of 28 severe COVID-19 patient (50% of total cases eventually died) from Seattle USA, published in NEJM, Bhatraju et al [19] also reported that 7 patients had received remdesivir, however the outcome in these patients on remdesivir was not reported.

Grein et al [20] in a data of 53 patients from the 9 countries, who received a 1 to hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6.

death. However, several limitations question the validity of the result, as also noted by the authors that include small size, short duration of follow-up, potential missing data including the lack of information on eight of the patients initially treated with remdesivir, lack of randomization and absence of control group.

In the first double-blind, placebo-controlled, randomized trial (DBRCT) conducted with remdesivir versus placebo (n=236) in severe COVID-19 patients, Wang et al [21] Preliminary results indicate that the median time to recovery was 11 days for patients treated with remdesivir compared to 15 days for those who received placebo, thereby suggesting that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). However, the survival benefit with remdesivir was not statistically significant compared to the control, since remdesivir group had a mortality rate of 8.0% compared to 11.6% for the placebo group (p=0.059) [15] . 60.0% vs. 52.3%, in 5-days vs. 10-days groups, respectively (p=0.14). Clinical recovery at Day 14 was 64.5% vs. 58.3% in 5-days vs. 10-days group, respectively.

Interestingly, the overall mortality rate in 320 patients on Day 14 was only 7% in both treatment groups but outside of Italy. An exploratory analysis of this study suggested a larger benefit, if remdesivir was initiated early within 10 days of symptoms. Pooled data from both the arm found that at Day 14, 62% vs. 49% got discharged from the hospital, if remdesivir was started within 10 days vs. after 10 days of symptoms, respectively [24] .

A second randomized, open-label SIMPLE trial (NCT04292730) is currently evaluating the safety and efficacy of 5-day and 10-days regime of remdesivir (n=600) in patients with moderate COVID-19, compared to the standard of care and is expected at the end of May 2020 [25] . Other randomized trials that are currently undergoing has been summarized in table 1 [26] [27] [28] .

These are the currently available efficacy studies with remdesivir as of now. A comparative pre-clinical, clinical, and cost analysis of 4 repurposed drug such as remdesivir, hydroxychloroquine, chloroquine and lopinavir/ritonavir have been summarized in table 2 . abnormal liver function and renal impairment. Serious adverse events (acute kidney injury, septic shock, multi-organ failure) was noted in 23%, while 60% had at least one adverse event and 8% discontinued due to various side effect of remdesivir [20] . Adverse events were similar in remdesivir (66%) and control arm (64%) in study of Wang et al [21] . Although serious adverse events reported in 18% vs. 26% in remdesivir vs. control arm respectively; more patients from the remdesivir group discontinued remdesivir (12%), compared to the control arm (5%) either because of adverse events or serious adverse events (5% in remdesivir group had acute respiratory distress syndrome or respiratory failure). The most common adverse events noted in SIMPLE trial occurring in more than 10% of patients in either group were nausea (10.0% vs. 8.6%, 5-days vs. 10-days group, respectively) and acute respiratory failure (6.0% vs.10.7%, 5-days vs. 10-days group, respectively). Grade 3 or higher liver enzyme elevations occurred in 7.3% of patients, while 5% in 5-days arm and 10% in 10-days arm had to withdraw from remdesivir due to severe adverse events [24] .

Although no evidence of nephrotoxicity was noted in healthy subjects, some caution is required while using remdesivir. A 150-mg dose of the remdesivir solution and lyophilized formulations of remdesivir contains 9.0 and 4.5 g, of sulfo-butyl-ether β-cyclodextrin-sodium (SBECD), respectively (maximum recommended daily dose is approximately 250 mg/kg, based on EMA safety review). SBECD is used in the formulation as a solubilizing agent due to the limited aqueous solubility of remdesivir. Since SBECD is renally cleared, subjects with moderate or severe renal impairment may have SBECD exposures. A close look on eGFR is necessary while administrating remdesivir, especially in patients with known renal impairment and discontinuation is required if eGFR decrease to ≥50%. Although the parent compound remdesivir has only minor renal excretion, but since urine is found to have 49% of its metabolite GS-441524, impaired renal impairment may theoretically increase plasma exposure to this metabolite.

Nevertheless, given the benefit-risk ratio in patients with COVID-19, no dose modification is currently recommended patients with mild and moderate renal impairment, although it is contraindicated in patients with severe renal impairment (eGFR <30 ml/min). It should be noted that no specific studies have been conducted with remdesivir in patients with renal impairment [4].

A substantial proportion of patients with acute EVD who received remdesivir in PALM trial had moderate to severe liver and renal dysfunction, however no additional renal or hepatic function deterioration attributed to remdesivir was noted. Remdesivir is believed to be rapidly cleaved by hydrolases and thus the effect of hepatic impairment on remdesivir plasma levels is likely low. Given the benefit-risk ratio, no dose modification is currently recommended in patients with COVID-19, though it is contraindicated in patients with alanine transferase (ALT) > 5-times upper limit of normal or severe hepatic dysfunction. There are no specific studies conducted with remdesivir in patients with hepatic dysfunction [4].

In non-clinical reproductive toxicity studies, no adverse effect on embryo-fetal development in pregnant animal or male infertility observed with remdesivir, however at a systematically toxic dose an embryonic toxicity was seen. Remdesivir has not been studied in pregnancy, lactating women and pediatric population.

Interestingly, in PALM study of acute EVD, 3% of pregnant women and 26% of children received remdesivir, without any notable side effects [4].

The potential of induction of CYP enzymes (CYP1A2, CYP2B6, and CYP3A4) following exposure of human hepatocytes to remdesivir has been seen (the reason for transient increase in liver enzymes), however, no data available currently for the drug-drug interaction [4].

Remdesivir for injection, 100 mg, is a sterile, preservative-free lyophilized solid that is to be reconstituted with 19mL of sterile water for injection and diluted into 0.9% saline prior to IV administration. Remdesivir for injection, 100 mg, vials should be stored below 30 °C until time of use. Remdesivir injection, 5 mg/mL vials should be stored at refrigerated temperatures (2 °C to 8 °C) until time of use.

Following dilution with 0.9% saline, the solution can be stored for up to 4 hours at room temperature (20 °C to 25 °C) or 24 hours at refrigerated temperatures (2 °C to 8 °C).

Current dose recommendation of remdesivir in COVID-19 is a bolus dose of 200 mg IV dilutes in normal saline (0.9%) or 5% dextrose to be given over 60 minutes on Day 1, followed by 100 mg IV to be given diluted over 60 minutes for the next 9 days.

Interestingly, in previous two clinical studies conducted in EVD such as PALM and PREVAIL IV, the dose used for remdesivir was 200 mg IV over an hour on Day 1 as loading dose and then 100 mg IV over one hour daily for 4 days (in PREVAIL IV) or 9 to 13 days (in PALM) as maintenance dose.

Remdesivir is an anti-viral agent that has shown a significant inhibitory effect in vitro and in vivo studies against SARS-CoV-2 and appears to be ahead with other repurposed drug being tried for the treatment of COVID-19. Table 2 

Remdesivir appears to have optimal safety profile although its efficacy in the treatment of COVID-19 appears to have a mixed outcome at the moment. Jury is still out and future trials should further enlighten its cost-effectiveness, in particular when the results of head-to-head trial with other low-cost repurposed drugs is available.

Conflict of interest: Nothing to declare by all the authors 

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We hereby declare that we have no conflict of interest related to this article Awadhesh Kumar SinghAkriti Singh

Anoop Misra