DHM COVID-19 Clinical DispatchBite-sized, weekly clinical updates
Issue #5: Remdesivir for COVID-19
This week we bring you the first target in our updates on therapeutics: Remdesivir We start with a look into the mechanism of remdesivir, followed by a brief history lesson on its origins and why it’s now being used for SARS-CoV2 (hint: it’s all about that RNA Polymerase). Then the real question: does it work in humans? Answer: it looks promising! Finally, if you’re wondering how to get your hands on some remdesivir, it turns out the process is quite
challenging! We talked to Dr. Peter Chin-Hong from infectious disease about the ways patients at UCSF have accessed the drug. Our Big Take-away for the week?
The remdesivir data remain mixed. The only published RCT was underpowered and showed no effect. Early data from the NIH suggest clinical improvement and we await their final results. Regardless, access to remdesivir remains quite limited, making broad applicability challenging. Also, be sure to check out "What We're Reading," our weekly literature round-up at the end. Happy Thursday! - The COVID Clinical Working Group
Spaced Learning time: Quiz Yourself!Our previous dispatch highlighted a paper by Xu et al. In the prospective study of patients with severe or critical COVID-19 given tocilizumab, improvements were observed in all of the following except: - Fever
- CRP level
- IL-6 level
- CT opacities
- Oxygen requirement
Find the answer here!
Looking Under the Hood - Mechanism of Action
Figure 1. Mechanism of action of Remdesivir on SARS-CoV2 replication. Created in BioRender
How does remdesivir work?
Remdesivir is an adenosine nucleoside analogue that inhibits RNA-dependent RNA polymerase (RdRp), a protein complex used for replication of RNA-based genomes by several different families of viruses. Remdesivir enters human cells and undergoes metabolic processing. When a metabolite of remdesivir becomes incorporated into viral transcripts, it prevents further extension of that transcript, thereby inhibiting the production of protein and in turn, preventing further viral replication. Why is remdesivir effective against SARS-CoV-2?
Developing antiviral drugs against coronaviruses has historically been challenging because these viruses contain a protein called nsp14, which functions to proofread RNA transcripts and correct them. This activity makes coronaviruses resistant to many other nucleoside analogs. Intriguingly, remdesivir circumvents this resistance mechanism and is effective even in cells with this exonuclease activity intact, potentially because this exonuclease is less effective at identifying it. Due to this lack of detection, remdesivir is able to potently inhibit SARS-CoV replication in human cells. The RNA polymerase of SARS-CoV-2 is almost identical to that of SARS-CoV, making this a promising drug in the setting of COVID-19.
And you may ask yourself: “Well, how did I get here?”
History time: remdesivir, known formally as GS-5735, was developed by Gilead in 2009 as a treatment for Hepatitis C, when they were trying all kinds of compounds. It didn’t work for HCV but found a second life during the Ebola outbreak. It proved safe, and showed initial promise in rhesus monkeys but ultimately was found to be significantly less effective than other treatments. As shown above, remdesivir is a potent inhibitor of the RNA-dependent RNA polymerase (RdRp) and therefore theoretically
should have activity against a broad range of viruses, including SARS-CoV and Middle East Respiratory Syndrome (MERS). Interestingly, the RdRp of SARS and SARS-Cov2 have 96% sequence identity. Unfortunately, though remdesivir showed activity against SARS-CoV in vitro, human studies did not reveal benefit. Similarly in MERS, remdesivir has shown potent antiviral activity in vitro, in mouse models, and prophylactically in non-human primates, but as of yet has no significant human data.
It Sure Sounds Good... but Does it Work?
The evidence so far for remdesivir in COVID-19 is limited, with mixed results but with some promise on the horizon. Our Paper of the Week (below) is an RCT from Wang et al comparing remdesivir to placebo, published at the end of April 2020 in the Lancet. In addition, an ongoing, NIH-sponsored RCT called The Adaptive COVID-19 Treatment Trial (ACTT) released preliminary results showing an improvement in time to recovery (11 days vs 15 days, p<0.001) and with a trend towards improved mortality (8% vs 11.6%) but this result did not meet significance. All-in-all it seems that remdesivir may shorten the duration of illness and is currently the most promising treatment we have for COVID-19. Stay tuned, however, for some interesting team-ups are in the works.
Quick Lit - One-Page Literature Review
Within Our Walls - The UCSF Remdesivir Experience
Can anyone get remdesivir now?
So far at UCSF there have been three ways for patients to access the drug: Compassionate Use - requires patient consent and approval from the IRB, FDA, and Gilead. Apply for each patient. Now used mostly for children and pregnant women. Expanded Access - very difficult application process from Gilead. Only given to one site in SF (Parnassus), but able to treat multiple patients. Randomized Control Trial (RCT) - now closed to enrollment
Per Dr. Peter Chin-Hong, Professor of Infectious Disease we have treated ~20 patients between compassionate use and expanded access, with ~40 patients enrolled in the RCT. Recently, Gilead donated 40% of its global stockpile of remdesivir to the US government. Unfortunately, a significant lack of transparency around the initial distribution of drug to medical centers raised serious concerns about equity. Following outcry from the infectious disease community and a letter from the IDSA, the responsibility for distribution was recently given to the states.
What We're ReadingHere are the articles that our team is reading this week, which are particularly relevant to this issue. To see these and all of our literature summaries please check out our Literature Database! “Compassionate Use of Remdesivir for Patients with Severe Covid-19” (Grein et al, NEJM, April 10): This Gilead-sponsored, prospective, multicenter, international study (mainly US, Japan, Italy) evaluated 53 patients who received at least 5 days of remdesivir for compassionate use. Overall mortality was 13%, while 68% showed improvement in O2 need, 75% on ECMO were taken off, and 82% had significant clinical improvement. The small sample size, conflict of interest, lack of control group and likely selection bias make this data poorly generalizable. “Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2” (Williamson et al, bioRxiv pre-print, April 15): This small RCT found that among 12 macaques inoculated with SARS-CoV-2, the six who received remdesivir developed less respiratory disease, fewer pulmonary infiltrates on imaging as well as significantly reduced viral titers on both BAL and histological (necropsy) organ samples. “Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection” (de Wit et al, PNAS, February 13): This prospective study in rhesus macaques showed that both prophylactic and therapeutic remdesivir are effective in reducing clinical disease and replication in Middle East Respiratory Syndrome coronavirus (MERS-CoV). “Remdesivir
in covid-19: A drug with potential—don’t waste time on uncontrolled observations” (Ferner and Aronson, BMJ, April 22): This editorial briefly reviews the early animal and human data on remdesivir and cautions against making clinical decisions until there are larger, randomized trials to better assess its utility in treating COVID-19. “Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease” (M. Agostini et al, mBio,
March 2018): This study provides some mechanistic insight into the efficacy of remdesivir against SARS-CoV (initial SARS outbreak), demonstrating that despite the intact exonuclease activity of SARS-CoV, remdesivir is able to adequately escape proofreading and effectively inhibit viral transcript synthesis in infected host cells. “Remdesivir for SARS-CoV-2 causing COVID-19: An evaluation of the evidence” (Cao et al, Travel Med Infect Dis, April 02): This review published ahead of Chinese RCTs on remdesivir strongly
supports for its candidacy as a "starring drug" in the treatment of COVID19. This article summarizes evidence for the drug’s mechanisms of action and pharmacokinetics in previous trials for MERS and SARS, its usage in a single case in Washington, resistance patterns of Coronavirus to remdesivir in cats, and the safety profile from existing phase II drug trials of remdesivir for other indications. “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in
vitro” (Wang et al, Nature, Feb 04): This research letter to Cell Research evaluates the efficacy of several known antiviral drugs - ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine, remdesivir (GS-5734) and favipiravir (T-705) - against a clinical isolate of 2019-nCoV in vitro. Chloroquine and remdesivir were found to control SARS-CoV2 infection at low concentrations and with high specificity, have favorable safety profiles, and thus are recommended for future in-vivo studies.
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