Remdesivir is being promoted as an anti-viral agent for the treatment of COVID-19.  The first randomized, blinded, placebo-controlled trial of remdesivir was just released (Wang et al.).  But before we dig into this trial, a little background…

Background:  Animal studies on Remdesivir

Remdesivir is an anti-viral agent with strong efficacy against COVID-19 both in vitro and in multiple animal models.  The basic science evidence on remdesivir is very impressive.  Perhaps most notable is the ability of remdesivir to decrease viral load and clinical symptoms across four animal studies:​1–4​

Of all the anti-viral treatments being investigated for COVID-19, this has perhaps the most persuasive body of supporting evidence. 

Wang et al:  Remdesivir in adults with severe COVID-19:  a randomized, double-blind, placebo-controlled, multicenter trial

This is a prospective, placebo-controlled, double-blind RCT of remdesivir performed among ten hospitals in China. ​5​

Key inclusion criteria were:

Patients were randomized in a 2:1 fashion, with twice as many patients receiving remdesivir as placebo.  The study was stopped early when the COVID-19 surge passed, due to slow recruitment. 

Baseline characteristics were similar between patient groups (Table below).  The median duration of illness prior to receiving remdesivir was 10 days.  Most patients required only low-flow oxygen:

The primary endpoint was time to clinical improvement (defined as discharge from hospital or as improvement by 2 points on a six-point ordinal scale of disease severity).  There was no difference in this endpoint:

Every secondary endpoint was also neutral, except for time to clinical improvement (which was two days shorter in the remdesivir group). Given the presence of about twenty secondary endpoints, this finding is of dubious statistical merit (using a p<0.05 cutoff, one of these secondary endpoints would be expected to be different purely due to chance).

Furthermore, remdesivir had no impact on viral load:

Remdesivir did appear to be safe, with a similar distribution of adverse events seen between the placebo and the remdesivir group:

This is a well-executed and well-designed trial.  Premature termination may have reduced the statistical power to detect subtle clinical differences.  However, if remdesivir is truly a miracle cure for COVID-19, then a signal should be discernable among 236 patients. 

The most notable finding here might be the lack of any impact on viral load.  Remdesivir’s mechanism of action is supposedly to reduce viral replication.  If remdesivir is having any biological impact, this should be most easily detectable in terms of reduced viral titers (figure below).  Lack of a signal here suggests that remdesivir has no biologically meaningful impact in these patients. 

Reconciling Wang et al. with prior animal model data on remdesivir

So why did this study fail, whereas prior animal studies worked so well?  The answer might relate to the timing of administration of remdesivir.

In prior animal studies of remdesivir, investigators felt that early administration of remdesivir would be critical to the drug’s efficacy.  Thus, remdesivir was used either prophylactically or within 12-24 hours of virus inoculation. 

Of course, in real-world clinical practice, remdesivir was given at a far later timepoint:

This leaves open the possibility that earlier administration of remdesivir could be more effective.  In the subgroup of patients treated within <10 days of symptoms, there was a non-significant trend towards faster clinical improvement in patients treated with remdesivir.  However, subgroup analysis still found no differences in viral load.

Shifting of the goal posts

With this negative trial, it’s time for a subtle shifting of the goal posts! 

Let’s step back a moment and consider what was initially suggested about remdesivir: 

These goals are looking increasingly unrealistic.  Thus, the future will likely bring a subtle shift towards less ambitious goals (e.g. reduced hospital length of stay).  Thus, remdesivir may begin to resemble oseltamivir – an aggressively promoted agent with dubious clinical benefit. 

related

references

  1. 1.
    Sheahan T, Sims A, Graham R, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396). doi:10.1126/scitranslmed.aal3653
  2. 2.
    Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. April 2020. doi:10.1101/2020.04.15.043166
  3. 3.
    Sheahan T, Sims A, Leist S, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. doi:10.1038/s41467-019-13940-6
  4. 4.
    de W, 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(12):6771-6776. doi:10.1073/pnas.1922083117
  5. 5.
    Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. April 2020. doi:10.1016/s0140-6736(20)31022-9
Josh Farkas
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