Other remdesivir news: top results from NIH and Gilead studies – emergency approval in US and Japan

Simon Collins, HIV i-Base

On the same day that the Lancet published the results of the Chinese placebo-controlled study reporting a lack of effect (see article in this HTB [1]), top-line results were released from two other studies.

The highest profile of these was probably the placebo-controlled NIAID study that enrolled more than 1000 people hospitalised with COVID-19.

NIAID ACTT study

The Adaptive COVID-19 Treatment Trial (ACTT) study had started on 21 February 2020, and randomised 1063 participants. On 27 April, the DSMB reported 31% shorter time to recovery (the primary endpoint, defined as well-enough for hospital discharge) in the remdesivir compared to the placebo group (p<0.001). [2, 3]

The median time to recovery was 11 days vs 15 days for the remdesivir vs placebo groups. The difference in mortality also showed a trend towards benefit: 8.0% vs 11.6% (p=0.059).

Further details have still to be released.

SIMPLE study (Gilead)

Also on 29 April 2020, Gilead Sciences issued a press statement releasing top-line results from the phase 3 SIMPLE study that randomised 397 hospitalised participants with symptoms of severe COVID-19 to either 5-day or 10-day remdesivir. [4]

The results included similar clinical outcomes at day 14 in both groups (OR: 0.75 [95% CI 0.51 to 1.12]). Importantly though, there is no control group receiving placebo or only standard of care.

Clinical improvement was defined by moving at least two points on a seven point scale (ranging from hospital discharge to death). Time to improvement was 10 vs 11 days in the 5 vs 10-day groups. More than half the participants in each group were discharged by day 14: 60% (120/200) vs 52% (103/197); p=0.14. At Day 14, 65% (129/200) vs 54% (106/197 achieved clinical recovery, both in 5 vs 10 day groups respectively.

Although the differences were not statistically significant, it is perhaps unusual that numerically all three of these parameters favoured the shorter 5-day dose.

In what sounds like a pooled post-hoc analysis, the press release states that earlier access to treatment (within 10 days of first symptoms) led to 62% vs 49% being discharged from hospital.

There were no differences between the two groups in terms of deaths (n=16 vs 21; 8% vs 11%, p=0.7) or serious adverse events.

FDA emergency authorisation

On 1 May 2020, on the basis of only the top-line results from the ACTT and SIMPLE studies, the US FDA issued an emergency use authorisation for remdesivir as a ‘potential’ new treatment for severe COVID-19 (defined as oxygen depletion <94% on room air or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). [5, 6]

The FDA letter of approval based the decision on three criteria:

SARS-CoV-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected by this virus.
Based on the totality of scientific evidence available to FDA, it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, when used under the conditions described in this authorisation, the known and potential benefits of remdesivir when used to treat COVID-19 outweigh the known and potential risks of such products. 
There is no adequate, approved, and available alternative to the emergency use of remdesivir for the treatment of COVID-19.

Approval in Japan

On 7 May 2020, Gilead also announced approval of remdesivir in Japan under an ‘exceptional approval pathway’. The trade name is Veklury.

Access to remdesivir in Japan will be provided free to patients by government hospitals.

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Remdesivir has an indication for severe COVID-19 (although hinting at data that suggests earlier use might be better), an antiviral profile that shows no impact compared to placebo on PCR in throat swabs or lung tissue, and despite a relatively clean side effect profile, no benefit from longer dosing (10 vs 5 days) in studies without a placebo or standard of care arm.

It is not so much (in a nod to the BHIVA/EACS statement) that full data are eagerly awaited, but a difficulty understanding these approvals without a more substantive data set being shared in the public domain.

Although there is recent animal data to support remdesivir being clinically effective in rhesus macaque studies using a comparable dose to that used in humans, with some reductions in viral load, the faster progression in macaques makes commenting on timing difficult. Nevertheless this paper discussed the potential benefits of using remdesivir as early as possible to get the maximum treatment effect. [8]

The EMA has already started a rolling review process for evaluating any decision on remdesivir approval in the European Union. This is a process to help faster evaluation of a new drug submission where additional data can be submitted during the review process. [9]

Compassionate access to remdesivir is already available in many European countries. [10]

References

Wang et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
NIAID press statement. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. (29 April 2020).
https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
NIH clinical trial of remdesivir to treat COVID-19 begins/ (25 February 2020).
https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins
Gilead press release. Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. (29 April 2020).
https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19
FDA news release. Coronavirus (COVID-19) Update: FDA issues emergency use authorization for potential COVID-19 treatment. (1 May 2020).
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
Remdesivir Safety information.
https://www.fda.gov/media/137566/download
Gilead press release. Gilead announces approval of Veklury (remdesivir) in Japan for patients with severe COVID-19. (7 May 2020).
https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-in-japan-for-patients-with-severe-covid19
B. Williamson, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Pre-peer review. DOI: 10.1101/2020.04.15.043166. (22 April 2020).
https://www.biorxiv.org/content/10.1101/2020.04.15.043166v2
European Medicine’s Agency press statement. EMA starts rolling review of remdesivir for COVID-19. (30 April 2020).
https://www.ema.europa.eu/en/news/ema-starts-rolling-review-remdesivir-covid-19
European Medicine’s Agency press statement. EMA provides recommendations on compassionate use of remdesivir for COVID-19. (3 April 2020).
https://www.ema.europa.eu/en/news/ema-provides-recommendations-compassionate-use-remdesivir-covid-19