Remdesivir for COVID-19: first results from compassionate access programme

17 April 2020. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

Some of the earliest studies of repurposed compounds and drugs for the new coronavirus (CoV-2) included a nucleotide inhibitor prodrug in development with Gilead called remdesivir. Remdesivir has in-vitro activity against a panel of viruses including Ebola, MERS, SARS-CoV-1 and SARS-CoV-2, although studies for Ebola were not successful.

Although a dozen studies are now ongoing for CoV-2 none of these studies has yet published efficacy or safety results. [1]

So while first results in have now been published as an open access paper in the new England Journal of Medicine, these are only preliminary data from the first compassionate use, rather than from a controlled clinical study. [2]

The report is based on 53 patients who received at least one dose of remdesivir from 25 January to 7 March 2020 and who had follow up data available. This is an international cohort including the US (n=22), Europe or Canada (n=22) and Japan (n=9). A further 8 participants received remdesivir but were not included in the analysis, mainly due to missing data.

Entry criteria included being hospitalised with confirmed COVID-19 and either an oxygen saturation of 94% or less while breathing ambient air or a need for oxygen support. Although there were no formal primary endpoints all key clinical factors and drug safety were recorded.

Baseline characteristics included median age 64 years (IQR: 48 to 71; range: 23 to 82), 75% men and 36 (68%) had a significant comorbidity. Clinical features included 30 patients (57%) on mechanical ventilation and 4 (8%) receiving extracorporeal membrane oxygenation. Median duration of symptoms before remdesivir was 12 days (IQR: 9 to 15).

Participants were able to receive a 10-day course of remdesivir, given IV:  200 mg on day 1, and then 100 mg daily. Overall, 40/53 (75%) received the 10-day course, 10 (19%) received 5 to 9 days of treatment, and 3 (6%) fewer than 5 days of treatment.

During a median follow-up of 18 days (95%CI: 13 to 23), 36 of 53 patients (68%) showed an improvement in the category of oxygen support, with 8 of 53 patients (15%) worsening. At most recent follow-up, 25/53 participants (47%) had been discharged (24% receiving invasive ventilation [8/34] and 89% [17/19] receiving noninvasive oxygen support).

Seven of the 53 participants (13%) died after remdesivir treatment, including 6/34 patients (18%) on invasive ventilation and 1/19 (5%) receiving noninvasive oxygen support.

Adverse events were reported in 30/53 participants (60%) many of which overlap with symptoms of COVID-19. Serious events in two or more people were multiple organ dysfunction (n=2), septic shock (n=2), acute kidney injury (n=2) and hypotension (n=2).

At 28 days post treatment, clinical improvement based on a six-point scale was reported for 84% of participants. Sex, country, coexisting conditions, and duration of symptoms before remdesivir were not significantly associated with clinical improvement.

Viral load data was not collected in this programme.

Although the paper refers to safety data from approximately 500 participants in the Ebola development programme, the NEJM paper doesn’t report on the remdesivir arm and the EMA document in only animal data. [3, 4]

comment

The urgency of effective treatment for COVID-19 makes the results from clinical studies essential, and hopefully the first of these might become available within the next few weeks.

The complexity and severity COVID-19 makes it difficult to interpret efficacy and safety results from this open label study. Comparing results to other other studies or historical results based on standard of care is also difficult.

Gilead have already announced plans for rapid large scale manufacturing and an expanded compassionate access and donation programme. It will be just as important for any price, post regulatory approval, to be easily affordable in all settings. [5]

The timeline for other results, including a randomised placebo-controlled study in approximately 800 people which are expect in May, was summarised in other Gilead press statements. Other results from open-label studies will be available by the end of April. [6]

References

1. clincaltrials.gov. Search results for remdesivir.
   https://clinicaltrials.gov/ct2/results?cond=&term=remdesivir&cntry=&state=&city=&dist=
2. Grein J et al. Compassionate use of remdesivir for patients with severe Covid-19. NEJM. DOI: 10.1056/NEJMoa2007016. (10 April 2020).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2007016
3. Mulangu S et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019;381:2293-2303. (12 December 2019).
   https://www.nejm.org/doi/full/10.1056/NEJMoa1910993
4. European Medicines Agency. Summary on compassionate use: remdesivir Gilead. (3 April 2020).
   https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf (PDF)
5. Gilead press statement. An Update on COVID-19 from our Chairman & CEO. (4 April 2020).
   https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo
6. Gilead press statement. An Open Letter from our Chairman & CEO. (10 April 2020).
   https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo-april-10