November 20, 2020

expert reaction to WHO Guideline Development Group advising against use of remdesivir for COVID-19

The World Health Organisation (WHO) have released an updated guideline on drugs for COVID-19, published in the BMJ, in which it advises against the use of the antiviral drug remdesivir for patients with COVID-19.

Dr Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said:

“The move by WHO to advise against the use of remdesivir in COVID-19 patients is disappointing news indeed, but almost certainly the right move. The drug, originally developed during hepatitis C virus antiviral programmes, has long been thought of as one of the best chances to repurpose a broad-spectrum antiviral drug against SARS-CoV2, based upon both efficacy in preclinical models as well as its safe administration in Ebola patients. The drug received emergency use authorisation earlier this year, and was recently approved by the FDA as standard of care for COVID-19.

“Early trials, including placebo-controlled randomised studies such as the NIH-sponsored ACTT-1, supported improved clinical responses for patients given a five day course of intravenous remdesivir. However, the much larger SOLIDARITY trial run by WHO across multiple countries failed to support this finding. Whilst it can sometimes be difficult to reconcile contradictory RCTs, the much greater size and patient diversity in SOLIDARITY makes these data compelling indeed. However, it may be that certain patient subgroups might benefit from Remdesivir, but its current approved status makes it difficult to conduct further trials. This is frustrating given the high cost and need to administer the drug via the intravenous route.

“Whilst this might be disappointing news, Remdesivir might still pave the way towards developing SARS-CoV2 antivirals. Remdesivir is in fact broken down in the body into an active form, and Gilead are currently exploring whether this might also be usable against SARS-CoV2 as it appears less toxic and could potentially be formulated for oral administration. Importantly, remdesivir is relatively unique in being able to subvert one of the defences that the virus uses to avoid damage to its genome – the exonuclease enzyme. This enzyme prevents many related drugs in this class from working well against SARS-CoV2, so understanding how remdesivir subverts this barrier will be important for future programmes.

“Finally, it is important that we do not give up on the development of antivirals against this virus. Whilst many of the drugs initially repurposed during the pandemic have failed to yield dividends, there will remain a need for effective treatments in the future. This stands even in light of recent encouraging reports from vaccine trials as there will likely be small, but significant patient cohorts that are unable to respond to the vaccine due to various immunological conditions, comorbidities or medications. Moreover, the longevity of the pandemic means that bespoke drug development might also be feasible within a meaningful timeframe to achieve patient benefit.”

Prof Martin Landray, Professor of Medicine & Epidemiology, Nuffield Department of Population Health, University of Oxford, said:

“COVID affects millions of people and their families around the world.  It is not a rare disease.  As I and others have said before, we need scalable, affordable, and equitable treatments.  The trials reported to date have shown no impact of remdesivir on survival.  People will argue about the need for earlier use but even if there were modest benefits (say, an improvement in survival of one-fifth), people with mild disease are at low risk so the absolute numbers of lives saved would be small.  Remember too that this is a drug that has to be given by intravenous infusion for 5 to 10 days and costs around £2000 per course.  So remdesivir is not cheap, it is not convenient, and it has no impact on the mortality among the people at highest risk.”

Prof Peter Horby, Professor of Emerging Infectious Diseases and Global Health in the Nuffield Department of Medicine, University of Oxford, said:

“This combined analysis of more than 7000 adults hospitalised with COVID-19 from four randomised controlled trials has found no evidence of a meaningful benefit from remdesivir.  Given this lack of evidence of any benefit on mortality, the risk of ending up on a ventilator or the time to clinical improvement, the World Health Organisation have reasonably recommended against the use of remdesivir in patients hospitalised with COVID-19, whatever their disease severity. Remdesivir is an expensive drug that must be given intravenously for five to ten days, so this recommendation will save money and other healthcare resources. Remdesivir has been recommended in several COVID-19 treatment guidelines so this new analysis will necessitate a rethink about the place of remdesivir in COVID-19.”

DOI: 10.1136/bmj.m3379

The updated  ‘A living WHO guideline on drugs for covid-19’ was published at 00:01 UK time Friday 20 November in the BMJ.

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Dr Stephen Griffin: “No conflicts.”

Prof Martin Landray: “- Co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR; contributions to supply of study treatment from Abbvie, Roche, and Regeneron).

– Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme.-

– Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence.

– Employee of University of Oxford with salary supported by Li Ka Shing Foundation, Health Data Research UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, and National Health Service.

– I do not accept personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries although reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings may be accepted. I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies. I comply with the Independence of Research Policy of the Nuffield Department of Population Health, Universityy of Oxford. For details see: https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf/@@download”

Prof Peter Horby: “Chief Investigator of the RECOVERY trial. The RECOVERY trial is supported by a grant to the University of Oxford from UK Research and Innovation and NIHR (MC_PC_19056 ). Tocilizumab is being studied in RECOVERY. Tocilizumab was provided free of charge for this study by Roche. Lopinavir–ritonavir was provided free of charge for this study by Abbvie.  REGN-COV2 was provided free of charge for this study by Regeneron.

Employee of University of Oxford with salary supported by Wellcome Trust and NIHR.

I do not accept any personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries.

I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies.”