Early COVID-19 drug studies: what have we learned?

The past week has seen first results from studies of existing antiviral drugs and repurposed agents in those hospitalised with COVID-19, raising at least as many questions as answers. A combination of two antivirals (lopinavir–ritonavir: Kaletra®) used to treat HIV infection did not reduce mortality in a randomised study conducted in almost 200 severely-ill Chinese patients[1], although with a hint that earlier treatment might just be of some benefit[2].

Avigan® (avilavir/ favipiravir), an influenza drug approved in Japan and China has been reported as clearing the COVID-19 virus in four days, versus those treated with another antiviral agents. However, this was not a randomised study and involved less severely ill subjects, with benefit confined to those receiving early treatment. Although while broadly hailed as “highly effective in media reports, Avigan’s developer (Fujifilm) has been cautious in making claims around efficacy. Avigan® has been associated with severe adverse events, limiting its use as an influenza treatment.

An investigational antiviral with a similar mechanism of action, remdesivir (GS-5734; Gilead Sciences, Inc), and which is known to be active against the SARS and MERS coronaviruses is in late-stage testing in China, the US and South Korea. Anecdotal findings from a small number of severely ill patients infected while aboard a cruise ship have suggested remdesivir may have reduced reliance on ventilator support. Despite an absence of hard evidence, the drug was approved for compassionate use in the US on March 19^th. As of today (Sunday 22^nd March), Gilead was forced to temporarily limit patient access to remdesivir due to “overwhelming demand”[3].

Similarly, chloroquine, a decades old antimalarial drug, has also been approved for compassionate use on the back of anecdotal evidence, with the hope that it may also have a prophylactic effect. A related drug, hydroxychloroquine, in combination with the antibiotic azithromycin, has been reported as reducing viral burden in a small study[4]. Both drugs have been reported to be in short supply through high demand in the US, leading to problems for autoimmune disease patients dependent on the same drugs.

Actemra®, a biologic developed for rheumatoid arthritis targets the cytokine IL-6, an immune system component responsible for the “cytokine storm” observed in CAR-T therapy and apparently a contributor to the pathology of severe COVID-10 infection has been observed to be of benefit in a small and uncontrolled study in China. A similar anti-IL-6 biologic, Kevzara® (Regeneron) is moving towards Phase III studies in COVID-19 infection.

No big wins, but, and perhaps the most you can hope for from early, essentially empirical interventions and anecdote are hints and glimmers of possible ways forward. More such early and empirical, will light the way, with China, not surprisingly, ahead of the curve with over thirty medicines (including traditional Chinese medicines) identified as having an anti-COVID-19 effect in the laboratory.

[In case you missed it in my Favourites sidebar, check out Derek Lowe's blog: 
https://blogs.sciencemag.org/pipeline/archives/2020/03/24/the-latest-coronavirus-clinical-trials#comment-314221]

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[1] A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. Cao B et al. NEJM

Online March 18^th 2020 March 18, 2020 DOI: 10.1056/NEJMoa2001282 https://tinyurl.com/ulpek4c

[2] Covid-19 — The Search for Effective Therapy. Baden LR et al. NEJM online March 18^th 2020 DOI: 10.1056/NEJMe2005477 https://tinyurl.com/yx6jrrxe

[3] Gilead pauses access to experimental Covid-19 drug due to ‘overwhelming demand’. Herper M. STAT online March 22^nd 2020 https://tinyurl.com/tum92s6

[4] Information for Clinicians on Therapeutic Options for COVID-19 Patients. CDC website accessed 22^nd March 2020. https://tinyurl.com/rx7ujpz