Unexpected win opens the way to an oral Covid antiviral

Molnupiravir, a repurposed flu antiviral with a poor history, delivers in a pivotal study in Covid-19 outpatients.

If Merck’s acquisition of Acceleron yesterday had been widely expected the same cannot be said of today’s positive results for the group’s Covid-19 antivital molnupiravir. The Ridgeback Biotherapeutics-partnered project had already failed in hospitalised subjects, so today’s pivotal study success in outpatients is a major shot in the arm.

With analysts hailing the data, from a planned interim analysis of the Move-Out trial, a “game changer”, Merck opened up 10% this morning, equivalent to a market cap increase of almost $20bn. The success comes in contrast to the lacklustre performance of some other Covid treatments, and marks a turnaround for molnupiravir, a repurposed flu antiviral.

As Evaluate Vantage had pointed out, the pipeline for oral antivirals for Covid-19 was looking thin. Merck itself, in addition to scrapping part of its molnupiravir work, had abandoned MK-7110, a separate project it had gained via Oncoimmune, in hospitalised patients after an FDA request for more data made it unviable for the coronavirus in the short term.

Oral game-changer

Today the story is quite different, however, and molnupiravir's oral dosing is the main reason why this is being hailed as such a success. The convenience of a drug that can be taken as a tablet, at home, within five days of Covid-19 symptoms starting, cannot be understated.

Not only that, but Move-Out has shown a 50% reduction in risk of hospitalisation or death, Merck said today, hitting a p value of 0.0012 at an interim analysis triggered by the evaluation of the first 775 of a total 1,550 mild-to-moderate Covid-19 patients. A decision to stop recruitment based on compelling interim efficacy was taken on August 5, Merck said, with over 90% of the total enrolled, and full analysis is forthcoming.

The only US-approved antiviral is Gilead’s Veklury, but this has the disadvantage of IV dosing. Moreover, its clinical backing is somewhat unconvincing: two trials showed an improved time to recovery versus placebo but a third did not, and no decrease in mortality has been demonstrated with Veklury.

Remaining existing competition in the treatment setting comes from antibodies. Regeneron’s Regen-Cov, a combo of the MAbs casirivimab and imdevimab, and Lilly/Abcellera’s bamlanivimab plus etesevimab are both available under emergency use authorisation for post-exposure prophylaxis, and both have demonstrated reductions in hospitalisation or death.

However, like Veklury both have to be injected. Another MAb combo, Astrazeneca’s AZD7442, does have the convenience of intramuscular dosing and a long half life, but failed in post-exposure prophylaxis. It did succeed in pre-exposure prophylaxis, but clearly this is a separate market from the treatment setting Merck is now targeting.

Oral antivirals for treating Covid-19 
Project  Company  Setting  Note
Molnupiravir Merck & Co/Ridgeback  Ph3 in outpatients succeeded (Move-Out, NCT04575597);
Ph2/3 in hospitalised pts terminated (Move-In; NCT04575584)
Repurposed flu antiviral 
AT-527 Roche/Atea Ph3 in outpatients ends Nov 2021 (Morningsky, NCT04889040) Repurposed hep C antiviral 
PF-07321332 Pfizer Ph3 in low-risk outpatients ends Oct 2021 (NCT05011513)
Ph3 in high-risk outpatients ends Nov 2021 (NCT04960202)
Ritonavir combo
Favipiravir Appili Ph3 in outpatients ends Sep 2021 (Preseco, NCT04600895) Repurposed flu antiviral 
Upamostat Redhill Biopharma Ph2/3 in outpatients ends Sep 2022 (NCT04723537) Repurposed oncology project (Mesupron)
Source: Evaluate Pharma & clinicaltrials.gov.

The Move-Out data have yet to be scrutinised in full, but the interim readout breaks down into a 39% reduction in day-29 hospitalisation, and zero deaths on molnupiravir versus eight on placebo. It will be important for these data to hold up at final analysis.

Other reasons for optimism is that Merck said the results were consistent across the viral variants Gamma, Delta and Mu in patients where sequencing had been carried out. Logically, Merck intends to file for US emergency use authorisation.

In terms of competition the next dataset to look out for will come from Roche/Atea’s AT-527, Pfizer’s PF-07321332 and Appili's favipiravir, but beyond that the oral antiviral space looks bleak. Illustrating the game-changing nature of an oral Covid-19 treatment, Atea this morning traded up 20%, while the MAb players Regeneron and Abcellera were off 7% and 8% respectively.

A final point to consider is why this took Merck so long; Move-Out had begun last October, yet with the Covid-19 pandemic raging in many of the countries in which the trial was run it took 10 months to generate 775 patients’ worth of 29-day data. Perhaps this illustrates just how low hopes had been.

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