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A blockbuster drug developed by US pharmaceutical group Merck to treat Covid-19 has been linked to mutations transmitted when the coronavirus spreads between patients, a finding that will increase scrutiny about its usefulness and the billions spent by governments on its procurement.
Researchers analysed a family tree of 15mn sequences of coronavirus to see which mutations had occurred and when, with the results showing they increased in 2022 after molnupiravir, which is also known by the trade name Lagevrio, was introduced in many countries.
The mutations were also more likely to be seen in older age groups and people more at risk of severe disease who were taking molnupiravir, and in countries where the antiviral treatment was more widely used.
The findings will raise concerns about the effectiveness of antiviral drugs to treat Covid-19 as health authorities prepare for a busy autumn after a rise in cases driven by Omicron subvariants with a large number of mutations.
The researchers, from the UK’s Francis Crick Institute, the universities of Cambridge, Liverpool and Cape Town, Imperial College London and the UK Health Security Agency, matched the signature in these mutations to those seen in trials of the drug.
“Molnupiravir treatment can sometimes result in viruses that carry large numbers of mutations but remain viable, and in some cases transmissible,” said Theo Sanderson, lead author and postdoctoral researcher at the Francis Crick Institute, who said the findings were useful for assessing the drug’s risks and benefits. “The possibility of persistent antiviral-induced mutations needs to be taken into account for the development of new drugs which work in a similar way.”
Antiviral medicines target viruses in a bid to prevent them infecting healthy cells, helping immune systems fight off the infection. Molnupiravir, marketed by Merck and co-developed with US biotech group Ridgeback Biotherapeutics, works by inducing small mutations in the virus itself.
The study, which is peer-reviewed and was published in Nature, also suggests there were small clusters of mutations that were able to transmit between patients, though the genetic signature is not linked to any current variants of concern. There is no evidence the uptick of cases driven by Omicron variants such as BA. 2.86 is linked to the use of molnupiravir.
The European Medicines Agency denied molnupiravir marketing authorisation, as first reported by the Financial Times in 2022, and it is now very seldom used in other western countries. Merck initially contested the European regulator’s decision but later withdrew its appeal.
In the US, the Food and Drug Administration in late 2021 approved emergency use for certain categories of patients.
Yet Merck recorded sales worth more than $6bn between 2021 and 2022, and the figure does not include sales in poorer markets where licensed companies make generic versions of the drug.
Andrew Hill, a senior visiting research fellow at Liverpool university’s pharmacology and therapeutics department, said the drug also had potential side effects for pregnant women.
Moreover, the drug failed to show it could lower the risk of hospitalisation and death among adults at higher risk from the disease, according to the results of a clinical trial in the UK released last year. The results were a significant setback after early-stage data showed molnupiravir cut the risk of death or hospitalisation in half, a figure later revised to about 30 per cent.
Merck told the FT on Monday that the study had limitations that the authors themselves had acknowledged and that it was “confident” in the clinical profile of the drug.