On 4 November, the UK became the first country in the world to approve Molnupiravir, an oral antiviral treatment for Covid-19. Molnupiravir, developed by US companies Merck & Co and Ridgeback Biotherapeutics, was approved by the UK Medicines and Healthcare products (MHRA) for the treatment of mild-to-moderate Covid-19 in adults with a positive Covid-19 diagnostic test and who have at least one risk factor for developing severe illness. In the UK the planned trademark is Lagevrio.
Approval of the drug could provide much needed respite to NHS hospitals struggling to cope with the number of Covid-19 patients being admitted. In clinical trials its use in Covid-19 patients was found to reduce hospitalisations by around 50%.
In October 2021, the UK government secured 480,000 doses of the Merck & Co drug. The UK will start to roll out molnupiravir for use on the NHS through a drug trial later in November in vaccinated people. The drug has so far been tested only in unvaccinated people.
Drug approval was based on results of the MOVe-OUT trial, a phase 3 trial, that recruited patients across the globe, including counties in South America, Europe, Asia, the UK and the USA.
The trial, which was placebo-controlled, tested the drug in non-hospitalised adult patients with laboratory-confirmed mild-to-moderate Covid-19. Patients in the study were unvaccinated and had at least one risk factor associated with poor disease outcomes (e.g., heart disease, diabetes). Patients were enrolled on the trial and randomised to either placebo or drug treatment within five days of developing symptoms. The primary objective of MOVe-OUT was to assess the efficacy of molnupiravir compared to placebo as determined by the percentage of participants who were hospitalised and/or died from the time of randomisation through to day 29.
The study included patients who had Delta, Gamma and Mu variants of Covid-19, which accounted for nearly 80% of the viral variants that had been sequenced at the time of the interim analysis of the study.
Merck & Co reported interim phase 3 results in October 2021. Molnupiravir (800 mg twice daily for five days) was found to have reduced the risk of admission to hospital or death by around 50% in non-hospitalised adults who had mild to moderate Covid-19 and were at risk of poor outcomes when the drug was given within five days of onset of symptoms. At day 29 no deaths were reported in the molnupiravir group, while eight were reported in the placebo group. Recruitment to the trial was then stopped on the advice of the independent data monitoring committee because of the positive results.
In contrast to the developers of the Covid-19 vaccines, Merck & Co is making the drug widely available throughout the world. The company has entered into a licensing agreement with the Medicines Patent Pool to increase broad access in low- and middle-income countries, plus non-exclusive voluntary licensing agreements with Indian generic manufacturers. These agreements will accelerate availability of molnupiravir in more than 100 low- and middle-income countries, many in Asia and Africa, following approvals or emergency authorisation by local regulatory agencies. The availability of the drug at a cheap cost could help economically disadvantaged countries as they struggle to get their population vaccinated. The drug has a short and simple treatment regimen – four pills, twice a day for five days.
Molnupiravir is the first oral antiviral to be approved for Covid-19. It is simple to administer with tablets twice a day. In contrast, remdesivir, the first antiviral approved for Covid-19 has to be administered by IV and is not very effective – it speeds up recovery but does not save lives. Remdesivir is also very difficult and costly to produce; it is not a drug that could be used in economically disadvantaged countries.
A day after molnupiravir approval, Pfizer announced results for its oral antiviral Paxlovid, with a late-phase trial showing that Paxlovid reduces the risk of hospitalization or death by 89% if administered within three days of symptom onset. Paxlovid could possibly be approved in the UK early in 2022. Paxlovid is a combination of PF-07321332 and ritonavir; the latter is an antiviral already approved for the treatment of HIV. As a result of these positive results the trial, known as EPIC-HR, was stopped and Pfizer has sought emergency use authorisation from the FDA. Albert Bourla, Chairman and Chief Executive Officer of Pfizer, called the trial results “a game-changer in the global efforts to halt the devastation of this pandemic.” The UK government has bought 250,000 doses of Paxlovid.
The results of the Paxlovid study suggest the drug is more effective than Merck’s drug, but the trial results may not be directly comparable. Like Merck, Pfizer has said it will offer cheaper prices for Paxlovid to developing countries. The Ritonavir component of Paxlovid is no longer covered by patents and is already made by companies that make generic drugs.
Although both Merck and Pfizer will make the drugs available cheaply in many countries, a major problem in many low to middle income countries will be testing – both drugs need to be administered early in the infection which means testing needs to be easily accessible and with a quick turnaround of results.
Another issue is the possibility of the development of resistance. Most if not all previous antiviral drugs have seen resistance develop and treatments often comprise a cocktail of drugs, such as those given for HIV and hepatitis. Any virus variant that is less susceptible to the way molnupiravir or Paxlovid acts to prevent viral replication could survive and become dominant and drive the evolution of a resistant variant.
On the positive side, the short period of time that both drugs are administered – for just four to five days – will help as there is only a short time for resistance to develop. In addition, short treatment times mean that people are much more likely to take the full course of treatment; not taking the full course means virus left in the body with even slight drug resistance can multiply and become dominant. Both Pfizer and Merck have said that the drugs were well-tolerated in the study population and side effects were mild.
Merck has highlighted that in the trials molnupiravir demonstrated “consistent efficacy” across the Gamma, Delta, and Mu variants of the virus, which suggests that existing strains of the virus have not yet succeeded in developing resistance against the drug.
There is still much to be investigated around the use of both these oral antivirals and how they will perform in a real world setting. How do they work in vaccinated people? Do they prevent viral transmission? How can a combination of vaccine and drugs be used to clamp down on outbreaks of disease? Despite the number of unanswered questions and the need for more trials, the approval of these drugs is very welcome and could signal a turning point in the global fight against Covid-19.
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