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A press release from Merck and Ridgeback states that their oral antiviral molnupiravir reduced the risk of hospitalization or death by approximately 50% compared to placebo for patients with mild or moderate COVID-19 in positive interim analysis of the phase 3 study.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“Drugs that might be beneficial in responding to the SARS-CoV-2 virus may have effects at different stages of the disease process caused by the virus. Dexamethasone only works at a late stage, but other drugs may work if given early enough in the process. The new anti-viral drug molnupiravir is intended to inhibit viral propagation. The “MOVe-IN” trial used this drug in patients who were in hospital with COVID-19 and was stopped in April 2021 because of insufficient clinical benefit.
“This trial was instead done at an earlier stage of the disease process and was carried out in non-hospitalized adult patients with mild-to-moderate COVID-19, comparing the drug with placebo. The patients had to have had symptoms for less than six days and a positive test for the virus. They also had to have at least one risk factor for poor disease outcome such as obesity, older age (>60 years), diabetes mellitus, and heart disease.
“Although it had relatively small numbers analysed (fewer than 400 per group), it had much better results than the study done in hospitalised patients. It approximately halved the rate of hospitalisation and notably reduced the number of deaths. Preventing the virus from replicating at an early stage seems very beneficial.
“An encouraging feature is that Merck (known as MSD in the UK) have committed to “plans to implement a tiered pricing approach based on World Bank country income criteria to reflect countries’ relative ability to finance their health response to the pandemic.” Many anti-viral drugs of this type are very expensive and for those unable to be vaccinated but who get COVID-19 disease, having an alternative is very good news. Whether the actual cost will be affordable is not yet clear.
“This seems to be a well-conducted trial done in many countries, especially Latin America and Europe. Although sites in the US were planned, most patients seem to be from other countries.
“Most patients with mild COVID-19, even with risk factors for severe outcomes, do not progress to hospital or die, and if it could be predicted who would progress, then targeting the drug at them would mean even greater benefit.”
Ruth McKernan, Chair of the UK Bioindustry Association, said:
“The addition of oral drugs directed specifically at the virus for use in the community is a really valuable addition to our toolkit. They have good efficacy and should work across many variants. We need a full set of treatments from preventative vaccines, oral treatments for those infected and additional drugs for hospital use.’
Dr Simon Clarke, Associate Professor in Cellular Microbiology at the University of Reading, said:
“Today’s announcement from Merck of the first antiviral pill to combat Covid-19 seems extremely promising. Although the trials data are yet to be peer reviewed, the claimed 50% reduction in hospitalisation and death in early-stage infections would be impressive.
“When someone is infected by a virus, it makes the cells in their body produce copies of itself. This drug works by causing the machinery that reproduces Covid-19’s genetic material to make mistakes, thereby stopping effective replication. That mode of action could cause problems with our own cells, and while reports are that the drug is well tolerated, we still don’t have full details of any side effects. It’s worth noting that people involved in the trial were instructed to abstain from heterosexual sex or use contraception. While this is routine practice with some other medicines, such as cancer chemotherapy, it suggests that the drug has the potential to cause birth defects should someone become pregnant.
“This news is positive, but we must not be carried away. It would be good for the 50% of patients that it could save from getting seriously ill, but not so much for those who are still hospitalised, despite taking it. There’s currently no way of knowing which group someone will be in. It’s worth remembering that another drug, dexamethasone, was found to save around a third of people who would have died with severe Covid-19, but its clinical introduction did not prevent nearly 100,000 deaths in the UK in the past twelve months.
“There is still no “cure” for covid. It remains the case that the best first line of defence against this disease is to not get infected in the first place, and getting vaccinated is one of the most effective ways to support this. Drugs like molnupiravir may be most useful in cases where the vaccine doesn’t work as well as had been hoped.”
Prof Peter Horby, Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, said:
“A safe, affordable, and effective oral antiviral would be a huge advance in the fight against COVID. Molnupiravir has looked promising in the lab, but the real test was whether it shows benefit in patients. Many drugs fail at this point so these interim results are very encouraging.
“The proportional reduction in the risk of hospitalisation or death is impressive, but it is important to remember that the absolute risks were 14% reduced to 7%, so quite a lot of people need to be treated to prevent one hospitalisation or death. This means the drug needs to be very safe and affordable. The safety data also look good, so again this is encouraging.
“These results are based on an interim analysis of 775 subjects. It is reported that more than 90% of the target 1550 patients have been recruited, so more precise data should become available; as long as the trial subjects are not unblinded, which I really hope they are not.
“A final note on resistance. We need to watch for resistance and think from the outset about the potential role of combination antiviral therapies.”
Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“There are a number of phases to Covid-19 infection:
“Not everybody moves from one stage to the next; and some develop long term sequelae without ever having being symptomatic or seriously unwell
“Symptoms in stages 4 and 5 above appear to be caused by viral replication. At these stages antiviral drugs may be effective, and could prevent patients from developing stage 3 or 4 disease.
“Serious illness in stage 6 above is caused by an immune overreaction – including the dramatically-named “cytokine storm” in many. But at this stage the immune system has usually – perhaps invariably – cleared the virus. There may be non-viable viral RNA to detect on PCR tests; but the viral-replication stage of the disease has passed. At this point treatments need to target the immune overreaction. Antivirals, per se, are useless.
“The problem for antivirals like Merck’s molnupiravir,1 2 is that they would have to be used before people are (usually) deemed ill enough to need anything other than symptomatic self-care treatment. It’s also the case with many other antivirals, like those for influenza or cold sores, that they are only effective if used very early in the course of the disease.
“We have yet to see a peer-reviewed publication with a lot of the underlying data on this drug; but the press release says that “all patients [in the trial] had laboratory-confirmed mild-to-moderate COVID-19, with symptom onset within 5 days of study randomization…”. In other words, the drug worked when it could be given within 5 days from the onset of symptoms. Before it is likely that serious symptoms would have developed, and before hospitalisation is necessary.
“The findings have been met by somewhat breathless enthusiasm by some.3 (That reference – a twitter thread from US epidemiologist Feigl-Ding – contains some useful background references.)
“In my opinion, these drugs might have a role IF you can first identify people at risk of more serious disease (there are lots of measures to use from the simple – are they a care home resident? are they old? – to tools such as QCovid4-6 – that might help with this).
“If you can do this, you could offer antiviral drugs (and/or monoclonal antibodies or convalescent serum) to these individuals, to reduce viral replication with the hope that this will prevent them from becoming seriously ill.
“Sadly, however, quite a lot of the people who enter stage 3 don’t have any significant risk factors. Unless an antiviral medication could be made so cheap and so safe that it can be used “on spec” by people who might have Covid-19, they are unlikely to be widely useful.”
References
Prof Penny Ward, Independent Pharmaceutical Physician, Visiting Professor in Pharmaceutical Medicine at King’s College London, said:
“At last news from Merck-Ridgeback in a press release this morning sharing data from an interim analysis of the ongoing phase-3 treatment trial with molnupiravir in patients with mild to moderate COVID 19.
“The trial enrolled patients with at least one risk factor for severe illness presenting with lab-confirmed COVID. Treatment began within 5 days of first onset of symptoms. The primary outcome was hospitalisation/death within 29 days. Among the placebo group, 14.1% of patients (~1:7) were hospitalised/died compared to 7.3% (~1:14) of the patients that received molnupiravir treatment. Importantly, all reported deaths (8) occurred among patients receiving placebo. The product was reported to be well tolerated. The study continued recruitment while the interim analysis was completed and we can expect a further update when the final data are analysed: early publication of the complete information will be extremely useful to practitioners that might soon be able to prescribe this treatment for their patients.
“The availability of a well-tolerated, effective oral antiviral will be particularly useful in supplementing vaccination as a means to reduce the proportion of patients needing hospital care. It is greatly hoped that the antiviral task force has, like the vaccines taskforce, pre-ordered courses of this medication so that the UK can, at last, properly manage this condition by treating vaccine breakthrough disease and relieve pressure on the NHS during the forthcoming winter.”
Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study
SMC Q&A Briefing with MSD’s Chief Scientific Officer.
Declared interests
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs. I am a participant in the Oxford/Astra Zeneca trial, and on 13th January 2021 learnt I had received the active vaccine.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody). These are my personal views and do not reflect those of either institution.”
Prof Peter Horby: “Co-Chief Investigator of the RECOVERY trial. 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.”
Dr Peter English: “Dr English is on the editorial board of Vaccines Today: an unpaid, voluntary, position. While he is also a member of the BMA’s Public Health Medicine Committee, this comment is made in a personal capacity. Dr English sometimes receives honoraria for acting as a consultant to various vaccine manufacturers, most recently to Seqirus.”
None others received.