Merck has announced that its experimental drug for severe COVID cuts the risk of hospitalisation or death by about half, according to interim clinical trial results The tablet, molnupiravir, was given twice a day to patients recently diagnosed with the disease.
US drug-maker Merck said its results were so positive that outside monitors had asked to stop the trial early, reports the BBC. It said it would apply for emergency use authorisation for the drug in the US in the next two weeks.
Dr Anthony Fauci, chief medical adviser to US President Joe Biden, said the results were “very good news”, but urged caution until the US Food and Drug Administration (FDA) had reviewed the data.
If authorised by regulators, molnupiravir would be the first oral antiviral medication for COVID-19.
The pill, which was originally developed to treat influenza, is designed to introduce errors into the genetic code of the virus, preventing it from spreading in the body. An analysis of 775 patients in the study found:
* 7.3% of those given molnupiravir were hospitalised
* that compares with 14.1% of patients who were given a placebo
* there were no deaths in the molnupiravir group, but eight patients who were given a placebo in the trial later died of COVID.
The data were published in a press release and have not yet been peer-reviewed.
Unlike most COVID vaccines, which target the spike protein on the outside of the virus, the treatment works by targeting an enzyme the virus uses to make copies of itself. Merck, known by the name MSD in the UK, said that should make it equally effective against new variants of the virus as it evolves in the future.
Daria Hazuda, Merck's vice-president of infectious disease discovery, told the BBC: “An antiviral treatment for people who are not vaccinated, or who are less responsive to immunity from vaccines, is a very important tool in helping to end this pandemic.”
Trial results suggest molnupiravir needs to be taken early after symptoms develop to have an effect. An earlier study in patients who had already been hospitalised with severe COVID was halted after disappointing results.
Global approval
Merck is the first company to report trial results of a pill to treat COVID, but other companies are working on similar treatments. Its US rival Pfizer has recently started late-stage trials of two different antiviral tablets, while Swiss company Roche is working on a similar medication.
Merck has said it expects to produce 10m courses of molnupiravir by the end of 2021. The US government has already agreed to spend $1.2bn on the drug if it receives approval from the regulatory body, the FDA.
The company said it is in ongoing discussion with other countries, including the UK, and has also agreed licencing deals with a number of generic manufacturers to supply the treatment to low and middle-income countries.
Prof Penny Ward, from King’s College London, who was not involved in the trial, said: “It is greatly hoped that the antiviral task force has, like the vaccines taskforce, pre-ordered courses of this medication. [This is] 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.”
Prof Peter Horby, an expert in infectious diseases at 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 positive clinical trial results for molnupiravir have reverberated through the healthcare sector, and Reuters reports Merck's stock price has soared, while denting high-flying shares of vaccine companies and makers of other coronavirus therapies.
While experts have hailed the news as potentially a huge advance in the fight against COVID-19, shares of vaccine makers such as Moderna, Pfizer and partner BioNTech SE have been hit, with some analysts saying the promise of an oral drug that can be taken at home could change the public perception of risks associated with COVID-19.
Merck leads the race in developing the first oral antiviral medication for COVID-19, adds Reuters, with rivals Pfizer and Roche Holding AG, with partner Atea Pharmaceuticals, running late-stage trials of their pills.
However, there are still unanswered questions about the drug, writes STAT in an in-depth article unpacking "what we know and don't know about molnupiravir".
Rightly so, doctors are excited about the medicine because a regimen of pills, even one that involves taking several pills twice daily for five days, should be far easier to deliver to patients than current antiviral COVID-19 treatments, given intravenously. But it’s still unclear how widely this treatment will be used.
Here are some things to keep in mind about molnupiravir and about other COVID-fighting pills in development at other companies.
How many other anti-COVID pills will end up proving effective? One of the reasons he success of molnupiravir is such a big deal is that there were questions regarding whether an antiviral pill could help COVID-19 patients if given early enough. This medicine certainly did, reducing hospitalisations by 50%; it also appeared to have an impact on whether patients survived.
Results for other drugs are likely to be released by the end of the year. That includes data about a similar pill, also a five-day course, from Atea Pharmaceuticals and Roche, and about a pill developed by Pfizer that is from a different drug class and might be combined with molnupiravir.
Another positive note for all these drugs: remdesivir, the intravenous antiviral made by Gilead Sciences, also showed positive results when used for three days after onset of symptoms. That’s not practical — it had to be given via IV for three days — but bodes well for antiviral pills showing some efficacy. It’s even possible those pills might be combined.
How safe is molnupiravir?
Obviously, a drug given early in COVID needs a clean safety profile. So far, the data included in the press release look very good. Patients in the placebo arm were three times more likely to withdraw from the study due to apparent side effects than those who actually received molnupiravir. That probably means the side effects of COVID were worse than those of the drug.
But, says STAT, only so much can be seen from that kind of data. Molnupiravir works by messing up how the virus copies RNA, its genetic material, preventing viral replication. There is some concern it could be mutagenic, meaning it could cause mutations. One result could be that it causes birth defects. In the clinical trial, both women and men were told to either abstain from sexual intercourse or to use contraception while they were taking the drug and for at least four days after. Women of childbearing age also needed a negative pregnancy test to start taking the medicine.
Could there be other effects? In a conference call with reporters last Friday, Merck virologist Daria Hazuda said that Merck and Ridgeback had studied the mutagenic potential of the drug in both cell lines and in animal models that are routinely used in drug development and which are accepted by regulatory agencies.
“I would say that in all of the models where we have looked, we have seen no evidence of the potential for mutagenicity for this agent,” Hazuda said. “We’re very comfortable that the drug will be safe if used as intended and at the concentrations where we have looked and in the concentrations which we are achieving in patients.”
Will molnupiravir be used only in unvaccinated patients?
Merck’s trial was conducted entirely in patients who had not been vaccinated. That made it much easier to show that the medicine can reduce hospitalisation and death — because patients who have not previously been vaccinated are more likely to be hospitalised or die. But does that mean that, in practice, the drug will only be used in unvaccinated patients, or will it be used in cases of breakthrough infections? It’s hard to say. Patients with breakthrough infections are at lower risk of hospitalisation, which could change the risk-benefit calculus around the medicine.
So how big will the market be? Daina Graybosch, an analyst at SVB Leerink, forecast in a note to investors on Monday morning that molnupiravir sales will peak near $5 billion a year in 2022. Built into this are various assumptions, adds STAT, among them that the first-mover advantage will mean Merck and Ridgeback will be used more than the other pills in development and that vaccinated patients with breakthrough infections will be eligible to receive the drug, too.
How will the availability of COVID pills affect vaccines and other treatments? It doesn’t make any sense to forego a COVID vaccine because a pill to treat the disease exists. The benefits are additive, and someone who got a breakthrough infection and then the pill has a much lower risk of hospitalisation than someone who just relied on the pill.
But it’s likely some people will feel less urgency to get vaccinated as a result of molnupiravir’s existence, and shares in Pfizer, BioNTech, and Moderna all fell on Friday. The latter two were down again Monday morning.
Shares in Regeneron also fell, as oral drugs create uncertainty for its monoclonal antibody treatment for COVID. The landscape there is uncertain, with other companies coming forward with antibodies that may have advantages. One small firm, Adagio Therapeutics, recently presented early data on an antibody it thinks could be given as a single shot.
How does this treatment relate to Ivermectin?
This is simple: it doesn’t. But it’s worth taking a look at what data are available for each. Ivermectin, ironically, is another Merck drug. The company’s donation of the medicine to be used to combat a parasitic disease called river blindness is one of the great examples of pharmaceutical philanthropy. It’s also used as a veterinary drug to treat heartworm.
Early in the pandemic, continues STAT, there were studies in cell cultures that showed that Ivermectin and another drug, hydroxychloroquine, might be worth testing as COVID-19 treatments. Multiple studies have failed to show a benefit for hydroxychloroquine, but the picture is murkier for Ivermectin. Still, one of the largest studies showing a benefit was withdrawn due to widespread flaws.
A study conducted in Brazil, the Together Trial, that tested a three-day course of Ivermectin compared with placebo, showed there was no benefit on hospitalisations and ER visits. That would make it unlikely that ivermectin, an old antiparasitic, would have efficacy approaching this newer antiviral.
Drug companies, writes STAT, are unlikely to conduct large, rigorous studies of older generic medicines — although Novartis did begin, then stop, a hydroxychloroquine study. But right now it is unlikely that Ivermectin is the oral COVID medicine the world needs. Molnupiravir, on the other hand, might be.
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
Molnupiravir Phase 3 Interim Trial Results
The planned interim analysis evaluated data from 775 patients who were initially enrolled in the Phase 3 MOVe-OUT trial on or prior to 5 August 2021. At the time of the decision to stop recruitment based on the compelling interim efficacy results, the trial was approaching full recruitment of the Phase 3 sample size of 1,550 patients, with more than 90% of the intended sample size already enrolled.
The phase 3 MOVe-OUT trial was a global, randomised, controlled, double-blinded assessment of molnupiravir versus placebo in non-hospitalised adults with mild to moderate COVID-19. Eligible trial participants had ≥1 risk factor associated with poor COVID-19 outcomes and symptom onset within 5 days prior to their randomisation.
Investigators sought a primary efficacy outcome of percentage of participants who are hospitalised and/or who have died through 29 days post-randomisation.
At the time of non-peer reviewed, unpublished interim data being shared, the Delta, Gamma, and Mu SARS-CoV-2 variants accounted for approximately 80% of the evaluable cases in MOVe-OUT. Global trial recruitment prominently included patients from Latin America (55%), Europe (23%), and Africa (15%).
The most commonly observed severe COVID-19 risk factors in participants included obesity, older age (≥60 years), diabetes mellitus, and heart disease.
Investigators planned to evaluate interim data from 775 MOVe-OUT participants who were enrolled prior to August 5 of this year.
The interim analysis showed molnupiravir reduced patient risk of COVID-19 hospitalisation or death by approximately 50%. Just 28 (7.3%) of patients to receive molnupiravir experienced either outcome, versus 53 (14.1%) patients administered placebo (P = .0012). No patients to receive molnupiravir had died through 29 days post-randomisation, versus 8 patients to receive placebo.
Based on available viral sequencing data from approximately 40% of trial participants, investigators observed consistent efficacy of the oral antiviral across Gamma, Delta, and Mu variants.
Adverse events occurred in 35% and 40% of all molnupiravir and placebo patients, respectively, with fewer molnupiravir patients reporting trial discontinuation due to an adverse event (1.3%) than placebo patients (3.4%).
BBC article – Covid antiviral pill can halve risk of hospitalisation (Open access)
STAT article – What we know — and don’t know — about Merck’s new Covid-19 pill (Open access)
See more from MedicalBrief archives:
Reduction in infectious SAR-CoV-2 with molnupiravir — Small US study
Promising early findings from Merck/Ridgeback Phase 2a trial of oral COVID-19 therapeutic
COVID jabs for billions of humans will earn their makers billions of dollars