- With the increase in mild to moderate Covid-19 cases among vaccinated and unvaccinated people, the eyes are on antivirals like molnupiravir.
- Molnupiravir has an attractive oral formulation ideal for outpatient use, but a lack of long-term data may limit initial deployment to those at high risk.
- Delays in when to use molnupiravir and the patient’s vaccination status are confounding factors in gathering evidence of efficacy in the trial and in practice if it garners regulatory support.
- Data on the reduction of viral isolates from a previous trial are encouraging, but these results still need a strong link to demonstrate that the antiviral leads to improved clinical outcomes.
Merck and Ridgeback Biotherapeutics’ molnupiravir could act as a convenient oral capsule to treat mild or moderate Covid-19 infections. But as clinicians await the results of a late-stage critical trial, questions about the deployment of the antiviral remain important.
If molnupiravir shows positive safety and efficacy data in its ongoing Phase II / III MOVe-OUT trial, particularly in clinically important outcomes such as hospitalization and mortality rates, the antiviral may change the game.
Yet the exact use of molnupiravir and the target population may ultimately come down to post-trial analyzes that measure molnupiravir activity within specific subpopulations. Experts say age, time to infection and vaccination status could all play an important role in determining each patient’s risk-benefit profile. If a major safety or tolerability issue arises in MOVe-OUT, molnupiravir would likely only be used in high risk patients.
While molnupiravir was safe and effective in reducing viral loads in an earlier trial, MOVe-OUT will help determine if this existing data can be transferred to the clinic. And the ongoing global deployment of the vaccine, along with the influx of groundbreaking cases among those who have already received the vaccine, will only complicate the interpretation of the molnupiravir data and their application in practice.
The phase III part of the MOVe-OUT trial, a placebo-controlled study of 1,550 patients of molnupiravir in out-of-hospital Covid-19 patients, recruited 1,100 to 1,200 patients out of its target of 1,550 volunteers, this news site reported on September 20. Test results are expected in November, a Merck spokesperson said. Merck is developing molnupiravir in collaboration with Ridgeback, based in Miami, Fla., Under an agreement announced in May 2020.
People at high risk are probably the first users
If molnupiravir receives regulatory support, doctors themselves will likely determine treatment eligibility based on each patient’s risk-benefit profile, said Dr. Myron Cohen, an infectious disease expert at the University of North Carolina. . MOVe-OUT participants must have at least one characteristic or underlying medical condition associated with an increased risk of severe Covid-19, but more details are not listed on ClinicalTrials.gov.
Compared to intravenous monoclonal antibodies, which are licensed to treat mild to moderate illnesses, small molecules like molnupiravir are less specific and have a higher risk of untargeted side effects, added immunology researcher Dr Sam Lai. and infectious diseases at the University of North Carolina. . Molnupiravir is an oral analogue of ribonucleoside that inhibits RNA virus replication. The drug has certain mutagenic characteristics by which human cells can also be targeted, so there is a theoretical potential to cause genetic alterations, or potentially cancers, noted research professor Dr Luis Menendez Arias at Consejo Superior de Investigaciones CientÃficas in Madrid.
Limiting access will be critical as safety concerns can become more pronounced if the drug is accessed through unregulated means, Menendez Arias explained. An Emergency Use Authorization (EUA) would limit use by physicians while full approval would give them flexibility but more accountability, Cohen said. Merck and Ridgeback have yet to say whether they want an EUA or full approval while reading Phase III.
Current safety data too small
While there were no major safety concerns in the Phase IIa study, it is too small to draw firm conclusions, said Dr. J Stone Doggett, infectious disease expert at Oregon Health. & Science University. In the Phase IIa trial of 202 patients, headache, insomnia and increased alanine aminotransferase were the only adverse events that occurred in more than four participants, according to a preprinted manuscript.
Based on the available data, the initial rollout of molnupiravir in high-risk patients should also take into account renal function, hypertension, household status, likelihood of illness, vaccination status, among others, said Cohen. If the analysis of the MOVe-OUT subgroup is insufficient to make treatment decisions, governments or health programs may undertake separate trials, explained University of Liverpool pharmacology professor Dr Saye Khoo. .
In a separate Phase III trial of molnupiravir as part of a prophylactic post-exposure, which launched earlier this month, any potential safety concerns will be even more relevant, experts agreed.
The delays, the vaccination status introduce challenges
The uncertainty about the optimal time to use molnupiravir adds another challenge to the rollout of the antiviral, explained Khoo, who is participating in a trial on the molnupiravir platform. MOVe-OUT recruits participants with a positive SARS-CoV-2 test based on a sample collected no more than five days before randomization.
Taking molnupiravir early to block the virus is essential and, if participants are enrolled later, the improvement in effectiveness may not be optimal, Menendez Arias added.
On day 3, infectious viral isolates from nasopharyngeal swabs decreased to only 1.9% in the 800 mg molnupiravir group versus 16.7% with placebo (p = 0.02), based on the preprint of the phase IIa. For reference, Gilead’s Veklury (remdesivir), the only approved Covid-19 antiviral, is for hospital patients, but individual patient histories dictate the specific start time of treatment.
Additionally, conducting trials when large numbers of the population are vaccinated will prove difficult for all types of Covid-19 treatment studies, Menendez Arias said. The global MOVe-OUT trial, which began in October 2020, does not list vaccine status as an inclusion / exclusion criteria on ClinicalTrials.gov. In western countries, the field faces breakthrough infections after vaccinations, which is different from infections in other parts of the world where vaccination rates are much lower, Khoo said, noting that viral dynamics will be different in the two cases.
The early efficacy of molnupiravir seems promising
While early viral load reduction data has been encouraging, clinical outcome data from MOVe-OUT is crucial in establishing the true value of molnupiravir, Doggett explained. But the field has yet to correlate viral load data with clinical outcomes, which is difficult given the lack of standardization in viral load measurement, a molnupiravir researcher said.
Hyderabad, India-based Hetero Pharma, the molnupiravir partner of Merck in India, recently announced interim results in 741 participants in its own phase III trial of molnupiravir. Clinical improvement, defined as a two-point decrease on the WHO Clinical Progress Scale, was observed in 63.43% of patients on molnupiravir compared to 22.33% for standard care on day 5, according to a study. July 9th Hetero Pharma publication. The same scale is a secondary MOVe-OUT endpoint.
But Menendez Arias has remained cautious in interpreting small datasets given past experience with Veklury. While the initial data from Veklury that led to its use was positive, the WHO’s largest SOLIDARITY clinical trial showed it offered only marginal improvement, he said.
Alleviating symptoms can be quite appealing
But even relieving symptoms might be enough to authorize an antiviral, because any real-world outcome measurement could convince people of its effectiveness, investigator MOVe-OUT said. Yet no outpatient study has so far shown that a drug can improve symptoms, the investigator added.
Resistance to treatment against molnupiravir is also a central concern of experts. Coronaviruses can be polymorphic with great genetic variability, opening up the risk of resistance to treatment, Khoo said. But there is very little concern about the development of resistance to molnupiravir among the immunocompetent population, as people only take a five-day course, the investigator said. This is different from long-term regimens for other viral diseases like HIV or hepatitis C.