Technology

The deployment of Molnupiravir in Merck and Ridgeback is difficult to map to the uncertain Covid-19 landscape

If molnupiravir shows positive safety and efficacy data in an ongoing Phase II / III MOVe-OUT trial, antiviral drugs may prove to be breakthrough. Credit: Shutterstock

You need to know:

  • Antiviral drugs such as molnupiravir are attracting attention due to the increasing number of mild to moderate Covid-19 cases in both vaccinated and unvaccinated individuals.
  • Molnupiravir has an attractive oral formulation ideal for outpatient use, but lack of long-term data may limit its initial deployment to high-risk people.
  • The timeline for when to use molnupiravir and the vaccination status of patients is a confounding factor in collecting evidence of efficacy in the case of trial and actual regulatory support.
  • Although viral isolate reduction data from previous trials are promising, these results require hard links to demonstrate that antiviral drugs lead to improved clinical outcomes.

Molnupiravir from Merck and Ridgeback Biotherapeutics may serve as a convenient oral capsule for the treatment of mild or moderate Covid-19 infections. However, as clinicians await the results of important late-stage trials, the question of antiviral deployment is still very urgent.

When molnupiravir shows good safety and efficacy data in ongoing Phase II / III MOV e-OUT trialAntiviral drugs can prove to be breakthrough, especially in clinically significant outcomes such as hospitalization and mortality.

-->

However, the exact use of molnupiravir and the target population may ultimately result in post-test analysis to measure the activity of molnupiravir within a particular subpopulation. Experts state that age, infection timeline, and vaccination status can all play an important role in determining the risk and benefit profile of an individual patient. Molnupiravir may only be used in high-risk patients if MOVe-OUT raises significant safety or tolerability concerns.

Molnupiravir was safe and effective in reducing viral load in previous trials, but MOVe-OUT reveals whether this existing data can be converted to a clinic.And in progress Global vaccine developmentIn addition to the influx of groundbreaking cases among those who already have jabs, it only makes it difficult to interpret and actually apply Molnupiravir data.

The Phase III portion of the MOVe-OUT trial is a placebo-controlled trial of 1,550 patients with molnupiravir in unhospitalized Covid-19 patients. Enroll 1,100-1,200 patients Of its 1,550 volunteer goals, the news site reported on September 20th. The test results are scheduled for November, according to a Merck spokeswoman.Merck is co-developing Molnupiravir Ridgeback based in Miami, Florida According to the transaction announced in May 2020.

High-risk individuals are probably the first users

Dr. Myron Cohen, an infectious disease expert at the University of North Carolina, said that if Molnupiravir is backed by regulatory agencies, doctors may themselves determine treatment eligibility based on each patient’s risk and benefit profile. Said it was expensive. MOVe-OUT participants must have at least one characteristic or underlying medical condition associated with an increased risk of severe Covid-19, but details are not listed on ClinicalTrials.gov.

Small molecules such as Mornupyrabir have lower specificity and a higher risk of untargeted side effects compared to intravenous monoclonal antibodies that are approved for the treatment of mild to moderate disease, according to the University of North Carolina Immunology and Infectious disease researcher Dr. Samurai added. .. Molnupiravir is an oral ribonucleoside analog that inhibits RNA virus replication. Dr. Luis Menendez Arias, a research professor at Consejo Superior de Investigaciones Científicas in Madrid, said the drug has certain mutagenicity and can target human cells, which can lead to genetic alterations and potentially cancer. I am.

Menendez Arias explained that restricting access is important because access to drugs by unregulated means can make safety issues more pronounced. According to Cohen, the Emergency Use Authorization (EUA) limits the use of physicians, and full approval gives physicians flexibility, but will give them more responsibility. Merck and Ridgeback have not yet indicated whether to pursue EUA or full approval when reading Phase III.

Current safety data is too small

There were no major safety concerns in the Phase IIa study, but it was too small to draw definitive conclusions, said Dr. J Stone Doggett, an infectious disease expert at Oregon Health & Science University. In a phase IIa study of 202 patients, headache, insomnia, and increased alanine aminotransferase were the only adverse events that occurred in 4 or more participants. Preprint manuscript..

Based on the available data, Cohen said the initial deployment of molnupiravir in high-risk patients should also consider, among other things, renal function, hypertension, family status, potential disease, and vaccination status. rice field. If the MOVe-OUT subgroup analysis is inadequate to make treatment decisions, the government or health program may conduct separate trials, explained Dr. Saye Khoo, a professor of pharmacology at the University of Liverpool.

of Another phase III trial Experts agreed that the use of molnupiravir in a post-exposure post-exposure setting, which began earlier this month, would further address potential safety concerns.

Timeline, vaccination status poses challenges

Uncertainty about the optimal timing of molnupiravir use adds another challenge to the deployment of antiviral drugs, explained Kuu, who is involved in the molnupiravir platform trial. MOVe-OUT is recruiting participants with a positive SARS-CoV-2 test based on samples collected within 5 days of randomization.

It is important to take molnupiravir early to block the virus, and if participants are enrolled later, improved efficacy may not be optimal, Menendez Arias added.

On day 3, infectious virus isolates from the nasopharyngeal swab decreased to only 1.9% in the 800 mg molnupiravir treatment group compared to 16.7% for placebo (p = 0.02), Phase IIa preprints is showing. For reference, Gilead’s Becklely (remdesivir), the only approved Covid-19 antiviral drug, is intended for inpatients, but the patient’s individual medical history determines the specific start time of treatment.

In addition, conducting trials when a large population is vaccinated proves difficult for all types of Covid-19 treatment studies, Menendez Arias said. The global MOVe-OUT trial, launched in October 2020, does not indicate vaccination status as a inclusion / exclusion criterion for ClinicalTrials.gov. In Western countries, this area is addressing breakthrough infectious diseases after vaccination. This is unlike infectious diseases in other parts of the world where vaccination rates are much lower, Kuu said, and the kinetics of the virus would be different in both cases.

The early effectiveness of molnupiravir looks promising

Although early viral load reduction data were promising, MOVe-OUT clinical outcome data are important for establishing the actual value of molnupiravir, Doggett explained. However, this area has not yet correlated viral load data with clinical outcomes. This is difficult given the lack of standardization of viral load measurements, said Molnupiravir researchers.

Hetero Pharma, based in Hyderabad, India, a Molnupiravir partner in Merck, India, recently released interim results of 741 participants from its own Phase III Molnupiravir trial. According to the July 9 release of Hetero Pharma, the clinical improvement defined by a 2-point reduction in the WHO Clinical Progression Scale was in 63.43% of patients with molnupiravir compared to 22.33% of standard treatment on day 5. It was observed. The same scale is the MOV e-OUT secondary endpoint.

However, Menendez Arias remained cautious in interpreting small datasets, based on his past experience with Veklury. The first Veklury data that led to its use were positive, but WHO’s larger SOLIDARITY clinical trial showed that it provided only minor improvements, he said.

Relieving symptoms may be attractive enough

However, even alleviating symptoms may be sufficient to license antiviral drugs, as actual outcome indicators can convince people of their effectiveness, MOVe-OUT said. Researchers said. Still, so far, no outpatient studies have shown that the drug may improve symptoms, the researchers added.

Treatment resistance to molnupiravir is also in the minds among professionals. Coronavirus can be a polymorphism with a lot of genetic diversity, opening up the risk of treatment resistance, Kuu said. However, because people only take a five-day course, there is little concern among immunists about developing resistance to molnupiravir. This is different from the long-term regimen for other viral diseases such as HIV and hepatitis C.



https://www.pharmaceutical-technology.com/analysis/molnupiravir-market/ The deployment of Molnupiravir in Merck and Ridgeback is difficult to map to the uncertain Covid-19 landscape

Back to top button