Drug Discovery and Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE

Early safety concerns accompanied Merck’s molnupiravir, the first potential oral COVID-19 therapy 

By Brian Buntz | October 4, 2021

Merck logoThe antiviral molnupiravir appears to be destined to become the first oral treatment for COVID-19. Merck and its partner Ridgeback Biotherapeutics intend to file for emergency use authorization after announcing that the drug appears to reduce the risk of hospitalization or death by about 50%.

One potential hurdle for the drug is whether unvaccinated individuals will accept the treatment, given their higher likelihood of contracting severe COVID-19. According to McKinsey, unvaccinated individuals tend to be most concerned about the potential of COVID-19 vaccines to cause long-term side effects.

The lack of long-term safety data concerning molnupiravir could be an obstacle for skeptical patients. That’s especially the case given early conclusions that there are “persistent side-effect concerns with mutagenic molnupiravir,” as a Clinical Trials Arena article observed. That article goes on to cite Ron Swanstrom, a professor at the University of North Carolina, Chapel Hill, who in January questioned “whether molnupiravir could be metabolized into a precursor of DNA,” and then “enter the host cell nucleus, leading to oncogenesis.”

In theory, mutagenic drugs can cause either birth defects or cancer. The inclusion criteria for the Phase 3 study of molnupiravir required males to refrain from donating sperm and either agree to abstain from sex or use contraception. Females were required to not be pregnant or breastfeeding. Women who were of child-bearing age had to agree to use a highly effective contraceptive method or be abstinent for 28 days from the start of the study intervention. In addition, women of childbearing age must have had a negative highly sensitive pregnancy test within 24 hours before receiving the first dose of medicine.

Merck did not immediately respond to a request for comment. However, in a conference call last week, Merck virologist Daria Hazuda stressed that Merck had seen “no evidence of the potential for mutagenicity” for this agent. She concluded that the company is “very comfortable that the drug will be safe if used as intended.”

Molnupiravir is a prodrug of nucleoside analogue β-D-N4-hydroxycytidine (NHC), which could potentially be incorporated in mammalian DNA.

One study determined there was evidence that the drug could potentially drive mutagenesis in both viral RNA and mammalian DNA. “It seems unlikely that a short course of therapy would spare the host from this exposure because both RNA precursors that affect the virus and DNA precursors that would affect the host pass through the common ribonucleoside diphosphate intermediate,” concludes an article in the Journal of Infectious Diseases.

SVB Leerink analyst Dr. Geoffrey Porges predicts that FDA would restrict who has access to the drug over safety concerns, according to Barron’s.

In the Phase 3 trial of the drug, the side effects of COVID-19 are apparently worse than that of molnupiravir as patients in the placebo group were more likely to withdraw early than recipients of the drug.

An August article published in the Journal of Infectious Diseases found that β-D-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) “displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.”

Last year, the former Head of U.S. Biomedical Advanced Research and Development Authority (BARDA) Rick Bright opposed granting additional funding to develop the drug, partly over safety concerns related to the drug. In a complaint summarized in Science, Bright wrote that “similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls.”

The Science article also quotes the Emory University chemist Raymond Schinazi who stated that his previous pharmaceutical company, Pharmasset, abandoned a similar drug in 2003 after discovering its mutagenic properties.

Scientists at Emory University’s Drug Innovation Ventures at Emory (DRIVE) report seeing no evidence of mutagenicity.

In April, Merck announced that it had performed extensive nonclinical research to characterize the safety profile of molnupiravir. “This program included assays such as Big Blue and PIG-a, which are designed to provide a robust measure of a drug or chemical’s ability to induce mutations in vivo,” the company said. “Animals were administered molnupiravir for longer and at higher doses (mg/Kg) than those employed in human studies.” The company concluded that the data from the studies indicate that molnupiravir is not “mutagenic or genotoxic in vivo mammalian systems.”

The first-in-human Phase 1 study also confirmed molnupiravir’s safety profile. There were no serious adverse events among monlupiravir recipients. In addition, fewer than half of those who received the drug reported an adverse event. Among those who did, 93.3% were mild, according to an article published in Antimicrobial Agents and Chemotherapy.

There was also no evidence of accumulation of the drug in the study, the report authors wrote.

It’s also worth noting that molnupiravir will likely be used on a short-term basis, which will likely limit adverse events.

“Molnupiravir demonstrated good tolerability and dose-proportional pharmacokinetics following administration to healthy volunteers at clinically relevant doses is well-positioned to be evaluated for clinical efficacy and safety in large-scale COVID-19 studies,” the report authors concluded.


Filed Under: clinical trials, Drug Discovery, Infectious Disease
Tagged With: coronavirus, covid-19, Merck
 

About The Author

Brian Buntz

As the pharma and biotech editor at WTWH Media, Brian has almost two decades of experience in B2B media, with a focus on healthcare and technology. While he has long maintained a keen interest in AI, more recently Brian has made making data analysis a central focus, and is exploring tools ranging from NLP and clustering to predictive analytics.

Throughout his 18-year tenure, Brian has covered an array of life science topics, including clinical trials, medical devices, and drug discovery and development. Prior to WTWH, he held the title of content director at Informa, where he focused on topics such as connected devices, cybersecurity, AI and Industry 4.0. A dedicated decade at UBM saw Brian providing in-depth coverage of the medical device sector. Engage with Brian on LinkedIn or drop him an email at bbuntz@wtwhmedia.com.

Related Articles Read More >

Lokavant’s Spectrum v15 uses AI to cut trial-feasibility modeling from weeks to minutes
Glass vial, pipette and woman scientist in laboratory for medical study, research or experiment. Test tube, dropper and professional female person with chemical liquid for pharmaceutical innovation
Unlocking ‘bench-to-bedside’ discoveries requires better data sharing and collaboration
How biosimulation and virtual trials can bust through clinical trial roadblocks
Complexity’s counterpoint: Understanding protocol optimization 
“ddd
EXPAND YOUR KNOWLEDGE AND STAY CONNECTED
Get the latest news and trends happening now in the drug discovery and development industry.

MEDTECH 100 INDEX

Medtech 100 logo
Market Summary > Current Price
The MedTech 100 is a financial index calculated using the BIG100 companies covered in Medical Design and Outsourcing.
Drug Discovery and Development
  • MassDevice
  • DeviceTalks
  • Medtech100 Index
  • Medical Design Sourcing
  • Medical Design & Outsourcing
  • Medical Tubing + Extrusion
  • Subscribe to our E-Newsletter
  • Contact Us
  • About Us
  • R&D World
  • Drug Delivery Business News
  • Pharmaceutical Processing World

Copyright © 2025 WTWH Media LLC. All Rights Reserved. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of WTWH Media
Privacy Policy | Advertising | About Us

Search Drug Discovery & Development

  • Home Drug Discovery and Development
  • Drug Discovery
  • Women in Pharma and Biotech
  • Oncology
  • Neurological Disease
  • Infectious Disease
  • Resources
    • Video features
    • Podcast
    • Webinars
  • Pharma 50
    • 2025 Pharma 50
    • 2024 Pharma 50
    • 2023 Pharma 50
    • 2022 Pharma 50
    • 2021 Pharma 50
  • Advertise
  • SUBSCRIBE