The 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