Dr. Michael Carome, director of Public Citizen’s health research group, is concerned about Merck’s SARS-CoV-2 antiviral molnupiravir.
If it wins emergency use authorization (EUA), molnupiravir would be the first oral treatment for COVID-19. But Carome brought up several potential problems with molnupiravir during today’s public comment period of the FDA’s Antimicrobial Drugs Advisory Committee meeting.
First, Carome argued that the drug appeared to have modest efficacy, offering a relative risk reduction against hospitalization or death of 30% through day 29 of the MK-4482-002 Phase 2/3 study.
Additionally, subgroup analyses of the MK-4482-002 study showed that the drug’s potential benefits appeared to be “substantially lower” in patients infected with the SARS CoV-2 Delta variant when the drug was provided at the proposed dosage of 800 mg every 12 hours for five days.
“Subgroup analyses also found no reduction in the risk of all-cause hospitalization or death through day 29 in subjects who tested positive for anti-SARS CoV-2 antibodies at baseline,” Carome said.
While acknowledging the good safety profile of molnupiravir in the MK-4482-002 study, Carome highlighted several potential safety concerns emerging from preclinical studies. Those potential concerns include embryo-fetal toxicity, bone and cartilage toxicity and mutagenicity, including mutagenicity in vitro and mammalian cells. “There’s also evidence that molnupiravir may increase the rate of mutation in the viral spike protein, which, in theory, could enhance SARS CoV-2 spike protein evolution and accelerate the development of new variants that escape the immune protection provided by COVID-19 vaccines or natural immunity following SARS-CoV-2 infection or that are resistant to the currently authorized anti-SARS CoV-2 monoclonal antibodies,” Carome said.
“The risk of evolutionary viral mutations may be enhanced by tissue exposure to low hydroxycytidine concentrations, which is likely to occur given the proposed 12-hour dosing interval of molnupiravir,” Carome added.
“Based on the available clinical and preclinical data for molnupiravir, there is significant uncertainty regarding whether the known and potential benefits of the drug for treating COVID-19 at the proposed dosage outweigh the known risks of the drug,” Carome concluded.
FDA should investigate whether the dosage of 800 mg every 12 hours is “adequate to provide sustained effective antiviral activity against the SARS CoV-2 Delta variants in vivo,” Carome said.
If FDA decides to grant emergency use authorization to molnupiravir, Public Citizen recommends that certain groups be ineligible for it, including all or most fully vaccinated individuals. In addition, given molnupiravir’s potential risk of embryo-fetal toxicity, Carome recommended verifications that individuals of childbearing potential be verified not to be pregnant and to use effective contraception or abstinence from sexual intercourse for the duration of molnupiravir treatment and four days after administration of the final dose of the drug.
Furthermore, Carome asked for lactating individuals to abstain from breastfeeding for the course of treatment and four days afterward.
“Finally, if the FDA subsequently issues an EUA for another oral antiviral drug product for which the known and potential benefits appear to be greater than those for molnupiravir and for which there are no safety concerns regarding embryo-fetal toxicity, bone and cartilage toxicity, mutagenicity and acceleration of the development of new SARS CoV-2 variants, the agency should promptly consider whether the EUA for molnupiravir should be revoked,” Carome concluded.