AV-COVID-19

With little explanation for why Merck’s potential Covid-19 antiviral was less effective in reducing Covid hospitalizations and deaths in a full analysis of a Phase III trial versus an interim look, the FDA’s antimicrobial drugs advisory committee on Tuesday voted 13-10 in favor of the pill’s benefits outweighing the risks for adults within 5 days of developing Covid symptoms. Molnupiravir will likely be authorized by FDA in the coming days for adults with mild or moderate Covid-19. While Pfizer’s antiviral may prove to be more effective, Merck’s pill will be another weapon in the armamentarium of Covid-19 treatments for countries around the world, adding to the mAb treatments already in use in the outpatient space from Regeneron, Eli Lilly and Vir/GlaxoSmithKline. Adcomm member David Hardy of the Charles Drew University School of Medicine and Science said he voted “yes” because the pandemic is still an emergency situation, and this is the first opportunity for an oral drug to be available. There needs to be a warning about using this drug in pregnant women, he said, noting of the potential for fetal abnormalities. Panelist Timothy Burgess of the Uniformed Services University of the Health Sciences said he voted “no” on the basis of the very difficult to explain differences in the population before and after the interim analysis (see below), and the heterogeneity of the benefit, particularly for those with diabetes. During the discussion portion of the adcomm, panelists centered their questioning on the Merck pill’s efficacy and the cause of this drop off in preventing hospitalizations and deaths, from 50% to 30% between interim and final results. Neither Merck nor the FDA could really offer any specific causes. Subgroup analyses seem to suggest that molnupiravir did better against the Gamma and Mu variants than the Delta variant, but that doesn’t explain how steeply the efficacy fell. For instance, in the post-interim analysis population, FDA showed how there were more Covid-related hospitalizations among trial participants receiving molnupiravir compared to those receiving placebo. “It doesn’t really add up to us,” Nicholas Kartsonis, SVP of clinical research, infectious diseases at Merck, said. He noted that the company expected some regression to the mean with the later data, but not this kind of reduction in benefit. He pointed to several potential factors, including the rise of Delta, more female trial participants who are less likely than their male counterparts to be hospitalized or die of Covid, and more participants in Europe in the second part of the trial. “I don’t have a satisfying answer but that’s the totality of data,” Kartsonis said. When FDA sought to direct the conversation to questions about the efficacy of molnupiravir in pregnant women, several panelists also questioned the efficacy in adults in general. “We’re skirting the issue of is there a benefit of the medication in adults,” said adcomm panelist Uma Reddy, who’s an OBGYN at Yale. Panelist Michael Green, professor of the University of Pittsburgh School of Medicine, voted in favor of the pill’s benefits and noted the lack of availability of an alternative oral treatment for unvaccinated people, and the potential loss of mAbs due to the new variant Omicron, which Merck said it thinks the antiviral will be effective against. “Should an alternative oral drug with a better safety profile, the agency might consider this authorization,” Green said. Another issue for the adcomm members is the way that molnupiravir works, which is to drive the mutagenesis of the SARS-COV-2 virus to kill it off, and which could theoretically increase the likelihood of variants occurring as a result of widespread treatment. But the FDA noted in its presentation that there’s no evidence that the emergence of spike protein amino acid changes affected virologic or clinical outcomes in outpatients. Kartsonis said Merck will be strongly recommending that people complete their 5-day treatment courses to avoid any theoretical concerns. “We are exploring the feasibility of using sequence databases to monitor for the emergence of these novel variants,” Kartsonis added. “To date, if you treat people for 5 days, we’ve yet to identify a single case of infectious virus at day 5, so that’s a very positive sign.” Several panelists also said they thought the risk for the general public is low compared to the substantial amount of natural mutations, but a few did raise concerns, particularly if millions of people access the drug. The overall thumbs up from the panel is based on results from a Phase III trial of about 1,500 unvaccinated adults, finding 68 hospitalizations and 9 deaths in the placebo group, compared to 48 hospitalizations and one death for those on the Merck pill. The FDA said in its analysis of Merck’s data that the pill is safe and reduces the risk of hospitalization or death among adults with mild to moderate Covid-19 and who are at high-risk for progression to severe Covid. Similar to the UK, the FDA is not likely to recommend the pill for pregnant women due to the potential of embryo-fetal toxicity. The US has now purchased more than 3 million courses of the Covid-19 antiviral, to be acquired from authorization through early 2022, Merck said. The contracts have earned Merck a cool $2.2 billion so far, and there are two million courses available through further options.