What EPs Should Know about Oral COVID Drugs
BY LEON GUSSOW, MD
Two new oral medications to treat COVID-19 received Emergency Use Authorization from the U.S. Food & Drug Administration early this year. Emergency physicians and medical toxicologists will soon be dealing with these drugs with which they have little or no experience.
The most eagerly anticipated new oral treatment for COVID-19 is Pfizer’s formulation of ritonavir/nirmatrelvir (Paxlovid). The company reported that the drug reduces the risk of hospitalization or death by 89 percent if treatment is started within three days of symptom onset in high-risk outpatients with COVID-19. That sounds great, but keep in mind several important caveats, most importantly that Pfizer has not yet published the results of its clinical trial.
The claim from EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) of 89 percent reduction of hospitalization or death comes from a Pfizer press release describing results from the planned interim analysis of the data. (Nov. 5, 2021; https://bit.ly/3GIr53N.) The FDA issued an Emergency Use Authorization for the drug in December, and the agency apparently reviewed the data and was impressed by the results. Still, I find it somewhat discomforting to base clinical treatment on a press release rather than a real scientific publication.
All subjects in the EPIC-HR trial were high risk and unvaccinated. It is not clear that any potential benefit would be as impressive in other populations. Word has it that an additional study of ritonavir/nirmatrelvir in 662 vaccinated volunteers showed a 70 percent reduction in hospitalizations and deaths over placebo, but these data have also not been published. EPIC-HR also enrolled patients from July 2021 to September 2021 before the Omicron variant was detected and a little before Delta was widespread. Pfizer apparently expects that ritonavir/nirmatrelvir will be effective against Omicron based on laboratory studies and the fact that the drug does not target the virus’s spike protein. Still, it would be nice to have published clinical confirmation.
The SARS-CoV-2 virus when it infects human cells induces synthesis of long protein chains that have to be cleaved at specific points to produce shorter proteins crucial to viral replication. Nirmatrelvir inhibits the main viral protease that enables this precise cleavage. The drug is metabolized by the CYP3A hepatic enzyme system. Ritonavir is another protease inhibitor long used in treating HIV/AIDS, but its role in Paxlovid is to inhibit CYP3A, prolonging the half-life and activity of nirmatrelvir. The combination is given as three tablets twice daily for five days.
Because ritonavir inhibits CYP3A, the potential for numerous significant drug interactions is a real concern. Use of ritonavir could increase concentrations of many other drugs metabolized by CYP3A. Conversely, nirmatrelvir levels may be reduced to subtherapeutic amounts in patients on drugs that induce CYP3A. Clinicians should be aware of these potential drug interactions, and frequently invite input from clinical pharmacists and medical toxicologists when prescribing Paxlovid. (See the table for potential drug interactions in the upcoming March issue.)
In contrast to Paxlovid, the initial Merck study on its COVID-19 drug molnupiravir (Lagevrio) has been posted online. (N Engl J Med. 2021 Dec 16; https://bit.ly/3rxwdkS.) This phase 3, double-blind, randomized, placebo-controlled trial evaluated the use of oral molnupiravir to treat nonhospitalized adults with mild to moderate COVID-19. All subjects had PCR-confirmed infection and began treatment within five days of first signs and symptoms.
The subjects were also considered high risk for progression to severe disease based on at least one of the following: BMI over 30, age over 60, diabetes mellitus, active cancer, chronic kidney disease, chronic obstructive pulmonary disease, congestive heart failure, coronary artery disease, and cardiomyopathy. Exclusion criteria included ongoing hemodialysis, renal failure with a GFR less than 30, pregnancy, and previous vaccination for COVID-19. That last point is important: All the subjects in this study were unvaccinated. They received molnupiravir 800 mg bid for five days or placebo. The primary endpoints were hospitalization or death within 29 days of treatment initiation.
A total of 1433 subjects were randomized into the study, and a planned interim analysis was carried out after the first 775 patients were enrolled. The results initially looked promising. The interim analysis found that 7.3 percent of the group receiving molnupiravir reached a primary endpoint compared with 14.1 percent of the placebo group, a relative reduction of about 50 percent.
The final results from all 1433 study subjects were not as striking, with 9.7 percent of the placebo group reaching a primary endpoint v. 6.8 percent of the treated group, a relative reduction of 30 percent. It is not quite clear why these results were less positive than those from the interim analysis. The study took place from May 2021 to October 2021, so it is possible that few if any subjects from the interim analysis were infected with Delta variant, and that molnupiravir may be much less effective against the variants common now.
Notably, one death occurred in the treated subjects and nine in the placebo group during the 29 days after treatment was started. Adverse effects not directly related to COVID were generally nonspecific and included diarrhea, nausea, and dizziness.
It is important to realize that this trial was carried out among nonvaccinated subjects infected with mostly the Delta, Mu, and Gamma variants. Randomization also ended in early October 2021 before the Omicron variant was a concern. The results gave no indication of how effective the drug would be today, with new variants, or in vaccinated patients.
Monupiravir works by inducing multiple mutations as viral mRNA is copied in infected cells. There has been concern that this mechanism might accelerate development of more virulent or infectious mutations, but so far experience with the drug—although still quite limited—has not detected examples of this occurring.
Molnupiravir has been shown to induce mutations to mammalian DNA in cultures of hamster ovary cells (J Infect Dis. 2021:224:415; https://bit.ly/3IbuAQA), but no data yet suggest this would be a problem with therapeutic use. In any event, the drug is not recommended for pregnant patients or those who might become pregnant during treatment.
Dr. Gussow is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Follow him on Twitter @poisonreview, and read his past columns at http://bit.ly/EMN-ToxRounds.