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Molnupiravir failed to reduce the risk for hospitalization or death in high-risk COVID-19 outpatients who took the oral antiviral within 5 days of symptoms, a large open-label multicenter trial found.

In more than 25,000 participants in the PANORAMIC study, the rate of all-cause hospitalization or death at 28 days was an identical 0.8% whether individuals were randomized to molnupiravir or usual care (adjusted OR 1.06, 95% bayesian credible interval [BCI] 0.80-1.40), reported Christopher Butler, MD, of the University of Oxford in England, and co-authors.

"Molnupiravir did not reduce already low hospitalizations/deaths among higher-risk, vaccinated adults with COVID-19 in the community," they wrote on the preprint server .

"Trials of molnupiravir have, thus far, been conducted in largely unvaccinated participants and prior to the emergence of the Omicron SARS-CoV-2 variant," Butler and colleagues noted. "PANORAMIC provides an estimate of the effectiveness of molnupiravir in a multiply-vaccinated population whilst the Omicron SARS-CoV-2 strain is dominant."

The news wasn't all bad for molnupiravir, however.

Time to first reported recovery was a median 9 days in patients taking molnupiravir versus 15 days with usual care (HR 1.36, 95% BCI 1.30-1.40), which met prespecified criteria for success, the researchers said.

And in a group of 73 participants sampled for viral load, SARS-CoV-2 was undetectable at 7 days in 21% of patients in the molnupiravir group compared with only 3% of controls (P=0.039). Mean viral load was also lower in the molnupiravir group at 7 days (P<0.001).

But overall, the findings failed to support the benefit seen in the phase III MOVe-OUT trial, which mostly involved participants who were unvaccinated and was conducted when the predominant variants were Delta, Gamma, and Mu. Final MOVe-OUT results showed a lower risk of hospitalization or death with molnupiravir versus placebo (6.8% vs 9.7%), and led to FDA's under emergency use in December 2021 for patients unable to access alternative treatment options, or for when alternative treatments would not be clinically appropriate.

In the current study, molnupiravir may have done more harm than good, the researchers warned.

"While it is critical to ensure that patients who are likely to benefit receive treatment with antiviral agents, using these precious medicines for patients who are unlikely to benefit carries the risk of driving resistance, wasting resources, and exposing people unnecessarily to harm," wrote Butler and co-authors. "Due to the potential mutagenic properties of molnupiravir, there is a theoretical risk that administering this drug on a large scale could lead to new SARS-CoV-2 variants."

An analysis to assess mutation frequency will be ongoing and "will be reported separately," they noted.

PANORAMIC was conducted from December 2021 to April 2022 and included 25,783 participants who were randomly assigned to molnupiravir twice a day for 5 days plus usual care (n=12,821) or usual care alone (n=12,962) within 5 days of a COVID-19 infection.

Patients had to be either 50 years and older or 18 and older with comorbidities to enroll. Mean age of participants was 56.6 years, 58% were female, and 93% had received at least three vaccine doses. Comorbidities included lung disease in 24%, hypertension in 22%, obesity in 15%, diabetes in 12%, a weakened immune system in 9%, and heart disease in 8%.

In the group taking molnupiravir, 102 were hospitalized and two patients died. In the control group, 93 patients were hospitalized and five died.

Patients in the molnupiravir group started on the treatment a median 3 days from symptom onset, and adherence to the 5-day regimen was reported by 95.4% of patients taking the medication.

Overall, 0.4% of patients in each group experienced a serious adverse event (AE), and 142 participants on molnupiravir pulled out of the study due to toxicity. No AEs of special interest were reported.

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