Merck, known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics today announced that the U.S. Food and Drug Administration (FDA) has granted Emergency Use Authorization (EUA) for molnupiravir, an investigational oral antiviral (MK-4482, EIDD-2801). Molnupiravir has not been approved, but has been authorized for emergency use by the FDA under an EUA to treat mild to moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. Molnupiravir is not authorized for use in patients who are less than 18 years of age, for initiation of treatment in patients hospitalized due to COVID-19, for use for longer than five consecutive days, or for pre-exposure or post-exposure prophylaxis for prevention of COVID-19.
Robert M. Davis, chief executive officer and president, Merck, said:
The FDA Emergency Use Authorization of molnupiravir is an important milestone in the fight against COVID-19, and adds to Merck’s legacy of bringing forward innovative medicines that both address the world’s greatest health threats and help save lives. Because we recognized the promise of molnupiravir early, Merck invested at risk and we are executing an unprecedented global access strategy so that molnupiravir, now authorized, can be available to patients here in the U.S. and all around the world more quickly and more equitably than has ever been accomplished before.
Molnupiravir should be administered as soon as possible after a diagnosis of COVID-19 has been made, and within five days of symptom onset. The recommended dose for molnupiravir is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days, with or without food. Completion of the full five-day treatment course is important to maximize viral clearance and minimize transmission of SARS-CoV-2.
Molnupiravir is not recommended for use in patients who are pregnant. Based on findings from animal reproduction studies, molnupiravir may cause fetal harm when administered to pregnant individuals. There are no available human data on the use of molnupiravir in pregnant individuals to evaluate the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Before initiating treatment with molnupiravir, it should be assessed whether an individual of childbearing potential is pregnant or not, if clinically indicated. Females of childbearing potential should use a reliable method of contraception correctly and consistently, as applicable, for the duration of treatment and for four days after the last dose of molnupiravir. Males of reproductive potential who are sexually active with females of childbearing potential should use a reliable method of contraception correctly and consistently during treatment and for at least three months after the last dose. There is a pregnancy surveillance program that monitors pregnancy outcomes in individuals exposed to molnupiravir during pregnancy. Patients exposed to molnupiravir during pregnancy should report the exposure by contacting Merck by phone at 1-877-888-4231, or online at pregnancyreporting.msd.com. For more information, see “Selected Safety Information” below.
The authorization is based on the Phase 3 MOVe-OUT trial, which evaluated molnupiravir 800 mg twice-daily in non-hospitalized adult patients who were unvaccinated against SARS-CoV-2, had laboratory-confirmed SARS-CoV-2 infection, symptom onset within five days of study randomization, and at least one risk factor associated with poor disease outcomes (e.g., heart disease, diabetes).
In analyses from all randomized patients (n=1433), molnupiravir reduced the risk of hospitalization or death: 9.7% (68/699) of patients in the placebo group were hospitalized or died compared to 6.8% (48/709) of patients who received molnupiravir, for an absolute risk reduction of 3.0% (95% confidence interval [CI]: 0.1, 5.9). Nine deaths were reported in the placebo group, and one in the molnupiravir group.
The determination of primary efficacy was based on a planned interim analysis of 762 subjects. At the interim analysis, treatment with molnupiravir significantly reduced hospitalizations and death through Day 29 following randomization: 14.1% (53/377) of patients in the placebo group were hospitalized or died, compared to 7.3% (28/385) of patients who received molnupiravir. The absolute risk reduction between the molnupiravir and the placebo arm was 6.8 percentage points (95% CI: 2.4, 11.3; p=0.0024).
In the clinical study, the most common adverse reactions for molnupiravir (incidence ≥1%) were diarrhea (2% for molnupiravir, 2% for placebo), nausea (1% for molnupiravir, 1% for placebo) and dizziness (1% for molnupiravir, 1% for placebo). Discontinuation of study intervention due to an adverse event (AE) occurred in 1% of subjects receiving molnupiravir and 3% of subjects receiving placebo. Serious AEs occurred in 7% of subjects receiving molnupiravir and 10% receiving placebo; most serious AEs were COVID-19 related.
Dr. Dean Y. Li, president, Merck Research Laboratories said:
Based on the strong science behind molnupiravir – a single oral medicine that interrupts replication of the SARS-CoV-2 virus, with data demonstrating a significant reduction in the risk of hospitalizations and deaths – molnupiravir has the potential to become an important tool for healthcare professionals and appropriate patients. We are immensely grateful to all of our collaborators, including trial patients and clinical investigators, for their important contributions to this milestone.
Merck anticipates that it will begin shipping molnupiravir to AmerisourceBergen, the sole distributor of molnupiravir, within days. As previously announced, Merck entered into a procurement agreement with the U.S. Government under which, to date, the company has agreed to supply approximately 3.1 million courses of molnupiravir to the U.S. Government, upon EUA from the FDA.
Wendy Holman, chief executive officer, Ridgeback Biotherapeutics said:
Before the virus that caused this tragic pandemic had a name, the team at Ridgeback saw the need for urgent action. We joined with George Painter, Drug Research Innovations at Emory (DRIVE) and Merck with the hope of taking molnupiravir from a dream to the reality we see today. There is now a prescription oral antiviral, molnupiravir, for use by appropriate high-risk patients, that can be taken at home, as soon as possible after an appropriate patient tests positive for COVID-19, to help reduce the risk of hospitalization or death. It’s an oral therapeutic option with no known drug-drug interactions and without required dose modifications for those with impaired kidney or liver function. We are thrilled this tremendous global collaboration between Ridgeback, Merck and DRIVE has fulfilled our hopes of bringing forward an oral medicine to help keep people out of the hospital and alive.
Molnupiravir is also being evaluated for post-exposure prophylaxis in MOVe-AHEAD, a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study, which is evaluating the efficacy and safety of molnupiravir in preventing the spread of COVID-19 within households. Molnupiravir is not authorized for pre-exposure or post-exposure prophylaxis for prevention of COVID-19.
An EUA is an FDA authorization for the emergency use of an unapproved product or unapproved use of an approved product in the U.S. under certain circumstances, including a public health emergency. Molnupiravir is an investigational treatment and is still under review by the FDA.
Recently, the FDA Antimicrobial Drugs Advisory Committee (AMDAC) voted that the known and potential benefits of molnupiravir outweigh its known and potential risks for the treatment of mild to moderate COVID-19 in high risk adult patients who are within five days of symptom onset. Molnupiravir has received conditional marketing authorization in the United Kingdom for the treatment of mild to moderate COVID-19 in adults with a positive SARS-CoV-2 diagnostic test and who have at least one risk factor for developing severe illness. The European Medicines Agency (EMA) issued a positive scientific opinion for molnupiravir under Article 5.3 Regulation 726/2004, which is intended to support national decision-making on the possible use of molnupiravir prior to marketing authorization. Applications to other regulatory bodies worldwide are underway.