Japan’s Ministry of Health, Labor and Welfare Approves Molnupiravir for the Treatment of SARS-CoV-2 Infection

Molnupiravir, First Oral COVID-19 Antiviral Medicine To Receive Authorization in the World, Now Authorized in U.S., U.K. and Japan; Regulatory Submissions Are Under Review Around the World

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics today announced that Japan’s Ministry of Health, Labor and Welfare has granted Special Approval for Emergency in Japan for molnupiravir, an investigational oral antiviral medicine, for infectious disease caused by SARS-CoV-2. Special Approval for Emergency is the process under Article 14-3 of the Pharmaceuticals and Medical Devices Act to approve a medical product swiftly in an emergency situation to protect public health. Under a previously announced supply agreement, the Japanese government will purchase 1.6 million courses of molnupiravir to accelerate access to patients.

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“As a single oral medicine that can be taken at home, early treatment with molnupiravir significantly reduced the risk of hospitalization or death in patients at high risk for progressing to severe COVID-19. Importantly for patients, there were markedly fewer deaths among those taking molnupiravir in our clinical study. We believe that molnupiravir will be a critical addition to the measures available to help curb the impact of COVID-19 on patients, healthcare systems and public health in Japan,” said Dr. Dean Y. Li, president, Merck Research Laboratories. “All of us at Merck have embraced our responsibility to bring this important medicine forward to patients globally as quickly as possible.”

“We are proud to reach this important milestone alongside our collaborators, patients and physicians,” said Wendy Holman, chief executive officer, Ridgeback Biotherapeutics. “We are confident in the promise of molnupiravir as a medicine that can be taken at home with no known drug-drug interactions and believe it will have a positive impact as part of the global effort to fight the COVID-19 pandemic.”

Molnupiravir was the first oral COVID-19 antiviral medicine to receive authorization on Nov. 4, when the U.K.’s Medicines and Healthcare Products Regulatory Agency granted authorization. In the E.U., the European Medicines Agency 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. On Dec. 23, the U.S. Food and Drug Administration granted Emergency Use Authorization for molnupiravir. Regulatory applications are under review or are in the process of being submitted for molnupiravir around the world.

In Japan, LAGEVRIO^® (molnupiravir) is the planned trademark for molnupiravir. Molnupiravir is available in certain markets outside the U.S. as LAGEVRIO.

About the MOVe-OUT Study

The approval is based on positive results from a planned interim analysis from the Phase 3 MOVe-OUT clinical trial (NCT04575597), which evaluated molnupiravir 800 mg twice-daily in non-hospitalized, unvaccinated adult patients with laboratory-confirmed mild-to-moderate COVID-19, symptom onset within five days of study randomization, and at least one risk factor associated with poor disease outcomes (e.g. heart disease, diabetes). The primary efficacy objective of MOVe-OUT is to evaluate the efficacy of molnupiravir 800 mg twice daily for five days compared to placebo as assessed by the percentage of participants who are hospitalized and/or die through Day 29.

At the interim analysis, which was the primary analysis timepoint of the study, molnupiravir significantly reduced the risk of hospitalization and death: 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 who were hospitalized; at the interim analysis, no patients who took molnupiravir died through Day 29, compared to eight patients who received placebo. The absolute risk reduction was 6.8 percentage points (95% CI: 2.4, 11.3; p=0.0012, one-sided), which is approximately a 50% relative reduction in the risk of hospitalization or death through Day 29 for molnupiravir compared with placebo. In the all randomized analysis (n=1433), molnupiravir had a lower risk of hospitalization or death through Day 29: 9.7% (68/699) of patients in the placebo group compared to 6.8% (48/709) of patients in the molnupiravir group, for an absolute risk reduction of 3.0% (95% CI: 0.1, 5.9) and a relative risk reduction of 30%. Nine deaths were reported in the placebo group (29-day all-cause mortality rate of 1.3%) and one in the molnupiravir group (29-day all-cause mortality rate of 0.1%), representing a relative reduction in the risk of death of 89% (95% CI: 14, 99).

Adverse reactions were observed in 12.4% (48/386 participants) in the molnupiravir 800 mg group. The most common observed adverse reactions (greater than or equal to 1%) were diarrhea 3.1% (12/386 participants), nausea 2.3% (9/386 participants), dizziness 1.3% (5/386 participants) and headache 1.0% (4/386 participants).

About Merck’s Global Efforts to Accelerate Access to Molnupiravir Following Regulatory Authorizations or Approvals

Global access has been a priority for Merck and Ridgeback since the inception of their molnupiravir collaboration. The companies are committed to providing timely access to molnupiravir globally through our comprehensive supply and access approach, which includes investing at risk to produce millions of courses of therapy; tiered pricing based on the ability of governments to finance health care; entering into supply agreements with governments; and granting voluntary licenses to generic manufacturers and to the Medicines Patent Pool to make generic molnupiravir available in more than 100 low- and middle-income countries following local regulatory authorizations or approvals.

Supply: In anticipation of the results from MOVe-OUT and the potential for regulatory authorization or approval, Merck has been producing molnupiravir at risk and will produce 10 million courses of treatment by the end of 2021, with at least 20 million courses to be produced in 2022. To date, Merck has shipped molnupiravir to 14 countries; in countries where it is approved or authorized, patients have begun to receive the drug.

Supply agreements: Merck entered into a procurement agreement with the U.S. Government under which the company will supply approximately 3.1 million courses of molnupiravir to the U.S. Government, upon Emergency Use Authorization or approval from the U.S. Food and Drug Administration. Merck has entered into advance purchase and supply agreements for molnupiravir with governments for over 30 countries worldwide, including Australia, Canada, Korea, Japan, Thailand, United Kingdom and United States, pending regulatory authorizations, and is currently in discussions with additional governments. Merck plans to implement a tiered pricing approach based on World Bank country income criteria to reflect countries’ relative ability to finance their health response to the pandemic.

Voluntary licenses: As part of its commitment to widespread global access, Merck previously announced that it has entered into a licensing agreement with the Medicines Patent Pool to increase broad access for molnupiravir in low- and middle-income countries. Additionally, Merck previously announced that the company has entered into non-exclusive voluntary licensing agreements for molnupiravir with established generic manufacturers to accelerate availability of molnupiravir in more than 100 low- and middle-income countries following approvals or emergency authorization by local regulatory agencies.

Merck continues to discuss additional measures and collaborations to accelerate broad, global access to molnupiravir.

Authorized Use of Molnupiravir in the U.S.

The U.S. Food and Drug Administration (FDA) has issued an EUA for the emergency use of the unapproved molnupiravir, a nucleoside analogue that inhibits SARS-CoV-2 replication by viral mutagenesis, for the treatment of 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 FDA are not accessible or clinically appropriate. Molnupiravir is not FDA-approved for any use including for use for the treatment of COVID-19. Prior to initiating treatment with molnupiravir, carefully consider the known and potential risks and benefits.

Molnupiravir is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of molnupiravir under section 564(b)(1) of the Federal, Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

Molnupiravir is not authorized for use in patients less than 18 years of age or who are hospitalized due to COVID-19. Benefit of treatment with molnupiravir has not been observed in subjects when treatment was initiated after hospitalization due to COVID-19. Molnupiravir is not authorized for use for longer than five consecutive days. Molnupiravir is not authorized for pre-exposure or post-exposure prophylaxis for prevention of COVID-19. Molnupiravir may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the therapeutic class to which molnupiravir belongs (i.e., anti-infectives).

Selected Safety Information for Molnupiravir

Contraindications

No contraindications have been identified based on the limited available data on the emergency use of molnupiravir authorized under this EUA.

Warnings and Precautions

There are limited clinical data available for molnupiravir. Serious and unexpected adverse events may occur that have not been previously reported with molnupiravir use.

Molnupiravir is not recommended for use during pregnancy. 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.

Molnupiravir is authorized to be prescribed to a pregnant individual only after the healthcare provider has determined that the benefits would outweigh the risks for that individual patient. If the decision is made to use molnupiravir during pregnancy, the prescribing healthcare provider must document that the known and potential benefits and the potential risks of using molnupiravir during pregnancy were communicated to the pregnant individual.

There is a pregnancy surveillance program that monitors pregnancy outcomes in individuals exposed to molnupiravir during pregnancy. The prescribing healthcare provider must document that a pregnant individual was made aware of Merck’s pregnancy surveillance program at 1-877-888-4231 or pregnancyreporting.msd.com. If the pregnant individual agrees to participate in the pregnancy surveillance program and allows the prescribing healthcare provider to disclose patient specific information to Merck, the prescribing healthcare provider must provide the patient’s name and contact information to Merck. Pregnant individuals exposed to molnupiravir can also report the exposure by contacting Merck at 1-877-888-4231 or pregnancyreporting.msd.com.

Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently during treatment with molnupiravir and for 4 days after the final dose.

Prior to initiating treatment with molnupiravir, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated.

Molnupiravir is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. The safety and efficacy of molnupiravir have not been established in pediatric patients.

Adverse Reactions

The most common adverse reactions occurring in ≥1% of subjects in the molnupiravir treatment group in the Phase 3 double-blind MOVe-OUT study were diarrhea (2% versus placebo at 2%), nausea (1% versus placebo at 1%), and dizziness (1% versus placebo at 1%) all of which were Grade 1 (mild) or Grade 2 (moderate).

Serious adverse events occurred in 7% of subjects receiving molnupiravir and 10% receiving placebo; most serious adverse events were COVID-19 related. Adverse events leading to death occurred in 2 (<1%) of the subjects receiving molnupiravir and 12 (2%) of subjects receiving placebo.

Drug Interactions

No drug interactions have been identified based on the limited available data on the emergency use of molnupiravir. No clinical drug-drug interaction trials of molnupiravir with concomitant medications, including other treatments for mild to moderate COVID-19, have been conducted.

Pregnancy/Breastfeeding

There are no data on the presence of molnupiravir or its metabolites in human milk. It is unknown whether molnupiravir has an effect on the breastfed infant or effects on milk production. Based on the potential for adverse reactions in the infant from molnupiravir, breastfeeding is not recommended during treatment with molnupiravir and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of molnupiravir.

Males of Reproductive Potential

Nonclinical studies to fully assess the potential for molnupiravir to affect offspring of treated males have not been completed. Advise sexually active individuals with partners of childbearing potential to use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after last dose of molnupiravir. The risk beyond three months after the last dose of molnupiravir is unknown.

Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider’s designee are/is responsible for mandatory reporting of all serious adverse events and medication errors potentially related to molnupiravir within 7 calendar days from the healthcare provider’s awareness of the event.

Submit adverse event and medication error reports, using FDA Form 3500, to FDA MedWatch using one of the following methods:

• Complete and submit the report online: www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:
  • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
  • Fax to 1-800-FDA-0178
• Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to:

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA by:

Fax: 215-616-5677

E-mail: dpoc.usa@merck.com

About Molnupiravir

Molnupiravir (MK-4482 and EIDD-2801) is an investigational, orally administered nucleoside analogue that inhibits replication of SARS-CoV-2, the causative agent of COVID-19. Merck and Ridgeback’s “orange COVID-19 pill” is a Swedish Orange opaque capsule with the Merck corporate logo and “82” printed in white ink, available in certain markets outside of the U.S. as LAGEVRIO^®.

Results from the Phase 3 MOVe-OUT study demonstrated the efficacy benefit of molnupiravir treatment was generally consistent across patients infected with SARS-CoV-2 variants of concern, Delta, Gamma and Mu. Preliminary preclinical data has shown that molnupiravir has antiviral activity against the newly identified variant, Omicron (B1.1.529). Molnupiravir has yet to be evaluated against Omicron in clinical studies.

Molnupiravir was invented at Emory University. Drug Innovation Ventures at Emory (DRIVE), LLC, which was formed by Emory to develop early-stage drug candidates for viral diseases of global concern, advanced molnupiravir through IND submission. Emory/DRIVE received some research funding from the U.S. Department of Defense and the U.S. National Institutes of Health. Molnupiravir is being developed by Merck in collaboration with Ridgeback Biotherapeutics. Ridgeback received an upfront payment from Merck and also is eligible to receive contingent payments dependent upon the achievement of certain developmental and regulatory approval milestones. Any profits from the collaboration will be split between the partners equally. Since licensed by Ridgeback, all funds used for the development of molnupiravir have been provided by Merck and Ridgeback.

Molnupiravir was evaluated in MOVe-OUT, a global Phase 3, randomized, placebo-controlled, double-blind, multi-site study of non-hospitalized adult patients with symptomatic, laboratory-confirmed mild to moderate COVID-19 and at least one risk factor associated with poor disease outcomes. The Phase 3 portion of the MOVe-OUT trial was conducted globally in more than 170 sites in locations including Argentina, Brazil, Canada, Chile, Colombia, Egypt, France, Germany, Guatemala, Israel, Italy, Mexico, Philippines, Poland, Russia, South Africa, Spain, Sweden, Taiwan, Ukraine, the United Kingdom and the United States. For further information about the MOVe-OUT trial, please visit clinicaltrials.gov. Molnupiravir is also being evaluated for post-exposure prophylaxis in MOVe-AHEAD, a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of molnupiravir in preventing the spread of COVID-19 within households. For more information, please visit http://merckcovidresearch.com.

Please visit the Merck media library for molnupiravir images and b-roll.

About Ridgeback Biotherapeutics

Headquartered in Miami, Florida, Ridgeback Biotherapeutics LP is a biotechnology company focused on emerging infectious diseases. Ridgeback markets Ebanga^TM for the treatment of Ebola and has a late-stage development pipeline which includes molnupiravir for the treatment of COVID-19. The team at Ridgeback is dedicated to developing life-saving and life-changing solutions for patients and diseases that need champions as well as providing global access to these medicines. In line with Ridgeback’s mission for equitable global access, all Ridgeback services and treatment for Ebola patients in Africa are delivered free of charge.

About Merck

For over 130 years, Merck, known as MSD outside the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA.

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2020 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see the Molnupiravir FDA Letter of Authorization at https://www.merck.com/eua/Merck-EUA-letter.pdf, Fact Sheet for Healthcare Providers, including Mandatory Requirements for Administration of Molnupiravir under Emergency Use Authorization, at https://www.merck.com/eua/molnupiravir-hcp-fact-sheet.pdf and Fact Sheet for Patients and Caregivers at https://www.merck.com/eua/molnupiravir-patient-fact-sheet-english.pdf.

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