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Molnupiravir (MK-4482, EIDD-2801) Antiviral

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June 9, 2021
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Molnupiravir (MK-4482, EIDD-2801) Antiviral Description

Molnupiravir (MK-4482, EIDD-2801) is an experimental oral antiviral originally developed to treat influenza at Emory University. Molnupiravir is an orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19.

Molnupiravir (MK-4482, EIDD-2801) consists of the nucleoside analog N4-hydroxycytidine. Molnupiravir has been evaluated against coronaviruses (CoVs), including SARS-1, MERS-CoV. Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission.

Merck conducted a comprehensive nonclinical program to characterize the safety profile of molnupiravir, including assays such as Big Blue and PIG-a, which are designed to provide a robust measure of a drug or chemical’s ability to induce mutations in vivo. Animals were administered molnupiravir for longer and higher doses (mg/Kg) than those employed in human studies. These studies' totality indicates that molnupiravir is not mutagenic or genotoxic in vivo mammalian systems.

In addition, Merck plans to initiate a clinical program to evaluate molnupiravir for post-exposure prophylaxis in the second half of 2021.

Molnupiravir [USAN] RN: 2349386-89-4. UNII: YA84KI1VEW, InChIKey: HTNPEHXGEKVIHG-QCNRFFRDSA-N; PubChem CID145996610; CAS Number 2349386-89-4

Molnupiravir (MK-4482, EIDD-2801) Antiviral History

Molnupiravir was originally developed at Emory University in Georgia by its drug innovation company, Drug Innovation Ventures at Emory. It was later acquired by Ridgeback Biotherapeutics, which has partnered with Merck & Co. to continue developing the antiviral.

A study published on April 29, 2020, found the potency of NHC/EIDD-2801 against multiple CoVs, and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

On June 19, 2020, Miami-based Ridgeback Biotherapeutics announced the launch of two Phase 2 clinical trials to test the efficacy of EIDD-2801 as an anti-viral treatment for COVID-19. The Phase 2a randomized, placebo-controlled, double-blinded clinical trial of EIDD-2801 in adult men and women tested positive for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection within 144 hours of polymerase chain reaction confirmation and are hospitalized with a diagnosis of COVID-19. Rapid enrollment and treatment will be initiated such that the first dose of EIDD-2801 or placebo will be administered as soon as possible and within 7 days of onset of symptoms.

On July 1, 2020, Merck and Ridgeback Biotherapeutics LP announced that the U.S. Federal Trade Commission granted early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. All closing requirements have been completed for the previously announced partnership transaction to advance the development of EIDD-2801, an investigational orally-available antiviral agent currently in early clinical development to treat patients with COVID-19.

On January 25, 2021, Merck stated Molnupiravir is currently being evaluated in Phase 2/3 clinical trials in both the hospital and outpatient settings. The primary completion date for the Phase 2/3 studies is May 2021. The company anticipates initial efficacy data in the first quarter of 2021, which Merck plans to share publicly if clinically meaningful.

On March 6, 2021, Merck and Ridgeback Biotherapeutics announced preliminary results from the Phase 2a study evaluating the safety, tolerability, and efficacy to eliminate SARS-CoV-2 viral RNA of molnupiravir. Of the 182 participants with an evaluable nasopharyngeal swab, 42% (78/182) showed detectable levels of cultured virus at baseline.  The companies also reported findings on one secondary objective from the Phase 2a study, showing a reduction in time (days) to the negativity of infectious virus isolation in nasopharyngeal swabs from participants with symptomatic SARS-CoV-2 infection, as determined by isolation in Vero cell line culture. On day 5, there was a reduction (nominal p=0.001, not controlled for multiplicity) in positive viral culture in subjects who received molnupiravir (all doses) compared to placebo: 0% (0/47) for molnupiravir and 24% (6/25) for placebo.

“We are very pleased to share our initial Phase 2 infectivity data at this important conference, which remains at the forefront for critical clinical scientific information in infectious diseases,” shared Dr. Wendy Painter, Chief Medical Officer of Ridgeback Biotherapeutics, in a press release. “We continue to make progress in our Phase 2/3 clinical programs evaluating molnupiravir in both outpatient and hospital settings and plan to provide updates when appropriate,” added Dr. Roy Baynes, SVP and head of global clinical development CMO, Merck Research Laboratories.

On April 15, 2021, the companies announced, 'Based on a planned interim analysis of data from the Phase 2, a dose-finding portion (Part 1) of two ongoing placebo-controlled Phase 2/3 trials evaluating molnupiravir administered twice a day for five days in outpatients (MOVe-OUT) and hospitalized patients (MOVe-IN) with COVID-19, and from a previously completed Phase 2a dose-ranging study in outpatients, the decision has been made to proceed with the Phase 3 portion (Part 2) of MOVe-OUT in outpatients with COVID-19, evaluating the 800 mg dose of molnupiravir twice daily. Data from MOVe-IN indicate that molnupiravir is unlikely to demonstrate a clinical benefit in hospitalized patients, who generally had a longer duration of symptoms before study entry; therefore, the decision has been made not to proceed to Phase 3.'

“To advance a drug quickly and across the globe in all the countries where it is needed, you need the capacity of a company like Merck,” said George Painter, Ph.D., CEO of the non-profit Emory-owned DRIVE, at a media briefing on April 27, 2021. “It’s gratifying to see how quickly they moved and how they’re getting this into the hands of people in India to meet this threat.”

Wendy Holman, CEO, Ridgeback Biotherapeutics, said in a related press release, “We are pleased that molnupiravir continues to show promise as a potential treatment for non-hospitalized patients with COVID-19. Data from Ridgeback Bio’s EIDD-2801-2003 study (MK-4482-006) coupled with Merck’s MK-4482-002 study provides compelling evidence of molnupiravir's antiviral. We look forward to the initiation and completion of the Phase 3 portion of the MOVe-OUT study.”

On June 9, 2021, Merck confirmed in a press statement 'it plans to submit applications for emergency use or approval to regulatory bodies outside of the USA and is currently in discussions with other countries interested in advance purchase agreements for molnupiravir. Merck is committed to providing timely access to molnupiravir globally. As part of its access strategy, Merck has also entered into non-exclusive voluntary licensing agreements for molnupiravir with established generic manufacturers to accelerate the availability of molnupiravir in 104 low- and middle-income countries following approvals or authorization by regulatory agencies.

New Jersey-based Merck (NYSE: MRK), known as MSD outside of 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 their mission to save and improve lives. 

Florida-based Ridgeback Biopharmaceuticals was co-founded by CEO Wendy Holman and Dr. Wayne Holman, a scientific advisor to the company, focusing on developing anti-viral medications for diseases with epidemic and pandemic risk.

Molnupiravir (MK-4482, EIDD-2801) Antiviral Indication

Molnupiravir (MK-4482/EIDD-2801) antiviral is indicated to mitigate SARS-CoV-2 infection and block transmission, preventing COVID-19 disease.

Molnupiravir (MK-4482, EIDD-2801) Antiviral News

June 9, 2021 - Merck announced it has entered into a procurement agreement with the United States government for molnupiravir (MK-4482). Through the agreement, if molnupiravir receives Emergency Use Authorization or Approval by the U.S. FDA, Merck will receive approximately $1.2 billion to supply approximately 1.7 million courses of molnupiravir to the US government. Merck has been investing at risk to scale up production of molnupiravir and expects to have more than 10 million courses of therapy available by the end of 2021.

June 6, 2021 - Antiviral molnupiravir enters phase 3 clinical trial vs. COVID-19 at Lung Center of the Philippines, reported local media. Among those qualified to be included in the trial are symptomatic patients who tested positive within the past five days, aged 18 and above, and have yet to be vaccinated.

May 25, 2021 - MSN Laboratories Pvt. Ltd. confirmed it is initiating a phase III clinical trial of Molnupiravir capsules for the treatment of Covid-19 in India, with about 2,400 subjects suffering from mild-to-moderate Covid-19.

May 25, 2021 - Hyderabad- based Optimus Pharma stated, "Optimus is all geared to immediately begin clinical trials on Molnupiravir on COVID-19 patients in India. The clinical trial will let us know the efficacy of this molecule on COVID-19 patients," Chairman & Managing Director Dr. D Srinivas Reddy said.

May 18, 2021 - Optimus Pharma announced it received approval from the Drugs Controller General of India to conduct late-stage Phase III clinical trials for Molnupiravir treating COVID-19 patients. Today's Optimus group employs directly about 950 people and provides indirect employment to about 600 across the group. 

May 11, 2021 - A journal article: Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template found 'the biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand.'

May 10, 2021 - A University of Alberta virology lab has uncovered how an oral antiviral drug works to attack the SARS-CoV-2 virus, published in the Journal of Biological Chemistry. The researchers demonstrated the underlying mechanism of action by which the antiviral drug molnupiravir changes the viral genome, a process known as excessive mutagenesis or "error catastrophe." "The polymerase, or replication engine of the virus, mistakes molnupiravir molecules for the natural building blocks required for viral genome replication and mixes them in," explained Matthias Götte, professor and chair of the Department of Medical Microbiology & Immunology in the Faculty of Medicine & Dentistry and member of the Li Ka Shing Institute of Virology.

April 27, 2021 - Merck announced that the company has entered into non-exclusive voluntary licensing agreements for molnupiravir with five established Indian generics manufacturers. Merck entered into these agreements to accelerate the availability of molnupiravir in India and other low- and middle-income countries following approvals or emergency authorization by local regulatory agencies.

April 27, 2021 - Emory University article: Antiviral drug invented by Emory’s DRIVE licensed in India for COVID-19 emergency.

April 26, 2021 - India-based Natco Pharma Limited (NSE: NATCOPHARM; BSE: 524816) applied to the Central Drugs Standard Control Organization (CDSCO) in India for approval of Phase-III clinical trial of Molnupiravir Capsules for the treatment of COVID-19 positive patients. NATCO hopes that the CDSCO would give emergency approval of this drug based on “compassionate use” for patients. The company said it is ready to launch the product this month if approval is given.

April 26, 2021 - BMJ article: The UK government has launched an Antivirals Taskforce to identify treatments to be used at home by people who test positive for SARS-CoV-2 infection to stop the virus from spreading and speed up recovery time. The government’s chief scientific adviser, Patrick Vallance, said, “Antivirals in tablet form are another key tool for responding. They could help protect those not protected by or ineligible for vaccines. They could also be another layer of defense in the face of new variants of concern. The task force will help ensure the most promising antivirals are available for deployment as quickly as possible.”

April 15, 2021 - As Merck announces the discontinuation of MK-7110 to treat hospitalized patients, they are now going to focus their efforts on advancing molnupiravir. “Merck’s commitment from the outset of the pandemic has been to deploy our expertise and capabilities where they can have the most impact,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories.

March 6, 2021 - Ridgeback Biotherapeutics and Merck Announce Preliminary Findings from a Phase 2a Trial of Investigational COVID-19 Therapeutic Molnupiravir. The findings reported a secondary objective to reduce the negativity of infectious SARS-CoV-2 virus isolation from nasopharyngeal swabs from participants with symptomatic COVID-19.

February 9, 2021 - Study published by Nature: SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. 'Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad-spectrum antiviral currently in phase II–III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.'

February 4, 2021 - Merck announced Fourth-Quarter and Full-Year 2020 Financial Results. Merck continued the clinical development of molnupiravir, an orally available antiviral candidate for the treatment of COVID-19, in collaboration with Ridgeback Biotherapeutics LP. It is currently being evaluated in Phase 2/3 clinical trials in both the hospital and outpatient settings. The primary completion date for the Phase 2/3 studies is May 2021. The company anticipates interim efficacy data in the first quarter of 2021.

January 25, 2021 - Merck announced that the company plans to focus its SARS-CoV-2 / COVID-19 research strategy and production capabilities on advancing two therapeutic candidates, MK-4482 MK-7110. Merck stated in a press release it also continues to evaluate the potential of the measles-virus vector and vesicular stomatitis virus vector-based platforms and pursues broader pandemic-response capabilities.

December 21, 2020 - The research by scientists at the Institute of Biomedical Sciences, Georgia State University, has been published in Nature Microbiology. And Indian researchers plan to apply to the drug regulator to conduct human trials with the drug. The antiviral drug Molnupiravir, or MK-4482/EIDD-2801, is taken orally. Molnupiravir is being developed by the biotechnology firm Ridgeback Biotherapeutics in collaboration with the pharmaceutical firm Merck.

December 5, 2020 - Researchers in the Institute for Biomedical Sciences at Georgia State University, led by Dr. Richard Plemper, treated a SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours.

December 3, 2020 - Study: Therapeutically administered ribonucleoside analog MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. 'We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.'

July 7, 2020 - Ridgeback Biotherapeutics announced the start of enrollment in a Phase 2 trial of potential COVID-19 treatment EIDD-2801. The new trial will be conducted using the new COVID-19 drug testing platform, AGILE. AGILE will test multiple potential therapeutics, and EIDD-2801 was selected to be the first oral anti-viral to be studied in the AGILE platform.

July 1, 2020 - Miami-based Ridgeback Biotherapeutics LP announced an agreement with Merck that the U.S. Federal Trade Commission granted early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. All closing requirements have been completed for the previously announced partnership transaction to advance the development of EIDD-2801, an investigational orally-available antiviral agent currently in early clinical development to treat patients with COVID-19.

August 1, 2020 - Merck & Co. plans to begin two large clinical trials in September of an experimental oral antiviral therapy for Covid-19, pushing ahead with efforts to bring another treatment option to the market. There is a “profound medical need for an orally active treatment,” Roger Perlmutter, the pharmaceutical giant’s top scientist, said Friday on Merck’s earnings conference call. The therapy, known as MK-4482.

Molnupiravir (MK-4482, EIDD-2801) Antiviral Clinical Trials

The companies announced on April 15, 2021, based on a planned interim analysis of data from Phase 2, the dose-finding portion (Part 1) of two ongoing placebo-controlled Phase 2/3 trials evaluating molnupiravir administered twice a day for five days in outpatients (MOVe-OUT) and hospitalized patients (MOVe-IN) with COVID-19, and from a previously completed Phase 2a dose-ranging study in outpatients, the decision has been made to proceed with the Phase 3 portion (Part 2) of MOVe-OUT in outpatients with COVID-19, evaluating the 800 mg dose of molnupiravir twice daily. Data from MOVe-IN indicate that molnupiravir is unlikely to demonstrate a clinical benefit in hospitalized patients, who generally had a longer duration of symptoms before study entry; therefore, the decision has been made not to proceed to Phase 3.