Molnupiravir - Emory University/Georgia State University/Merck & Co/Ridgeback Biotherapeutics

At a glance

Originator Emory University; Georgia State University
Developer Emory University; Hetero Labs; Merck & Co; Merck Sharp & Dohme; Ridgeback Biotherapeutics
Class Antivirals; Esters; Hydroxylamines; Pyrimidinones; Ribonucleosides; Small molecules
Mechanism of Action Virus replication inhibitors

Orphan Drug Status

Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

No
New Molecular Entity Yes

Highest Development Phases

Marketed COVID 2019 infections
Phase II Respiratory syncytial virus infections
Phase I Influenza virus infections; Renal failure
Preclinical Chikungunya virus infections; Eastern equine encephalomyelitis; Ebola virus infections; Middle East respiratory syndrome coronavirus; Severe acute respiratory syndrome; Venezuelan equine encephalomyelitis

Most Recent Events

21 Aug 2023 Phase-I clinical trials in Influenza virus infections (In volunteers) in United Kingdom (PO) (NCT05818124)
21 Jun 2023 Regulatory submission withdrawn for COVID-2019 infections in European Union (PO)
21 Jun 2023 Merck Sharp & Dohme withdraws a marketing authorisation application for molnupiravir for COVID-19 infections in the European Union

Development Overview

Introduction

Molnupiravir is an orally bioavailable, isopropylester prodrug of the ribonucleoside analogue N ⁴-hydroxycytidine (NHC, EIDD 1931) that inhibits the replication of multiple RNA viruses, being developed by Ridgeback Biotherapeutics and Merck & Co for the prevention of severe acute respiratory syndrome (SARS), COVID-2019 infections, middle east respiratory syndrome coronavirus and for the treatment of COVID-2019 infections, chikungunya virus infections, eastern equine encephalomyelitis, ebola virus infections, hepatic impairment (Renal failure in Development table), influenza virus infections, middle east respiratory syndrome coronavirus (MERS), respiratory syncytial virus infections, severe acute respiratory syndrome and venezuelan equine encephalomyelitis. Emory University and Georgia State University had originally discovered the drug against influenza viruses, and later licensed to Ridgeback Biotherapeutics under a license from Drug Innovations at Emory (DRIVE, a wholly owned subsidiary of Emory University). Molnupiravir acts by tricking the RNA viruses to include the wrong building blocks as it tries to reproduce itself. The product is available in the UK and has been granted provisional approval in Australia for the treatment of COVID 2019 infections. The candidate has been granted Emergency Use Authorization in the EU, Japan, India, USA, Taiwan and conditional marketing authorization in China. Regulatory submissions are under rolling review around the world for the treatment of COVID 2019 infections. The drug was under regulatory review in the European Union for COVID-2019 infections but the application has been withdrawn by the company. Clinical development for treatment and prevention of COVID- 2019 infections is ongoing in multiple countries. Preclinical development for the prevention of SARS and MERS is ongoing in the US. Preclinical development for treatment of chikungunya virus infections, eastern equine encephalomyelitis, ebola virus infections, middle east respiratory syndrome coronavirus, renal failure, severe acute respiratory syndrome and venezuelan equine encephalomyelitis in ongoing in the US. Clinical development for influenza virus infections is ongoing in the UK and respiratory syncytial virus infections in the US and in the UK.

Company Agreements

In January 2022, Beximco Pharmaceuticals and Medicines Patent Pool (MPP) entered in a licensing agreement for molnupiravir. According to the terms of the agreement, MPP granted a sub-license of the production of the drug in Bangladesh. The domestic distribution and export of molnupiravir is expected to start from the end of 2022m after a successful technology transfer and manufacturing regulatory approvals.^[1]

In January 2022, Hikma Pharmaceuticals entered into a license agreement with Medicine Patent Pool (MPP) for molnupiravir, in the Middle East and North Africa (MENA) region. The sub-license agreement is a result of the voluntary licensing agreement signed by MPP and MSD in October 2021 to facilitate affordable global access for molnupiravir, which MSD is developing in partnership with Ridgeback Biotherapeutics. Under the terms of the agreement, Hikma will have rights to sublicense MSD patents and manufacturing know-how for molnupiravir. Hikma will be responsible for manufacturing and commericalising the product. The agreement allows the supply of molnupiravir to 105 low and middle-income countries and Hikma will focus its efforts on the seven MENA markets where it has a presence.^[2]

In January 2022, Merck and Ridgeback Biotherapeutics signed a long-term supply agreement with the United Nations Children’s Emergency Fund (UNICEF) to facilitate broad global access for molnupiravir, an investigational oral antiviral COVID-19 medicine. Under the agreement, Merck will allocate up to 3 million courses of molnupiravir to UNICEF throughout the first half of 2022 for distribution in more than 100 low- and middle-income countries following regulatory authorisations.^[3]

In December 2021, Merck Canada entered into an agreement with Thermo Fisher Scientific to manufacture molnupiravir. Thermo will manufacture molnupiravir for distribution in Canada and the United Kingdom as well as markets in the European Union, Asia Pacific and Latin America, pending local market approvals. Financial details of the deal were not disclosed.^[4]

In December 2021, Merck Canada entered into a supply agreement with the Government of Canada to provide up to 1 million patient courses of molnupiravir, its investigational oral antiviral medicine being developed by Merck in collaboration with Ridgeback Biotherapeutics. Through this agreement, the Government of Canada has secured access in 2022 to 500,000 patient courses, with options for up to 500,000 more pending Health Canada approval.^[5]

In November 2021, Merck and Ridgeback Biotherapeutics entered into a supply agreement with Government of Japan for molnupiravir (MK-4482) to be supplied in Japan for the treatment of COVID-2019 infections. Upon approval, Government of Japan will purchase approximately 1.6 million courses of molnupiravir. Under the agreement, if molnupiravir receives authorization or approval by Japan’s Pharmaceuticals and Medical Devices Agency, Merck will supply approximately 1.6 million courses of molnupiravir to the Japanese government for approximately $US 1.2 billion including applicable taxes. In anticipation of results from the phase III MOVe-OUT clinical trial, and the potential for regulatory authorization or approval, Merck has been investing at risk to support development and scale-up production of molnupiravir and expects to produce 10 million courses of treatment by the end of 2021, with at least 20 million courses to be produced in 2022.^[6]

In November 2021, Merck and Ridgeback Biotherapeutics entered into a supply agreement with the United States government for molnupiravir (MK-4482) to be supplied for the treatment of COVID-2019 infections in the US. United States government will exercise two of its options to purchase a total of 1.4 million additional courses of molnupiravir, an investigational oral antiviral medicine, if the medicine is granted Emergency Use Authorization (EUA) or approval by the U.S. Food and Drug Administration (FDA), for approximately $1 billion. With these exercised options, the U.S. government has now committed to purchasing a total of approximately 3.1 million courses of molnupiravir, for approximately $2.2 billion, between authorization and early 2022. The U.S. government also can purchase more than 2 million additional courses through further options that remain in the contract. Merck is developing molnupiravir in collaboration with Ridgeback Biotherapeutics. In anticipation of the results from MOVe-OUT and the potential for regulatory authorization or approval, Merck has been producing molnupiravir at risk and expects to produce 10 million courses of treatment by the end of 2021, with at least 20 million courses to be produced in 2022. Earlier, in June 2021, Merck entered into a procurement agreement with the US government for molnupiravir (MK-4482) to be supplied for the treatment of COVID-2019 infections in the US. Under the agreement terms, if molnupiravir receives Emergency Use Authorization (EUA) or approval by the US Food and Drug Administration (FDA), Merck will receive approximately $US 1.2 billion to supply approximately 1.7 million courses of molnupiravir to the US government. Merck has been investing at risk to support the development and scale-up the production of molnupiravir while expecting to have more than 10 million courses of therapy available by the end of 2021. Also, this procurement of molnupiravir will be supported in whole or in part with federal funds received from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, in collaboration with the DOD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), under contract number W911QY21C0031.^[7]^[8]

In October 2021, The Medicines Patent Pool (MPP) and Merck entered into a licensing agreement to create broad access for molnupiravir use in 105 low and middle-income countries (LMICs) following appropriate regulatory approvals. Under the terms of the agreement, MPP, through the license granted by Merck, will be permitted to further license non-exclusive sublicenses to manufacturers (MPP License) and diversify the manufacturing base for the supply of quality-assured or WHO-prequalified molnupiravir to countries covered by the MPP License, subject to local regulatory authorization. Merck, Ridgeback Biotherapeutics and Emory University will not receive royalties for sales of molnupiravir under this agreement for as long as COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization.^[9]

In April 2021, Merck & Co.signed non-exclusive voluntary licensing agreements with Cipla, Dr. Reddy’s Laboratories , Emcure Pharmaceuticals, Hetero Labs and Sun Pharmaceutical Industries and Torrent Pharmaceuticals for molnupiravir. Under the terms of agreements, Merck will provide licenses to these manufacturers to supply molnupiravir in India and in more than 100 other low and middle income countries (LMICs) following approvals or emergency authorization by local regulatory agencies. Merck is also in discussions with the Medicines Patent Pool to explore the potential for additional licenses.^[10]^[11]^[12]

In June 2021, Cipla, Dr Reddys Laboratories, Emcure Pharmaceuticals Limited, Sun Pharmaceutical Industries and Torrent Pharmaceuticals entered into a collaboration agreement for clinical trial of molnupiravir for the treatment of mild COVID-19 in an outpatient setting in India. The five companies will jointly sponsor, supervise and monitor the clinical trial in India. As per the directive of the Subject Expert Committee (SEC) of the Central Drugs Standard Control Organization, Dr. Reddy’s will conduct the clinical trial using its product, and the other four pharma companies will be required to demonstrate equivalence of their product to the product used by Dr. Reddy’s in its clinical trial. Following the clinical trial protocol approval given by the Drugs Controller General of India, the clinical trial will be conducted for the treatment of mild COVID-19 in an outpatient setting.^[11]

In May 2020, Ridgeback Biotherapeutics entered into a licensing agreement with Merck for the development of EIDD 2801. Under the terms of agreement, Merck, through a subsidiary, has acquired exclusive worldwide rights to develop and commercialise EIDD 2801 and related molecules. Ridgeback will continue to fund and conduct multiple Ridgeback-sponsored phase I and II trials and fund manufacturing campaigns for clinical supply. Merck will be responsible for clinical development, regulatory filings and manufacturing. Merck and Ridgeback also plan to explore the potential development of EIDD 2801 in other severe acute viral diseases, including Ebola virus infections. In July 2020, Ridgeback Biotherapeutics and Merck announced that the US Federal Trade Commission (FTC) granted early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act and also announced the closing of collaboration agreement and licensing transactions to advance the development of EIDD 2801.^[13]^[14]

In March 2020, Ridgeback Biotherapeutics entered into a licensing agreement with Drug Innovations at Emory (DRIVE, a wholly owned subsidiary of Emory University) for the development of EIDD 2801. Under the terms of the agreement, Ridgeback Biotherapeutics will be responsible for advancing the drug through clinical development and ensuring that EIDD 2801 is available during the COVID-19 pandemic. Ridgeback Biotherapeutics will also be responsible for conducting the necessary trials to bring EIDD 2801 to licensure. Financial terms of the agreement were not disclosed^[15]

In December 2021, Merck and Ridgeback entered into a purchase agreement with the United Kingdom government for the purchase of molnupiravir (MK 4482) for the treatment of COVID-2019 infections in the UK. United Kingdom Government will purchase an additional 1.75 million patient courses of molnupiravir (MK-4482). In the UK, LAGEVRIO^® is the planned trademark for molnupiravir; the trademark for molnupiravir in other countries has not been approved. With this additional procurement agreement, which follows a previously announced agreement for 480,000 courses of treatment, the UK Government has now committed to purchase a total of 2.23 million courses of molnupiravir ^[16]

Key Development Milestones

As of January 2022, molnupiravir (LAGEVRIO^®) was launched in the United Kingdom for the treatment of COVID-2019 infections. In November 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) had approved molnupiravir (LAGEVRIO^®) for the treatment of mild-to-moderate COVID-2019 infections in adults with a positive SARS-CoV-2 diagnostic test and who have at least one risk factor for developing severe illness in the UK. The MHRA announced that molnupiravir is safe and effective at reducing the risk of hospitalization and death in people with mild to moderate COVID-19 who are at increased risk of developing severe disease. The authorization is based on positive results from a planned interim analysis from the phase III MOVe-OUT trial^[17].

In January 2022, the Therapeutic Goods Administration (TGA), Australia, granted provisional approval to molnupiravir (LAGEVRIO) for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death. The decision to approve this indication was made on the basis of the analysis of efficacy and safety data from a phase III trial. The evaluation of the drug commenced in August 2021 ^[18].

In December 2021, Merck and Ridgeback Biotherapeutics reported that the US FDA has granted Emergency Use Authorization (EUA) for molnupiravir to treat mild to moderate 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. The authorization was based on the phase III MOVe-OUT trial [see below] ^[19]. In November 2021, Merck and Ridgeback Biotherapeutics announced that the US Food and Drug Administration’s (FDA) Antimicrobial Drugs Advisory Committee (AMDAC) voted positive regarding the Emergency Use Authorization (EUA) application for molnupiravir (MK-4482, EIDD-2801), an investigational oral antiviral medicine, for the treatment of mild to moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19 and/or hospitalization ^[20]. Earlier, in October 2021, Merck and Ridgeback Biotherapeutics announced submission of an Emergency Use Authorization (EUA) application to the US FDA for molnupiravir for the treatment of mild-to-moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalisation. The submission is based on positive results from an interim analysis from the phase III MOVe-OUT clinical trial (see below), which evaluated molnupiravir in non-hospitalized adult patients with mild-to-moderate COVID-19 who were at risk for progressing to severe COVID-19 and/or hospitalization. As of October 2021, the US FDA held an advisory committee (Antimicrobial Drugs Advisory Committee (AMDAC)) to discuss emergency use authorization (EUA) for molnupiravir in COVID 2019 infections. On November 30, 2021 the advisory committee will meet to discuss the available data supporting the use of molnupiravir to treat mild-to-moderate COVID 2019 infections in adults who have tested positive for COVID-19, and who are at high risk for progression to severe COVID-19, including hospitalisation or death. The interim analysis and the additional analyses that support the efficacy and overall favourable benefit-risk assessment of molnupiravir for the treatment of mild to moderate COVID-19 in adults at high risk for disease progression will be shared by Merck with the FDA and be presented to the FDA’s Antimicrobial Drugs Advisory Committee^[21]^[22]^[23]^[24].

In December 2021, Cipla reported that molnupiravir (LAGEVRIO^®) was granted an emergency use authorisation (EUA) permission by the Drug Controller General of India (DCGI) for the launch of molnupiravir in India to treat mild to moderate COVID-2019 infections^[25].

In December 2022, the National Medical Products Administration of China has granted conditional marketing authorization for molnupiravir in adult patients with mild to medium COVID-19 infection and a high risk of progressing to severe cases^[26].

In January 2022, Merck and Ridgeback announced that molnupiravir was approved for the treatment of COVID-2019 infections in Taiwan^[3].

Merck reported that the Ministry of Health, Labor and Welfare had granted special approval for an emergency use authorization (EUA) in Japan for molnupiravir (LAGEVRIO^®) to treat mild to moderate COVID-2019 infection (SARS-CoV-2) in adults^[27]. Kyorin Pharmaceutical signed a memorandum of understanding regard a negotiation right toward local co-promotion collaboration of molnupiravir (Lagevrio® capsule 200mg) for which Merck received its manufacturing and marketing approval. Under the memorandum, Kyorin Pharmaceutical will negotiate with Merck on the contract for co-promotion collaboration of molnupiravir in Japan^[28].

In June 2023, Merck withdrew its application for marketing authorisation seeking approval of molnupiravir (Lagevrio™) for the treatment of COVID-19 infections in adults. In its letter notifying the regulatory authority, the company stated that the withdrawal was based on the CHMP's view that the data provided did not allow the committee to conclude on a positive benefit-risk balance for molnupiravir^[29]^[30]^[31]. In February 2023, Ridgeback Biotherapeutics announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the refusal of the marketing authorization for molnupiravir (LAGEVRIO™) for the treatment of certain adults who have been diagnosed with COVID-19 in the European Union (EU). Merck and Ridgeback will appeal the decision and request a re-examination of the CHMP’s opinion^[32]. Earlier in November 2021, the EMA’s CHMP had issued advice on the use of molnupiravir for the treatment of COVID-2019 infections. The drug can be used to treat adults with COVID-2019 who do not require supplemental oxygen and who are at increased risk of developing severe COVID-2019 infection ^[33]. The European Medicines Agency (EMA) announced that it will review more data from the phase II/III MOVe-OUT trial of molnupiravir for the treatment of COVID-19 infections^[34]. In October 2021, Merck and Ridgeback Biotherapeutics announced that the EMA had initiated a rolling review for molnupiravir for the treatment of COVID-19 in adults. Company plans to work with the EMA’s Committee for Medicinal Products for Human Use (CHMP) to complete the rolling review process to facilitate initiating the formal review of the marketing authorisation application (MAA). The submission is based on the positive results from the phase III MOVe-OUT clinical trial [see below]^[35]. The EMA issued a positive scientific opinion for molnupiravir under Article 5.3 Regulation 726/2004, which was intended to support national decision-making on the possible use of molnupiravir prior to marketing authorisation^[36].

In August 2021, Merck announced initiation of rolling submission under the Minister of Health's interim order, to Health Canada for molnupiravir for the treatment of COVID-2019 infections^[37]

In November 2022, Merck Sharp & Dohme completed a phase III MOVe-AHEAD trial that evaluated the efficacy and safety of molnupiravir for the prevention of COVID-19 infection in healthy volunteers (4482-013; MK4482-013; EudraCT2021-000904-39; NCT04939428). The randomised, placebo-controlled, double blind trial initiated in August 2021, enrolled 1539 healthy volunteers in Turkey, Spain, Hungary, the US, Argentina, Brazil, Colombia, France, Guatemala, Japan, Mexico, Romania, Russia, Ukraine, Dominican Republic, Bulgaria, Egypt, Kenya, Malaysia, Peru, Philippines, South Africa and Thailand^[38]^[39]^[40]. In February 2023, Adverse events data from a phase III trial in COVID-2019-infections released by Merck & Co^[41].

Prior to July 2021, Hetero Labs initiated a phase III trial to evaluate the efficacy and safety of molnupiravir plus standard of care versus standard of care alone, in mild COVID-2019 infection patients with a positive SARS CoV-2 RT PCR test for COVID-2019 and randomised within five days of onset of symptoms. The open label, randomised trial enrolled 1 218 patients in India^[42]. In July 2021, Hetero released interim efficacy and safety data from the trial^[43]. In February 2022, the company presented updated results from the trial at the 29th Conference on Retroviruses and Opportunistic Infections (CROI-2022)^[44]^[45].

As of October 2021, Merck Sharp & Dohme discontinued phase II/III MOVe-OUT trial as per the US FDA recommendation. In October 2020, Merck Sharp & Dohme initiated a phase II/III MOVe-OUT trial to evaluate safety, tolerability and efficacy of molnupiravir in patients with COVID-2019 infection (MK-4482-002; EudraCT2020-003368-24; NCT04575597; PHRR201209-003186; jRCT2031210148 ). The randomised, placebo controlled, double blind trial enrolled 1433 patients in the Argentina, Brazil, Canada, Chile, Colombia, Egypt, France, Germany, Guatemala, Israel, Italy, Japan, Mexico, Philippines, Poland, Russia, South Africa, Spain, Sweden, Taiwan, Ukraine, United Kingdom, the US. As of April 2021, part I of trial enrolled 302 patients. The external Data Monitoring Committee suggested amendments to the MOVe-OUT protocol to focus enrolment on patients early in the course of disease and those considered high risk for poor COVID-19 outcomes. Based upon these recommendations, company will amend the inclusion criteria by reducing the allowable symptom duration for enrolment to <5 days and by enrolling participants with at least one risk factor for progression to severe disease. Merck plans to start enrolling patients in Phase III portion (Part 2) by late April or early May 2021. Company released interim data from the trial. In July 2021, Merck announced that the phase III portion of the trial is underway. In October 2021, Merck and Ridgeback Biotherapeutics announced that at the recommendation of an independent data monitoring committee and in consultation with the US Food and Drug Administration (FDA), recruitment into the phase III MOVe-OUT trial was being stopped early due to these positive interim results. In November 2021, updated results from the trial were released by Merck Sharp & Dohme and Ridgeback Biotherapeutics. In January 2022, data were published in the New England Journal of Medicine^[46]^[21]^[47]^[48]^[49]. In September 2021, data from the trial was presented at Conference on Infectious Diseases (IDWeek-2021). In April 2021, efficacy data from the phase II/III trial was released by Merck & Co^[50]^[51]

In April 2021, Merck Sharp & Dohme discontinued a phase II/III MOVe-IN trial, as an interim analysis, study was unlikely to demonstrate a clinical benefit in hospitalised patients. In October 2020, trial was initiated to evaluate the efficacy, safety and pharmacokinetics of molnupiravir in hospitalised adult patients with COVID-19 infections (4482-001; NCT04575584; EudraCT2020-003367-26). The randomised, double-blind trial was intends to enrol 1300 patients in the US, in the UK, Sweden, Poland, Italy, Brazil, Canada, Chile, Colombia, France, South Korea, Mexico, Philippines, Russia, South Africa, Spain, Ukraine and Israel^[52]. As of April 2021, phase II portion enrolled 304 patients^[48]. In September 2021, data from the trial was presented at Conference on Infectious Diseases (IDWeek-2021)^[51] .

In August 2023, Merck Sharp & Dohme initiated a phase I trial to evaluate the efficacy and safety of molnupiravir (MK-4482) in healthy participants inoculated with experimental influenza virus (MK-4482-019) (NCT05818124; 4482-019). This double-blind, randomised, placebo-controlled study is designed to enrol 160 healthy
volunteers in UK^[53].

In July 2020, Liverpool in collaboration with University of Southampton, Liverpool School of Tropical Medicine, Lancaster University and Liverpool University Hospitals NHS Foundation Trust initiated a phase Ib/IIa AGILE trial to evaluate the optimal dose, activity and safety of multiple candidates including VIR 7832 [see ADIS insight drug profile800058115], VIR 7831 [see ADIS insight drug profile800058114], molnupiravir (EIDD 2801) and nitazoxanide for the treatment of COVID-2019 infections (NCT04746183; oL001542). The randomised trial intends to enrol 600 patients in the UK and may extends to South Africa^[54]^[55]. In February 2022, the pharmacokinetic data from the trial were presented at 29^thConference on Retroviruses and Opportunistic Infections (CROI-2022)^[56].

In February 2021, Ridgeback Biotherapeutics and Merck completed a phase IIa protocol 6 trial that evaluated the safety, tolerability, and antiviral activity of molnupiravir versus placebo as measured by infectious virus detection in symptomatic adult outpatients with COVID-19 (NCT04405570; EIDD-2801-2003). This randomised, double-blind, placebo-controlled trial was initiated in June 2020. The trial had recruited 202 patients in the US^[57]. In March 2021, Ridgeback Biotherapeutics and Merck released preliminary findings from the phase IIa trial^[58]. In the same month, Ridgeback Biotherapeutics also presented the results from the trial at the 28^th Conference on Retroviruses and Opportunistic Infections (CROI-2021)^[59].

In February 2022, Ridgeback Biotherapeutics completed the phase II END-COVID trial that assessed the efficacy and safety of molnupiravir on SARS-CoV-2 virus shedding in newly hospitalised adults with polymerase chain reaction (PCR)-confirmed COVID-2019 infections (NCT04405739; EIDD-2801-2004). The randomised, double-blind trial was initiated in June 2020, and enrolled 71 patients in the US. In September 2021, data from the trial was presented at Conference on Infectious Diseases (IDWeek-2021)^[60]^[61].

In May 2023, Merck Sharp & Dohme completed a phase IIa trial that evaluated the efficacy and safety of molnupiravir in healthy volunteers inoculated With experimental respiratory syncytial virus (NCT05559905; 4482-017; MK-4482-017). The double-blind, randomised, placebo-controlled trial was initiated in November 2022 and enrolled 116 volunteers in the UK^[62].

In February 2023, Merck Sharp & Dohme completed a phase I trial that evaluated the safety, tolerability and plasma pharmacokinetics (PK) of N-hydroxycytidine (NHC), the nucleoside metabolite of molnupiravir, after its single dose of 800 mg in patients with severe renal impairment compared to healthy mean matched control volunteers (NCT05386758; 4482-003; MK4482-003). The multicentre, open study was initiated in July 2022 and enrolled 16 patients in the US^[63].

In December 2022, Merck Sharp & Dohme completed a phase I trial that evaluated the pharmacokinetics (PK) of N-hydroxycytidine (NHC) following a single oral dose of molnupiravir in participants 18 to 75 years (inclusive) with moderate hepatic impairment and healthy matched controls (NCT05386589; 4482-016; MK-4482-016). The open-label, single-dose study was initiated in June 2022 and enrolled 14 participants in the US^[64].

In March 2021, Ridgeback Biotherapeutics released results and reported that the phase I trial met its primary and key secondary endpoints. In August 2020, Ridgeback Biotherapeutics completed the randomised, double-blind, placebo-controlled, first-in-human, phase I study that evaluated the safety, tolerability, and pharmacokinetics of molnupiravir oral administration in healthy volunteers for the treatment of COVID-2019 infections (EIDD-2801-1001; EudraCT2020-001407-17; NCT04392219). The trial was initiated in April 2020 and enrolled 130 healthy subjects in the UK^[65]. The UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the clinical trial application and granted permission to initiate clinical testing in the same month^[66]. In May 2020 and March 2021, Ridgeback Biotherapeutics released data for the trial^[67]^[13].

In a comprehensive nonclinical safety program of molnupiravir, animals administered with molnupiravir for longer and at higher doses (mg/Kg) indicated that molnupiravir was not mutagenic or genotoxic in in vivo mammalian systems^[58].

In April 2020, the US FDA approved an IND application of molnupiravir by Ridgeback Biotherapeutics to initiate the clinical trial for the treatment of COVID-2019 infections in the US^[68].

In December 2020, Georgia State University released preclinical data of molnupiravir (MK 4482 or EIDD 2801) for the treatment of COVID-2019 infections^[69].

Molnupiravir demonstrated potent activity against seasonal and bird influenza, respiratory syncytial virus, chikungunya virus, Ebola virus, Venezuelan equine encephalitis virus, and Eastern equine encephalitis virus in laboratory studies. In April 2020, pharmacodynamics data from preclinical studies of two distinct coronaviruses (SARS-CoV1 and MERS) were released by Ridgeback Biotherapeutics^[66].

In six preclinical studies, molnupiravir was active against SARS-CoV-2 variant, Omicron (B1.1.529), in vitro. The company anticipated that molnupiravir will be active against variants of concern and an important tool in the fight against COVID-19^[46].

In preclinical studies, molnupiravir prevented the replication of SARS-CoV-2 virus that cause COVID-2019 infections and also showed potent activity against severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) in animal model of infection^[68].

In October 2019, results from preclinical studies in influenza were released by Emory University^[70].

In September 2021, data from early research was presented at Conference on Infectious Diseases (IDWeek-2021)^[71]

Patent Information

As of December 2021, Merck & Co has patent protection for molnupiravir in the US with an anticipated expiry in 2038^[72].

Drug Properties & Chemical Synopsis

Route of administration PO
Formulation Capsule, unspecified
Class Antivirals, Esters, Hydroxylamines, Pyrimidinones, Ribonucleosides, Small molecules
Target Virus replication
Mechanism of Action Virus replication inhibitors
WHO ATC code
J05A-X (Other antivirals)
EPhMRA code
J5B9 (Antivirals, others)
Chemical name [(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate
Molecular formula C13 H19 N3 O7
SMILES C(C(C)C)(=O)OCC1OC(C(C1O)O)N1C=CC(=NC1=O)NO
Chemical Structure

Download PNG Download MOL file
CAS Registry Number 2349386-89-4

Indication	Biomarker Function	Biomarker Name	Number of Trials
cOVID 2019 infections	Eligibility Criteria	T-cell surface antigen CD4 L-Aspartic acid ALT 1 more biomarker names Show less	3 1 1
COVID-19 respiratory infection	Arm Group Label	cystatin SA cystatin D	1 1
COVID-19 respiratory infection	Eligibility Criteria	T-cell surface antigen CD4 L-Aspartic acid ALT 1 more biomarker names Show less	1 1 1
SARS-CoV-2 acute respiratory disease	Arm Group Label	cystatin SA cystatin D	1 1
SARS-CoV-2 acute respiratory disease	Eligibility Criteria	T-cell surface antigen CD4	1

Drug Name	Biomarker Name	Biomarker Function
Molnupiravir - Emory University/Georgia State University/Merck & Co/Ridgeback Biotherapeutics		ALT	Eligibility Criteria
	cystatin D	Arm Group Label
	cystatin SA	Arm Group Label
	L-Aspartic acid	Eligibility Criteria
	T-cell surface antigen CD4	Eligibility Criteria

Indication	Phase 0	Phase I	Phase II	Phase III	Phase IV
Influenza virus infections	-	4	1	1	-
Respiratory syncytial virus infections	-	3	1	-	-
COVID-19 respiratory infection	-	-	3	2	2
Severe acute respiratory syndrome	-	3	1	-	-
Myelodysplastic syndromes	-	-	-	-	1
Non-Hodgkin's lymphoma	-	-	-	-	1
Venezuelan equine encephalomyelitis	-	3	1	-	-
Influenza A virus infections	-	-	-	1	-
Chronic myeloid leukaemia	-	-	-	-	1
SARS-CoV-2 acute respiratory disease	-	-	2	1	2
Hodgkin's disease	-	-	-	-	1
Community-acquired pneumonia	-	-	-	1	-
Chikungunya virus infections	-	3	1	-	-
COVID-19 pneumonia	-	-	-	1	-
Acute myeloid leukaemia	-	-	-	-	1
Influenza B virus infections	-	-	-	1	-
COVID 2019 infections	-	4	6	8	19
Middle East respiratory syndrome coronavirus	-	3	1	-	-
Renal failure	-	1	1	-	-
Eastern equine encephalomyelitis	-	3	1	-	-
Chronic lymphocytic leukaemia	-	-	-	-	1
Ebola virus infections	-	3	1	-	-

Indication	Qualifier	Patient Segment	Phase	Countries	Route / Formulation	Developers	Event Date
COVID 2019 infections	Non-Hospitalised Adults With COVID-19	-	Marketed	United Kingdom	PO / Capsule	Merck & Co	25 Jan 2022
COVID 2019 infections	Non-Hospitalised Adults With COVID-19; Emergency use approval Non-Hospitalised Adults With COVID-19Emergency use authorisation	-	Registered	Japan, Taiwan	PO / Capsule	Merck & Co	18 Jan 2022
COVID 2019 infections	Emergency Use Authorisation(EUA)	-	Registered	India	PO / Capsule	Hetero Labs	29 Dec 2021
COVID 2019 infections	Provisional approval	-	Registered	Australia	PO / Capsule	Merck Sharp & Dohme	20 Jan 2022
COVID 2019 infections	Non-Hospitalised Adults With COVID-19, Emergency Use Authorization	-	Registered	USA	PO / Capsule	Merck & Co, Ridgeback Biotherapeutics	23 Dec 2021
COVID 2019 infections	conditional marketing authorization	-	Registered	China	PO / unspecified	Merck & Co	01 Dec 2022
COVID 2019 infections	Non-Hospitalised Adults With COVID-19.	-	Preregistration	Canada	PO / Capsule	Merck & Co	13 Aug 2021
COVID 2019 infections	in adults residing with a person with COVID-19 infection.	Prevention	Phase III	Hungary, Spain, Turkey, USA	PO / Capsule	Merck & Co	11 Aug 2021
COVID 2019 infections	Non-Hospitalised Adults With COVID-19. Non-Hospitalised Adults With COVID-19	-	Phase III	Argentina, Brazil, Chile, Colombia, Egypt, Guatemala, Israel, Mexico, Philippines, Russia, South Africa, Ukraine	PO / Capsule	Merck & Co	01 Oct 2021
COVID 2019 infections	in adults residing with a person with COVID-19 infection.	Prevention	Phase III	Argentina, Brazil, Bulgaria, Colombia, Dominican Republic, France, Guatemala, Japan, Kenya, Malaysia, Mexico, Peru, Philippines, Romania, Russia, South Africa, Thailand, Ukraine	PO / Capsule	Merck Sharp & Dohme	11 Aug 2021
COVID 2019 infections	Hospitalised Adults With COVID-19	-	Phase II/III	South Korea	PO / Capsule	Merck & Co	19 Oct 2020
COVID 2019 infections	-	-	Preregistration Submission Withdrawal	European Union	PO / Capsule	Merck & Co	21 Jun 2023
Chikungunya virus infections	-	-	Preclinical	USA	PO / unspecified	Emory University	19 Mar 2020
Eastern equine encephalomyelitis	-	-	Preclinical	USA	PO / unspecified	Emory University	19 Mar 2020
Ebola virus infections	-	-	Preclinical	USA	PO / unspecified	Ridgeback Biotherapeutics	15 Apr 2020
Influenza virus infections	-	In volunteers	Phase I	United Kingdom	PO / unspecified	Emory University, Ridgeback Biotherapeutics	21 Aug 2023
Middle East respiratory syndrome coronavirus	-	-	Preclinical	USA	PO / unspecified	Emory University	19 Mar 2020
Middle East respiratory syndrome coronavirus	-	Prevention	Preclinical	USA	PO / unspecified	Ridgeback Biotherapeutics	13 Apr 2020
Renal failure	-	Late-stage disease	Phase I	USA	PO / unspecified	Merck Sharp & Dohme	06 Jul 2022
Respiratory syncytial virus infections	-	In volunteers	Phase II	United Kingdom	PO / unspecified	Merck Sharp & Dohme	02 Nov 2022
Respiratory syncytial virus infections	-	-	Preclinical	USA	PO / unspecified	Emory University	19 Mar 2020
Severe acute respiratory syndrome	-	-	Preclinical	USA	PO / unspecified	Emory University	17 Mar 2020
Severe acute respiratory syndrome	-	Prevention	Preclinical	USA	PO / unspecified	Ridgeback Biotherapeutics	13 Apr 2020
Venezuelan equine encephalomyelitis	-	-	Preclinical	USA	PO / unspecified	Emory University	19 Mar 2020

Adverse drug reaction	Total safety reports	Serious reports	First reports
Behaviour and behaviour mechanisms	2	2	-
Cardiovascular disorders	3	3	-
Digestive system disorders	4	2	-
Disorders of environmental origin	1	1	-
Drug response related complications	20	20	-
Ear nose and throat disorders	1	-	-
Endocrine disorders	1	1	-
Eye disorders	1	1	-
Immunological disorders	2	2	-
Infections	6	6	-
Neurological disorders	8	5	-
Pathological conditions signs and symptoms	6	3	-
Pathology and biological functions	1	1	-
Respiratory tract disorders	2	2	-
Signs symptoms and ill defined conditions	6	5	-
Skin and connective tissue diseases	6	4	-

Scientific Summary

Adverse Events Occasional: Diarrhoea; Headache; Nausea; Somnolence

Pharmacokinetics

In phase Ib/IIa AGILE trial, molnupiravir was detected in 11% of saliva samples [median (range) 4.86 ng/ mL (2.63-31.44)] and not evaluated in swabs. Quantifiable EIDD 1931, following molnupiravir 300, 600 and 800 mg twice daily were i) saliva: 17.7 (2.8-133), 16.6 (2.9-469), 25.8 (4.0-230) ng/mL, ii) nasal swabs: 182 (18-1700), 136 (18-917), 295 (24-1879) ng/mL and iii) tears: 297 (24-1650), 176 (16-1260), 307 (32-2760) ng/mL. Median (range, CV%) pooled NP:P ratio for saliva was 0.03 (0.01-0.11, 60%; n=16). Nasal and tear ratios were 6-fold higher with values of 0.21 (0.05-0.73, 70%; n = 17) and 0.22 (0.09-1.05, 92%; n=12), respectively. Non-plasma and plasma concentrations were significantly correlated (r2: 0.360-0.677; p<0.0001). In saliva, nasal and tear samples, 6, 50 and 61%, respectively were within or above the EIDD-1931 EC ₉₀ against SARS-CoV-2 in primary human airway epithelia cultures (approximately 0.5-1 µM ≈ 130-260 ng/mL)^[56].

In a phase I trial, treatment with molnupiravir in a fed state demonstarted a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was found to appear rapidly in plasma, with a median time of maximum observed concentration of one to 1.75 hours, and declined with a geometric half-life of approximately one hour. Mean maximum observed concentration and area under the concentration versus time curve was found to increase in a dose-proportional manner, and there was no accumulation following multiple doses. Plasma exposures exceeded expected efficacious exposures based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached^[67]^[65]

Adverse Events

Updated results of the open-label, randomized, phase III trial in patients (1 218) with mild COVID-2019 infection demonstrated that molnupiravir was well tolerated, while the adverse events were mild and rare. There were no serious adverse events. Mild and self-limiting adverse events occurred in 4.8% of molnupiravir plus standard of care (SOC) and 2.6% of SOC patients. The most common adverse events were neurological (headache, somnolence) and gastrointestinal^[44]. Interim results from mild COVID-19 patients (N=741) showed that all adverse events were non-serious, mild in severity, and none led to drug discontinuation. Most common adverse events reported were nausea, diarrhoea and headache which were resolved completely. There was no mortality reported in either groups^[43]^[42].

Updated results of the phase II/III MOVe-OUT trial in patients with mild-to-moderate COVID-19 infection (n = 1433) showed that nine deaths were reported in the placebo group, and one in the molnupiravir group. Previously, interim analysis results of the trial showed that the incidence of any adverse event was comparable in the molnupiravir and placebo groups (35% and 40%, respectively) (n=775). The incidence of drug-related adverse events was also comparable (12% and 11%, respectively). Fewer patients discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%)^[21]^[47]^[49]. Previously, in phase II/III MOVe-OUT trial, no evidence for unexpected findings or trends observed at any of the doses studied. In both trials, no deaths were considered drug-related by the investigators, and there were no drug-related adverse events that led to discontinuation in participants who received molnupiravir. 6.2% (14/225) patients who received molnupiravir and 6.8% (5/74) of those received placebo reported drug-related adverse events^[48].

In phase II/III trial MOVe-IN trial, 11.0% (24/218) of patients treated with molnupiravir and 21.3% (16/75) of those received placebo reported drug-related adverse events. No evidence for unexpected findings or trends observed at any of the doses studied. In both trials, no deaths were considered drug-related by the investigators, and there were no drug-related adverse events that led to discontinuation in participants who received molnupiravir^[48]

Phase I:

In a phase I trial, treatment with EIDD-2801 was generally safe and well tolerated. Adverse events were reported by fewer than half participants out of the 130 volunteers in the study. The incidence of reported adverse events was higher following administration of placebo, and 93.3% of adverse events were reported as mild. There were no serious adverse events and there were no statistically significant findings from results of clinical laboratory, vital signs or electrocardiography^[67]^[13]^[65].

Phase II

Preliminary findings from the secondary endpoint of a phase II trial demonstrated that of 202 treated participants, no safety signals were identified. Of the 4 serious adverse events reported, none were considered to be study drug related^[58]^[57].

Phase III

In the phase III MOVe-OUT trial of molnupiravir for the treatment of coronavirus disease demonstrated that the most common adverse reactions occurring in 1% of subjects in the LAGEVRIO treatment group 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) and serious adverse events occurred in 7% of subjects receiving LAGEVRIO 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 LAGEVRIO and 12 (2%) of subjects receiving placebo^[41]^[38].

Pharmacodynamics

Summary

In preclinical studies, oral administration of EIDD 2801 resulted in decreased group pandemic 1 and group 2 seasonal influenza A shed virus load by multiple orders of magnitude and alleviated fever, airway epithelium histopathology, and inflammation. In disease-relevant well-differentiated human air-liquid interface airway epithelia, inhibitory concentrations were low nanomolar against influenza A and B viruses. A therapeutic window >1713 was observed and dosing parameters required for efficacious human therapy was established when antiviral efficacy and cytotoxicity thresholds with pharmacokinetic profiles in human airway epithelium models were correlated^[70].

In animal models infected with Severe acute respiratory syndrome (SARS)/ Middle East respiratory syndrome coronavirus (MERS) treatment with EIDD 2801 led to therapeutic benefits. In models with (SARS-CoV1 and MERS), EIDD 2801 improved pulmonary function, decreased body weight loss and reduced the amount of virus in the lung. The candidate also prevented significant manifestations of disease following prophylactic administration in animals challenged with MERS and SARS^[66].

In preclinical studies for the treatment of COVID-2019 (SARS-CoV-2) infection, molnupiravir completely suppressed virus transmission within 24 hours. In a ferret model, the SARS-CoV-2 infected ferrets were treated with molnupiravir twice daily significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals^[69].

In preclinical invitro studies NHC was equally effective against SARS-CoV-2 variants B.1.1.7 (20I), B.1351 (20H), and P1 (20J), compared with the original WA1 (19B) isolate. In clinical trials, no discernable difference was observed in magnitude of viral response measured by change from baseline in RNA titer over time across all clades represented including 20A through 20E and 20G to 20I. No participants at the time of the study presented with 20F, 20J, or 21A. Both in vitro and clinical data suggest that spike protein substitutions do not impact antiviral activity of MOV and suggest its potential use for the treatment of SARS-CoV-2 variants^[71]

Therapeutic Trials

Updated results of the open-label, randomized, phase III trial in patients (1 218) with mild COVID-2019 infection demonstrated a lower rate of hospitalisation, earlier clinical improvement, and earlier SARS CoV2 RT PCR negativity document superiority of molnupiravir to standard of care (SOC) in mild SARS-CoV2 infection. In the molnupiravir plus SOC arm, nine patients (1.5%) required hospitalisation versus 26 (4.3%) in the SOC arm (p < 0.01). In the molnupiravir plus SOC arm 80.8%, 95.6% and 97.4% had clinical improvement by day 5, 10 and 14, respectively, when compared with 32.1%, 74.3% and 94.1% in the SOC arm (p < 0.0001 at day 5 and 10, and p < 0.01 at day 14). The rate of SARS CoV2 negativity was 77.1%, 91.3% and 93.9% in molnupiravir plus SOC arm versus 29.3%, 70.2% and 89.0% in SOC arm at day 5, 10 and 14, respectively (p < 0.001)^[44]. Interim results demonstrated that molnupiravir plus SOC reduced the risk of hospitalisation by over 65%, when compared with SOC alone. Early viral clearance (negative RT-PCR) and significant clinical improvement were observed within 5 days of administering the antiviral drug^[45]. Earlier results from mild COVID-19 patients (N = 741), molnupiravir demonstrated statistically significant fewer hospital admissions, faster time to clinical improvement and early negative SARS CoV-2 RT PCR with molnupiravir treatment when compared with standard of care alone. Earlier clinical improvement (2-point decrease in WHO Clinical Progression Scale) observed in molnupiravir group when compared with SOC (Day 5 (63.43% vs 22.33%; p=<0.0001), day 10 (78.96% vs 49.49%; p=<0.0001) and day 14 (81.55% vs 73.22%; p = 0.0150)). Median time to clinical improvement observed as early as 8 days in molnupiravir group compared to 12 days in SOC alone group (p=0.0001). Earlier SARS CoV-2 RT-PCR negativity observed in molnupiravir group compared standard of care (day 5 (77.35% vs 26.07%; p=<0.0001) day 10 (94.03% vs 57.20%; p=<0.0001) and day 14 (97.01% vs 85.21%; p=<0.0001)). Fewer hospital admissions reported in molnupiravir group, when compared with SOC alone (7 (1.89%) vs 23 (6.22%) p = 0.0027) over 14 days of observation^[43]^[42].

Updated data from the trial indicated that at day three none of the patients who were on treatment had detectable infectious SARS-CoV-2 compared to 21.8% of patients who didn't receive treatment. No infectious virus was detected in patients on treatment on day five compared to 2.2% of patients on placebo. None of the patients from either of the arm showed infectious SARS-CoV-2 at day ten. Earlier results of the phase II/III MOVe-OUT trial in patients with mild-to-moderate COVID-19 infections (n = 1433) showed that molnupiravir reduced the risk of hospitalisation or death from 9.7% in the placebo group (68/699) to 6.8% (48/709) in the molnupiravir group, for an absolute risk reduction of 3.0% [95% CI: 0.1, 5.9; p = 0.0218) and a relative risk reduction of 30% [relative risk 0.70; 95% CI: 0.49, 0.99]. Previously, interim analysis results of the trial in 775 patients showed that molnupiravir reduced the risk of hospitalisation or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalised or died through day 29 following randomisation (28/385), compared with 14.1% of placebo-treated patients (53/377); [absolute risk reduction 6.8%; 95% CI: 2.4, 11.3; p=0.0012]. Through day 29, no deaths were reported in patients who received molnupiravir, as compared to eight deaths in patients who received placebo. Molnupiravir reduced the risk of hospitalisation and/or death across all key subgroups; efficacy was not affected by timing of symptom onset or underlying risk factor. Based on the participants with available viral sequencing data (approximately 40% of participants), molnupiravir demonstrated consistent efficacy across viral variants Gamma, Delta, and Mu. In the trial, percentage of patients who were hospitalizsd and/or died in part 1 of the MOVe-OUT study was lower in the combined molnupiravir-treated groups versus the placebo arm. The efficacy of molnupiravir treatment was generally consistent across important patient subgroups, including patients infected with SARS-CoV-2 variants of concern, Delta, Gamma, and Mu. Among the all-randomised population with viral sequencing data available (55.3%), the three most common SARS-CoV-2 variants were Delta (58.1%), Mu (20.5%), and Gamma (10.7%). The largest overall magnitude of antiviral effect was observed in the 800mg dose, compared with the 200mg and 400mg doses^[50]^[46]^[48]^[21]^[47]^[20]^[49].

In phase II/III MOVe-IN trial, molnupiravir failed to demonstrate clinical benefit in hospitalised patients, who generally had a longer duration of symptoms prior to study entry^[48]

Combined data from phase II/III trial in hospitalized and non-hospitalized adults demonstrated an increase of ~2-4 fold in the viral mutation rate post-baseline in MOV treated compared with placebo. Mutations were distributed across the entire genome with only a minority being observed in more than one sample. The most frequent mutations were transitions of C to U observed in the highest MOV dose group (800 mg/BID)^[51] .

Updated results from the phase II trial in symptomatic adult outpatients with COVID-19 infections showed that molnupiravir therapy reduced infectiousness in the patients, and is unlikely to be impacted by the spike-protein variants. 45% (78/175) patients showed a positive SARS-CoV-2 culture at enrollment (52 - therapy arm; 26 - placebo arm). On Day 3, 20% patients from therapy group had positive viral culture as compared with
28% patients from placebo group (p = 0.56). On Day 5, 24% of placebo patients were culture positive as compared with none treated with molnupiravir (p = 0.001). Comparisons were performed by Fisher's exact test. Preliminary findings from the secondary endpoint of the trial in symptomatic adult outpatients with COVID-19 infections, demonstrated reduction in time (days) to 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. Of the 182 patients with an evaluable nasopharyngeal swab, 42% (78/182) exhibited detectable levels of cultured virus at baseline. At day 5, there was a reduction (nominal p=0.001, not controlled for multiplicity) in positive viral culture in patients who received molnupiravir (all doses) compared with placebo 0% (0/47) for molnupiravir and 24% (6/25) for placebo^[59]^[58]^[57].

In phase II trial IVDM showed data were best described when MOV acts on viral infectivity, consistent with the error catastrophe mechanism of action. A cascade of innate and adaptive immune response and a basal level activation enabled durable immunity and continued viral decay after treatment end. IVDM reasonably describes VL and viral titer data from animals and humans. Influence of MOV start time was explored using simulations. Consistent with the ferret studies, simulations showed when treatment is started within the first week post infection, MOV reduces viral growth, resulting in a lower and shortened duration of detectable VL. When started later (e.g. >7 days since symptom onset), the magnitude of drug effect is substantially diminished in a typical patient with an effective immune response which reduces VL prior to treatment start. Further work is needed to model response in patients with longer term infection, where MOV drug effects may have more persistent utility^[60]

Indication	Region	2021	2022	2023	2024	2025	Last Update
COVID-19	ex US	320	4161	1040	312	156	05 Nov 2023
COVID-19	US	632	1523	0	0	0	05 Nov 2023
Total		952	5684	1040	312	156

Expected Date	Event Type	Description	Updated
21 Jan 2023	Trial Update	Merck Sharp & Dohme plans a phase-II trial for Respiratory syncytial virus infections in January 2023 (NCT05559905)(700357318)	18 Nov 2022
10 Jun 2022	Trial Update	Merck & Co plans a phase I MK-4482-003 pharmacokinetic trial for Renal impairment (In volunteers) (PO, Capsule) in June 2022 (NCT05386758)	11 Jul 2022
10 Jun 2022	Trial Update	Merck & Co plans a phase I MK-4482-016 pharmacokinetic trial (In volunteers) (PO, Capsule) in June 2022 (NCT05386589)	05 Jul 2022
31 Dec 2021	Regulatory Status	Merck plans to submit Emergency Use Authorisation application in COVID-2019 infections in Second half of 2021 ^[48]	18 Oct 2021
29 Dec 2021	Regulatory Status	Cipla plans to launch molnupiravir to treat mild to moderate COVID-19 in India ^[25]	29 Dec 2021
30 Nov 2021	Regulatory Status	The USFDA plans to review the Emergency Use Authorization application of molnupiravir for COVID 2019 infections on November 30 2021 ^[22]	07 Mar 2023
30 Sep 2021	Trial Update	Dr Reddys Laboratories plans a clinical trial for COVID-2019 infections in India between June and September 2021 ^[11]	08 Jul 2021
16 Aug 2021	Trial Update	Merck plans to initiate phase III MOVe-AHEAD trial in COVID-2019 infections (Prevention) (PO, Capsule) (NCT04939428) (700323721) ^[40]	04 Sep 2021
19 Oct 2020	Trial Update	Merck Sharp & Dohme plans a phase II/III trial ((MK-4482-001) for COVID-2019 infections (In Adults) in October 2020 (PO) (NCT04575584) (700328347)	03 Nov 2020
19 Oct 2020	Trial Update	Merck Sharp & Dohme plans a phase II/III trial for COVID-2019 infections in October 2020 (NCT04575597) (700328369)	26 Oct 2020
30 Jun 2020	Trial Update	Ridgeback Biotherapeutics plans clinical trials for COVID-2019 infections and Influenza virus infections in Q2 2020 ^[15]	15 Apr 2020

Event Date	Update Type	Comment
05 Nov 2023	Financial Update	Credit Suisse financial data update Updated 05 Nov 2023
21 Aug 2023	Phase Change - I	Phase-I clinical trials in Influenza virus infections (In volunteers) in United Kingdom (PO) (NCT05818124) Updated 08 Sep 2023
21 Jun 2023	Phase Change - Preregistration-Submission Withdrawal	Regulatory submission withdrawn for COVID-2019 infections in European Union (PO) ^[29] Updated 23 Aug 2023
21 Jun 2023	Regulatory Status	Merck Sharp & Dohme withdraws a marketing authorisation application for molnupiravir for COVID-19 infections in the European Union ^[30] ^[31] Updated 31 Jul 2023
17 May 2023	Trial Update	Merck Sharp & Dohme completes a phase IIa trial in Respiratory syncytial virus infections (In volunteers) in United Kingdom (PO) (NCT05559905) Updated 22 May 2023
24 Feb 2023	Regulatory Status	EMA's CHMP recommends the refusal of the marketing authorization for molnupiravir for COVID-2019 infections in the European Union (EU) ^[32] Updated 28 Feb 2023
24 Feb 2023	Regulatory Status	Merck and Ridgeback plans to appeal the CHMP’s decision and request a re-examination of the marketing authorization for molnupiravir for COVID-2019 infections in the European Union (EU) ^[32] Updated 28 Feb 2023
21 Feb 2023	Scientific Update	Adverse events data from a phase III trial in COVID-2019-infections released by Merck & Co ^[41] Updated 23 Feb 2023
16 Feb 2023	Trial Update	Merck Sharp & Dohme completes a phase I trial in Renal failure (Late-stage disease) in USA (PO) (NCT05386758) Updated 03 Mar 2023
29 Dec 2022	Trial Update	Merck & Co completes a phase I pharmacokinetics trial (In volunteers) in USA (PO, Capsule) (NCT05386589) Updated 20 Jan 2023
01 Dec 2022	Phase Change - Preregistration	Preregistration for COVID-2019 infections in China (PO), prior to December 2022 ^[26] Updated 02 Mar 2023
01 Dec 2022	Phase Change - Registered	Registered for COVID-2019 infections in China (PO) ^[26] Updated 02 Mar 2023
16 Nov 2022	Trial Update	Merck Sharp & Dohme completes a phase-III clinical trials in COVID-2019 infections (Prevention) in Turkey, Spain, Hungary, the US, Argentina, Brazil, Colombia, France, Guatemala, Japan, Mexico, Romania, Russia, Ukraine, Dominican Republic, Bulgaria, Egypt, Kenya, Malaysia, Peru, Philippines, South Africa and Thailand (PO) (NCT04939428) Updated 12 Dec 2022
02 Nov 2022	Phase Change - II	Phase-II clinical trials in Respiratory syncytial virus infections (In volunteers) in United Kingdom (PO) (NCT05559905) Updated 18 Nov 2022
29 Sep 2022	Trial Update	Merck Sharp & Dohme plans a phase-II trial for Respiratory syncytial virus infections in January 2023 (NCT05559905) Updated 18 Nov 2022
06 Jul 2022	Phase Change - I	Phase-I clinical trials in Renal failure (Late-stage disease) in USA (PO) (NCT05386758) Updated 08 Jul 2022
14 Jun 2022	Trial Update	Merck & Co initiated a phase I pharmacokinetic trial (PO, Capsule) in USA (NCT05386589) Updated 05 Jul 2022
23 May 2022	Trial Update	Merck & Co plans a phase I MK-4482-003 pharmacokinetic trial for Renal impairment (In volunteers) (PO, Capsule) in June 2022 (NCT05386758) Updated 11 Jul 2022
23 May 2022	Trial Update	Merck & Co plans a phase I MK-4482-016 pharmacokinetic trial (In volunteers) (PO, Capsule) in June 2022 (NCT05386589) Updated 05 Jul 2022
01 Apr 2022	Scientific Update	Efficacy data from a phase II/III trial in COVID-2019 infections was released by Merck and Co ^[50] Updated 11 Apr 2022
21 Feb 2022	Trial Update	Ridgeback Biotherapeutics completes the phase II END-COVID trial in COVID-2019 infections in USA (PO) (NCT04405739) Updated 30 Mar 2022
19 Feb 2022	Scientific Update	Updated efficacy and adverse event data from a phase III trial in COVID-2019 infections released by Hetero ^[45] Updated 24 Feb 2022
12 Feb 2022	Scientific Update	Interim efficacy and adverse event data from a phase III trial in COVID-2019 infections presented at the 29th Conference on Retroviruses and Opportunistic Infections (CROI-2022) ^[44] Updated 31 Mar 2022
12 Feb 2022	Scientific Update	Pharmacokinetics data from phase Ib/IIa trial in AGILE trial in COVID-2019 infections presented at 29^thConference on Retroviruses and Opportunistic Infections (CROI-2022) ^[56] Updated 31 Mar 2022
30 Jan 2022	Scientific Update	Updated efficacy data from the phase III MOVe-OUT trial in COVID-2019 infections released by Merck ^[46] Updated 01 Feb 2022
25 Jan 2022	Phase Change - Marketed	Launched for COVID-2019 infections in United Kingdom (PO) Updated 04 Apr 2022
20 Jan 2022	Phase Change - Registered	Registered for COVID-2019 infections in Australia (PO) ^[18] Updated 04 Apr 2022
20 Jan 2022	Licensing Status	Molnupiravir licensed to Beximco Pharmaceuticals in Bangladesh ^[1] Updated 07 Feb 2022
20 Jan 2022	Licensing Status	Molnupiravir licensed to Hikma Pharmaceuticals in the Middle East and North Africa (MENA) region ^[2] Updated 24 Jan 2022
18 Jan 2022	Licensing Status	Merck collaborates with the United Nations Children’s Emergency Fund (UNICEF) for the supply of molnupiravir for COVID-2019 infections in low- and middle-income countries ^[3] Updated 20 Jan 2022
18 Jan 2022	Phase Change - Registered	Registered for COVID-2019 infections in Taiwan (PO) ^[3] Updated 20 Jan 2022
31 Dec 2021	Patent Information	Merck & Co has patent protection for molnupiravir in USA, before December 2021 ^[72] Updated 17 Mar 2022
29 Dec 2021	Phase Change - Registered	Registered for COVID-2019 infections in India (PO)- Emergency Use authorization ^[25] Updated 29 Dec 2021
29 Dec 2021	Phase Change - Registered	Registered for COVID-2019 infections in Japan (PO)- Emergency Use Authorization ^[27] Updated 29 Dec 2021
28 Dec 2021	Regulatory Status	Cipla plans to launch molnupiravir to treat mild to moderate COVID-19 in India ^[25] Updated 29 Dec 2021
24 Dec 2021	Regulatory Status	US FDA grants Emergency Use Authorization (EUA) for molnupiravir to treat mild to moderate COVID-2019 infections in adults ^[19] Updated 28 Dec 2021
23 Dec 2021	Phase Change - Registered	Registered for COVID-2019 infections in USA (PO) ^[19] Updated 20 Jan 2022
23 Dec 2021	Licensing Status	UK government collaborates with Merck and Ridgeback Biotherapeutics for purchase of molnupiravir for COVID-19 infections in United Kingdom ^[16] Updated 28 Dec 2021
09 Dec 2021	Biomarker Update	Biomarkers information updated Updated 11 Dec 2021
30 Nov 2021	Regulatory Status	US FDA's Antimicrobial Drugs Advisory Committee (AMDAC) votes positive for Emergency Use Authorization for molnupiravir in COVID-19 infections (In adults) ^[20] Updated 02 Dec 2021
29 Nov 2021	Phase Change - Preregistration	Preregistration for COVID-2019 infections in Japan (PO) ^[6] Updated 29 Nov 2021
26 Nov 2021	Scientific Update	Updated safety and and efficacy data from the phase III MOVe-OUT trial in COVID-2019 infections released by Merck and Ridgeback Biotherapeutics ^[21] Updated 30 Nov 2021
19 Nov 2021	Regulatory Status	CHMP issues positive advice on the use of molnupiravir for the treatment of COVID-2019 infections ^[33] Updated 25 Nov 2021
19 Nov 2021	Licensing Status	Merck and Ridgeback Biotherapeutics collaborate with the Government of Japan for the supply of molnupiravir for COVID-2019 infections in Japan ^[6] Updated 19 Nov 2021
09 Nov 2021	Licensing Status	Merck and Ridgeback Biotherapeutics collaborate with the US government for the supply of molnupiravir for COVID-2019 infections in USA ^[8] Updated 18 Nov 2021
04 Nov 2021	Phase Change - Registered	Registered for COVID-2019 infections in United Kingdom (PO) - first global approval ^[17] Updated 08 Nov 2021
27 Oct 2021	Licensing Status	Molnupiravir licensed to Medicines Patent Pool in low and middle income countries ^[9] Updated 29 Oct 2021
26 Oct 2021	Phase Change - Preregistration	Preregistration for COVID-2019 infections in European Union (PO) under rolling review on October 2021 ^[35] Updated 27 Oct 2021
14 Oct 2021	Regulatory Status	The USFDA plans to review the Emergency Use Authorization application of molnupiravir for COVID 2019 infections on November 30 2021 ^[22] Updated 07 Mar 2023
14 Oct 2021	Phase Change - Preregistration	Preregistration (Emergency Use Authorization) for COVID-2019 infections in USA (PO) ^[22] Updated 18 Oct 2021
01 Oct 2021	Phase Change - III	Phase-III clinical trials in COVID-2019 infections in Egypt, Argentina, Taiwan, Japan, Guatemala, Sweden, Poland, Ukraine, Spain, South Africa, Russia, Philippines, Mexico, Italy, Germany, France, Colombia, Canada, Chile, Brazil, Israel, USA, United Kingdom (PO) before October 2021 ^[47] (NCT04575597) Updated 06 Oct 2021
01 Oct 2021	Regulatory Status	Merck plans to submit Emergency Use Authorisation to US FDA and marketing applications to other regulatory bodies worldwide in COVID-2019 infections ^[47] Updated 06 Oct 2021
01 Oct 2021	Scientific Update	Adverse events and efficacy data from the MOVe-OUT phase III trial in COVID-2019 infections released by Merck and Ridgeback ^[47] Updated 06 Oct 2021
01 Oct 2021	Trial Update	Merck and Ridgeback Biotherapeutics discontinues recruitment in the MOVe-OUT phase III trial in COVID-2019 infections in Egypt, Argentina, Taiwan, Japan, Guatemala, Sweden, Poland, Ukraine, Spain, South Africa, Russia, Philippines, Mexico, Italy, Germany, France, Colombia, Canada, Chile, Brazil, Israel, USA, United Kingdom due to positive interim results ^[47] (NCT04575597) Updated 06 Oct 2021
29 Sep 2021	Scientific Update	Efficacy data from a phase II trial in COVID-19 infections presented at the Conference on Infectious Diseases (IDWeek-2021) ^[60] Updated 06 Feb 2022
29 Sep 2021	Scientific Update	Efficacy data from a phase II/III trial in COVID-19 infections presented at the Conference on Infectious Diseases (IDWeek-2021) ^[51] Updated 06 Feb 2022
29 Sep 2021	Scientific Update	Efficacy data from a preclinical trial in COVID-19 infections presented at the Conference on Infectious Diseases (IDWeek-2021) ^[71] Updated 06 Feb 2022
01 Sep 2021	Trial Update	Merck plans to initiate phase III MOVe-AHEAD trial in COVID-2019 infections (Prevention) (PO, Capsule) (NCT04939428) ^[40] Updated 04 Sep 2021
17 Aug 2021	Phase Change - Preregistration	Preregistration for COVID-2019 infections in Australia (PO) ^[18] Updated 04 Apr 2022
13 Aug 2021	Phase Change - Preregistration	Preregistration for COVID-2019 infections in Canada (PO) ^[37] Updated 13 Dec 2021
13 Aug 2021	Regulatory Status	Merck initiates rolling submission to Health Canada for molnupiravir in COVID-2019 infections in Canada ^[37] Updated 25 Aug 2021
11 Aug 2021	Phase Change - III	Phase-III clinical trials in COVID-2019 infections (Prevention) in Thailand, South Africa, Philippines, Peru, Malaysia, Kenya, Dominican Republic, Bulgaria (PO) Updated 12 Dec 2022
11 Aug 2021	Phase Change - III	Phase-III clinical trials in COVID-2019 infections (Prevention) in Argentina, Brazil, Colombia, France, Guatemala, Japan, Mexico, Romania, Russia, Ukraine (PO) (NCT04939428) Updated 08 Nov 2021
11 Aug 2021	Phase Change - III	Phase-III clinical trials in COVID-2019 infections (Prevention) in Hungary, Spain, Turkey, USA (PO) (NCT04939428) (EudraCT2021-000904-39) Updated 04 Sep 2021
09 Jul 2021	Phase Change - III	Phase-III clinical trials in COVID-2019 infections in India (PO), prior to July 2021 ^[43] Updated 14 Jul 2021
09 Jul 2021	Regulatory Status	Hetero announces its intention to seek Emergency Use Authorization (EUA) from the Drug Controller General of India (DCGI) for COVID-2019 infections in India ^[43] Updated 14 Jul 2021
09 Jul 2021	Scientific Update	Interim efficacy and adverse event data from a phase III trial in COVID-2019 infections released by Hetero ^[43] Updated 14 Jul 2021
29 Jun 2021	Licensing Status	Cipla, Dr Reddys Laboratories, Emcure Pharmaceuticals Limited, Sun Pharmaceutical Industries, Torrent Pharmaceuticals enters into a collaboration agreement to conduct clinical trial for COVID-2019 infections in India ^[11] Updated 08 Jul 2021
29 Jun 2021	Licensing Status	Molnupiravir licensed to Torrent Pharmaceutcials in India ^[11] Updated 08 Jul 2021
29 Jun 2021	Regulatory Status	Cipla, Dr Reddys Laboratories, Emcure Pharmaceuticals Limited, Sun Pharmaceutical Industries, Torrent Pharmaceuticals plans to submit regulatory approvals for COVID-2019 infections in India ^[11] Updated 08 Jul 2021
29 Jun 2021	Trial Update	Dr Reddys Laboratories plans a clinical trial for COVID-2019 infections in India between June and September 2021 ^[11] Updated 08 Jul 2021
09 Jun 2021	Licensing Status	Merck collaborates with the US government for the supply of molnupiravir for COVID-2019 infections in USA ^[7] Updated 16 Jun 2021
09 Jun 2021	Regulatory Status	Merck intends to file marketing applications in multiple countries for COVID-2019 infections ^[7] Updated 16 Jun 2021
27 Apr 2021	Licensing Status	Molnupiravir licensed to Cipla, Dr. Reddy’s Laboratories, Emcure Pharmaceuticals, Hetero Labs and Sun Pharmaceutical Industries in India and other low and middle income countries ^[10] Updated 30 Apr 2021
15 Apr 2021	Regulatory Status	Merck plans to submit Emergency Use Authorisation application in COVID-2019 infections in Second half of 2021 ^[48] Updated 18 Oct 2021
15 Apr 2021	Regulatory Status	Merck plans to share finding from ongoing clinical development of molnupiravir with regulatory agencies ^[48] Updated 21 Apr 2021
15 Apr 2021	Scientific Update	Efficacy and safety data from phase II/III MOVe-OUT and MOVe-IN trial in COVID-2019 infections released by Merck ^[48] Updated 21 Apr 2021
15 Apr 2021	Trial Update	Merck and Co discontinues its phase II/III MOVe-IN trial in COVID-2019 infections in Brazil, Canada, Chile, Colombia, France, Germany, Italy, Mexico, Philippines, Russia, South Africa, Spain, Ukraine, USA, Israel, South Korea, Sweden, Poland as drug unlikely to demonstrate a clinical benefit in hospitalised patients ^[48] Updated 21 Apr 2021
06 Mar 2021	Scientific Update	Updated efficacy data from a phase IIa trial in COVID-2019 infections presented at the 28th Conference on Retroviruses and Opportunistic Infections (CROI-2021) ^[59] Updated 20 Apr 2021
06 Mar 2021	Scientific Update	Efficacy and adverse events data from a phase II trial in COVID-2019 infections released by Ridgeback Biotherapeutics ^[58] Updated 09 Mar 2021
03 Mar 2021	Scientific Update	Pharmacokinetics and safety data from a phase I trial for COVID-2019 infections released by Ridgeback Biotherapeutics ^[67] Updated 05 Mar 2021
21 Feb 2021	Trial Update	Ridgeback Biotherapeutics completes a phase II trial in COVID-2019 infections (in symptomatic adult outpatients) in USA (PO) (NCT04405570) Updated 04 Mar 2021
09 Dec 2020	Scientific Update	Pharmacodynamics data from preclinical trials in COVID-2019 infections released by Georgia State University ^[69] Updated 15 Dec 2020
19 Oct 2020	Phase Change - II/III	Phase-II/III clinical trials in COVID-2019 infections in Egypt (PO) (NCT04575597) Updated 06 Oct 2021
19 Oct 2020	Phase Change - II/III	Phase-II/III clinical trials in COVID-2019 infections in Argentina, Taiwan, Japan, Guatemala, Poland, United Kingdom (PO) (NCT04575597) Updated 04 Sep 2021
19 Oct 2020	Phase Change - II/III	Phase-II/III clinical trials in COVID-2019 infections in Brazil, Canada, Chile, Colombia, France, Germany, Italy, Mexico, Philippines, Russia, South Africa, Spain, Ukraine, USA, Israel (PO) (NCT04575597) Updated 21 Apr 2021
19 Oct 2020	Phase Change - II/III	Phase-II/III clinical trials in COVID-2019 infections in Poland, South Korea, Sweden (PO) (NCT04575584) Updated 21 Apr 2021
19 Oct 2020	Phase Change - II/III	Phase-II/III clinical trials in COVID-2019 infections in United Kingdom (PO, Capsule) (EudraCT2020-003368-24) Updated 26 Oct 2020
08 Oct 2020	Trial Update	Merck Sharp & Dohme plans a phase II/III trial ((MK-4482-001) for COVID-2019 infections (In Adults) in October 2020 (PO) (NCT04575584) Updated 03 Nov 2020
05 Oct 2020	Trial Update	Merck Sharp & Dohme plans a phase II/III trial for COVID-2019 infections in October 2020 (NCT04575597) Updated 26 Oct 2020
11 Aug 2020	Trial Update	Ridgeback Biotherapeutics completes the first-in-human phase I trial in COVID-2019 infections in United Kingdom (PO) (NCT04392219) Updated 31 Aug 2020
07 Jul 2020	Licensing Status	Ridgeback Biotherapeutics closes collaboration agreement with Merck ^[55] Updated 10 Jul 2020
07 Jul 2020	Phase Change - I/II	Phase-I/II clinical trials in COVID-2019 infections in United Kingdom (PO) ^[55] (NCT04746183) Updated 10 Jul 2020
07 Jul 2020	Trial Update	Merck in collaboration with Ridgeback plans clinical trials for COVID-2019 infections ^[55] Updated 10 Jul 2020
16 Jun 2020	Phase Change - II	Phase-II clinical trials in COVID-2019 infections in USA (PO) (NCT04405739) Updated 25 Jun 2020
16 Jun 2020	Trial Update	Ridgeback Biotherapeutics initiates a phase II trial for COVID-2019 infections (in symptomatic adult outpatients) in USA (PO) (NCT04405570) Updated 25 Jun 2020
02 Jun 2020	Trial Update	Ridgeback Biotherapeutics plans a phase II trial for Severe acute respiratory syndrome (in patients with COVID-2019 infections) in USA, in May 2020 (NCT04405570) Updated 02 Jun 2020
28 May 2020	Trial Update	Ridgeback Biotherapeutics plans a phase II trial for COVID-19 infections in May 2020 (PO, Capsule) (NCT04405739) Updated 01 Jun 2020
27 May 2020	Licensing Status	Ridgeback Bio signs agreement with Merck to develop and commercialise EIDD 2801 ^[13] ^[14] Updated 01 Jun 2020
27 May 2020	Scientific Update	Adverse events data from a phase I trial in COVID-2019 infection released by Ridgeback Biotherapeutics ^[13] Updated 01 Jun 2020
15 Apr 2020	Phase Change - Preclinical	Preclinical trials in Ebola virus infections in USA (PO) before April 2020 ^[66] Updated 15 Apr 2020
13 Apr 2020	Phase Change - Preclinical	Preclinical trials in Middle East respiratory syndrome coronavirus (Prevention) in USA (PO) before April 2020 ^[66] Updated 15 Apr 2020
13 Apr 2020	Phase Change - Preclinical	Preclinical trials in Severe acute respiratory syndrome (Prevention) in USA (PO) before April 2020 ^[66] Updated 15 Apr 2020
13 Apr 2020	Scientific Update	Pharmacodynamics data from preclinical studies in Severe acute respiratory syndrome and Middle east respiratory syndrome coronavirus released by Ridgeback Biotherapeutics ^[66] Updated 15 Apr 2020
10 Apr 2020	Phase Change - I	Phase-I clinical trials in COVID-2019 infections in United Kingdom (PO) ^[66] Updated 15 Apr 2020
09 Apr 2020	Regulatory Status	The UK Medicines and Healthcare products Regulatory Agency (MHRA) approves clinical trial application for EIDD 2801 in COVID-2019 infections ^[66] Updated 15 Apr 2020
06 Apr 2020	Regulatory Status	The US FDA approves IND application for EIDD 2801 to commence the clinical trial for COVID-2019 infections ^[68] Updated 08 Apr 2020
19 Mar 2020	Trial Update	Ridgeback Biotherapeutics plans clinical trials for COVID-2019 infections and Influenza virus infections in Q2 2020 ^[15] Updated 15 Apr 2020
19 Mar 2020	Licensing Status	Ridgeback Biotherapeutics in-licenses EIDD 2801 from Emory University Updated 23 Mar 2020
19 Mar 2020	Phase Change - Preclinical	Preclinical trials in COVID-2019 infections in USA (PO) before March 2020 ^[15] Updated 23 Mar 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Eastern equine encephalomyelitis in USA (PO) before October 2019 ^[15] Updated 01 Apr 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Respiratory syncytial virus infections in USA (PO) before October 2019 ^[15] Updated 01 Apr 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Chikungunya virus infections in USA (PO) before October 2019 ^[15] ^[70] Updated 23 Mar 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Influenza virus infections in USA (PO) before October 2019 ^[15] ^[70] Updated 23 Mar 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Middle East respiratory syndrome coronavirus in USA (PO) before October 2019 ^[15] ^[70] Updated 23 Mar 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Severe acute respiratory syndrome in USA (PO) before October 2019 ^[15] ^[70] Updated 23 Mar 2020
23 Oct 2019	Phase Change - Preclinical	Preclinical trials in Venezuelan equine encephalomyelitis in USA (PO) before October 2019 ^[15] ^[70] Updated 23 Mar 2020
23 Oct 2019	Scientific Update	Pharmacodynamics data from preclinical studies in Influenza virus infections released by Emory University ^[70] Updated 23 Mar 2020

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