Candidate: Molnupiravir (also known as MK-4482 and EIDD-2801)
Type: Oral broad-spectrum NHC-prodrug (Beta-D-N4 hydroxycytidine-5’-isopropyl ester), a highly potent ribonucleoside analog designed to inhibit replication of multiple RNA viruses including SARS-CoV2.
2022 Status: Low-Cost Generic Drug Agreement– The Medicines Patent Pool (MPP) said January 20 it had signed agreements of undisclosed value with 27 generic drug manufacturers to produce molnupiravir for supply in 105 low- and-middle-income countries. The sublicence agreements are the result of a voluntary licensing agreement signed by MPP and Merck in October 2021.
Five companies will focus on producing the raw ingredients, 13 companies will produce both raw ingredient and the finished drug and 9 companies will produce the finished drug. The companies span 11 countries, Bangladesh, China, Egypt/Jordan, India, Indonesia, Kenya, Pakistan, South Africa, South Korea, and Vietnam.
Neither Merck, nor Ridgeback Biotherapeutics, nor Emory University, will receive royalties from sales of molnupiravir from the MPP sublicensees while COVID-19 remains classified as a Public Health Emergency of International Concern by the World Health Organization (WHO), the MPP said.
UNICEF Supply Agreement—Merck said January 18 that it signed of a long-term supply agreement of undisclosed value with the United Nations Children’s Fund (UNICEF) to facilitate broad global access for molnupiravir. Merck agreed to 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 authorizations. As of January 18, molnupiravir has been authorized for use in more than 10 countries, including in the U.S., the U.K., and Japan.
2021 Status: FDA AUTHORIZES EMERGENCY USE—The FDA on December 23 granted emergency use authorization (EUA) to Merck for molnupiravir to treat mild to moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate.
Molnupiravir is not authorized for use in patients who are less than 18 years of age, for initiation of treatment in patients hospitalized due to COVID-19, for use for longer than five consecutive days, or for pre-exposure or post-exposure prophylaxis for prevention of COVID-19.
According to Merck, molnupiravir should be administered as soon as possible after a diagnosis of COVID-19 has been made, and within five days of symptom onset. The recommended dose for molnupiravir is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days, with or without food. Completion of the full five-day treatment course is important to maximize viral clearance and minimize transmission of SARS-CoV-2.
However, Merck acknowledged that molnupiravir is not recommended for use in patients who are pregnant, since it may cause fetal harm when administered to pregnant individuals, based on findings from animal reproduction studies; no human data is available.
Merck said it anticipated starting to ship molnupiravir to AmerisourceBergen, the sole distributor of molnupiravir, “within days.” The company has agreed to supply approximately 3.1 million courses of molnupiravir to the U.S. government for approximately $2.2 billion.
Canada Buys 500,000 Courses—The government of Canada said December 3 it agreed to purchase 500,000 courses of molnupiravir with options for 500,000 more, all for an undisclosed price pending authorization by Health Canada.
FDA Panel Narrowly Recommends Molnupiravir Approval—The FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) on November 30 recommended Emergency Use Authorization (EUA) by the agency of molnupiravir 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. The AMDAC voted 13-10, with oppponents of recommending molnupiravir, like Sankar Swaminathan, MD, of the University of Utah School of Medicine, citing “modest at best” efficacy, reflected in revised Phase III data reported four days earlier.
Risk Reduction Falls in Updated Analysis—Merck and Ridgeback acknowledged November 26 that the reduction in the risk of hospitalization or death in patients 29 days after treatment with the pill was 30% based on data from all 1,433 enrolled participants in the Phase III MOVe-OUT trial (also called MK-4482-002; NCT04575597), not 50% as reported in interim data from 762 participants earlier in November. Molnupiravir reduced the risk of hospitalization or death from 9.7% in the placebo group (68/699 participants) to 6.8% (48/709 participants) in the molnupiravir group. Nine deaths were reported in the placebo group, and one in the molnupiravir group.
Investors sent Merck shares sliding 4% on November 26, to $79.16 from $82.28.
U.S. BUYS 1.4M MORE DOSES FOR $1B—The U.S. government will exercise two of its options to purchase a total of 1.4 million additional courses of molnupiravir for approximately $1 billion, subject to the antiviral receiving Emergency Use Authorization (EUA) or approval by the FDA, Merck and Ridgeback said November 9. With these exercised options, the U.S. government has now committed to purchase 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 has the ability to purchase more than 2 million additional courses through further options.
The U.S. government procurement of molnupiravir is being supported in whole with federal funds from the U.S. 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.
U.K. AUTHORIZATION—The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) on November 4 granted authorization for molnupiravir as a treatment for mild-to-moderate COVID-19 in adults with a positive SARS-CoV-2 diagnostic test and who have at least one risk factor for developing severe illness. The drug will be marketed in the U.K. as LAGEVRIO®.
Merck said the authorization was based on positive results from a planned interim analysis from the Phase III MOVe-OUT trial (also called MK-4482-002; NCT04575597), which evaluated molnupiravir 800 mg twice-daily in non-hospitalized, unvaccinated adult patients with laboratory-confirmed mild-to-moderate COVID-19, symptom onset within five days of study randomization and at least one risk factor associated with poor disease outcomes (e.g., heart disease, diabetes).
$5B-$7B Sales Forecast—Frank Clyburn, president of Merck’s Human Health division, told analysts on the company’s third-quarter 2021 earnings call that the pharma giant projected between $5 billion and $7 billion in sales for molnupiravir through the end of 2022—including between $500 million to $1 billion this year. The forecast assumes that molnupiravir will receive Emergency Use Authorization (EUA) from the FDA in December. Merck has also projected it will manufacture 10 million doses of molnupiravir by year’s end, and twice as many courses in 2022.
FDA Panel to Meet Nov. 30—The FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) will meet November 30 to discuss Merck and Ridgeback’s request for an emergency use authorization (EUA) for molnupiravir to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in adults who have tested positive for COVID-19, and who are at high risk for progression to severe COVID-19, including hospitalization or death. The meeting was scheduled as soon as possible following the submission of the EUA request, the FDA said.
PURSUING EUA AFTER POSITIVE PHASE III DATA–Merck & Co, said October 1 it will pursue FDA emergency use authorization (EUA) “as soon as possible” for molnupiravir, the COVID-19 oral antiviral candidate it is developing with Ridgeback Biotherapeutics, following Phase III data showing an approximately 50% reduction in the risk of hospitalization or death in patients 29 days after treatment with the pill.
Merck announced results from an interim analysis of data from 775 patients in the Phase III portion of the MOVe-OUT trial (also called MK-4482-002; NCT04575597), which it said showed that 28 of 385 patients (7.3%) who received molnupiravir were either hospitalized or died through Day 29 following randomization, compared with 53 of 377 patients (14.1%) treated with placebo.
Through Day 29, no deaths were reported in patients who received molnupiravir, compared with 8 deaths in patients who received placebo. Molnupiravir also reduced the risk of hospitalization and/or death across all key subgroups, Merck said.
CEO Predicts EUA– Merck CEO Robert Davis said September 13 at the Morgan Stanley 19th Annual Global Healthcare Conference that the company anticipates being granted FDA Emergency Use Authorization (EUA) for molnupiravir (MK-4482) before the end of 2021. Enrollment is progressing well for molnupiravir’s late-phase clinical trial program, he said.
$1.2B U.S. Supply Agreement—Merck said June 9 that it entered into a $1.2 billion supply agreement with the U.S. government, which committed to purchase approximately 1.7 million courses of Molnupiravir upon an Emergency Use Authorization or approval by the FDA. The company expects to have more than 10 million courses of therapy available by the end of 2021.
As of June 9, Molnupiravir remained under study in the Phase III portion of the MOVe-OUT trial (also called MK-4482-002; NCT04575597) assessing Molnupiravir as a treatment for non-hospitalized patients with laboratory-confirmed COVID-19 and at least one risk factor associated with poor disease outcomes. Pending favorable results, Merck said, the earliest possible EUA submission for Molnupiravir would be in the second half of 2021.
Merck and Ridgeback on April 15 said they would not advance molnupiravir into the Phase III portion of the Phase II/III MOVe-IN trial (also called MK-4482-001; NCT04575584), a 1,300-participant study assessing the drug in hospitalized patients, after data from the Phase II portion showed that molnupiravir was unlikely to demonstrate a clinical benefit in them.
The Phase II portion enrolled 304 participants randomized 1:1:1:1 to who received molnupiravir 200 mg, 400 mg, 800 mg or placebo twice daily for 5 days. The primary efficacy endpoint was to evaluate the efficacy of molnupiravir compared to placebo as assessed by the rate of sustained recovery from randomization through Day 29.
However, Merck said it will advance molnupiravir into the Phase III portion of another Phase II/III trial, MOVe-OUT (also called MK-4482-002; NCT04575597), a 1,450-participant study evaluating molnupiravir in outpatients. The primary efficacy objective of MOVe-OUT is to evaluate the efficacy of molnupiravir compared to placebo based on the percentage of patients who are hospitalized and/or die from the time of randomization through Day 29. Part 1 of MOVe-OUT enrolled 302 participants with symptom onset within seven days prior to randomization, who were assigned to receive molnupiravir 200 mg (75), 400 mg (77), or 800 mg (76), or placebo (74).
On March 6, Merck and Ridgeback reported findings on a secondary objective from Ridgeback’s Phase IIa EIDD-2801 2003 trial (NCT04405570) of molnupiravir, saying that the antiviral showed a 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. At day 5, there was a reduction 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.
The preliminary findings were presented during Science SpotlightsTM at the 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021). Findings from the primary efficacy and safety endpoints and additional secondary objectives will be presented at an upcoming medical meeting, Merck and Ridgeback said.
The randomized, double-blind, placebo-controlled trial enrolled 202 non-hospitalized adults who had signs or symptoms of COVID-19 within 7 days and confirmed active SARS-CoV-2 infection. The primary efficacy objective was reduction in time to viral negativity measured by reverse transcriptase polymerase chain reaction (RT-PCR) analysis of nasopharyngeal swabs.
In its form 10-K annual report for 2020, filed February 25, Merck pushed back one month, to June 2021, the primary completion date for the Phase II/III studies, but added that it still expects interim efficacy data in the first quarter.
Researchers at The University of North Carolina at Chapel Hill published a study in Nature on February 9 concluding that molnupiravir “dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19,” following replication of the virus in immune deficient mice implanted with authentic human lung tissue.
Merck & Co. said January 25 it would continue development of molnupiravir and another COVID-19 drug candidate, MK-7110, while halting development of two vaccine candidates against the virus, V590 and V591. As of that date, molnupiravir was in mid- to late-phase trials that included:
- MK-4482-001, a 1,300-participant Phase II/III study in hospitalized adults with COVID-19 (NCT04575584)
- MK-4482-002, a 1,450-participant Phase II/III study in non-hospitalized adults with COVID-19 (NCT04575597).
- END-COVID, an estimated 80-participant study assessing molnupiravir on SARS-CoV-2 virus shedding in newly hospitalized adults with PCR-confirmed COVID-19 (NCT04405739).
- A Phase II study of an estimated 204 participants designed to compare molnupiravir vs. placebo as measured by infectious virus detection in symptomatic adult outpatients with COVID-19 (NCT04405570)
The primary completion date for the studies is May 2021, with Merck saying today it expected to release initial efficacy data in the first quarter, “which Merck plans to share publicly if clinically meaningful.”
2020 Status: Merck said July 31 in releasing second-quarter results that MK-4482 (formerly EIDD-2801) was under study in the Phase II clinical trials announced in June by Ridgeback Biotherapeutics. The trials are designed to test the efficacy of MK-4482 as an antiviral treatment for COVID-19 in adults: Study 2003 (NCT04405570), which is enrolling recently symptomatic, newly diagnosed patients in a home, or out of hospital, setting, and Study 2004 (NCT04405739), which is enrolling hospitalized patients with COVID-19.
Study 2003 and Study 2004 were launched after Phase I trials determined that MK-4482 was safe in human doses that provide blood levels well above levels that animal models suggested should be effective against SARS-CoV-2. In the Phase I study, blood levels at and above those associated with potent anti-viral activity in animal models and the 3D Human Airway Epithelial model have been achieved in participants.
One Phase I trial (NCT04392219) is a randomized, double-blind, placebo-controlled, first-in-human study designed to evaluate the safety, tolerability, and pharmacokinetics of MK-4482 following oral administration to healthy volunteers. The trial began in April, has an estimated enrollment of 130 participants, and an estimated primary completion date of August 8.
In preclinical studies, MK-4482 demonstrated antiviral properties against SARS-CoV-2, the virus that causes COVID-19, as well as the coronaviruses responsible for MERS and SARS.
Ridgeback also said it has manufactured hundreds of thousands of doses of the antiviral candidate at its own risk and expense, with plans to produce up to 1 million treatment courses by the fall in advance of definitive clinical data.
On May 26, Merck & Co. said it planned to partner with Ridgeback Biotherapeutics in developing EIDD-2801. Miami-based Ridgeback gave Merck exclusive worldwide rights to develop and commercialize the drug formerly called EIDD-2801 and related molecules. Ridgeback Bio will receive an undisclosed upfront payment, specified milestones and a share of the net proceeds of EIDD-2801 and related molecules, if approved. Merck will be responsible for clinical development, regulatory filings and manufacturing.
Merck agreed to oversee clinical development, regulatory filings and manufacturing of MK-4482, while Ridgeback received an undisclosed upfront payment, specified milestones and a share of the net proceeds of the COVID-19 candidate and related molecules, if approved. Merck and Ridgeback also committed to ensure “that any medicines we develop for SARS-CoV-2 will be accessible and affordable globally.”
Merck and Ridgeback plan to co-develop MK-4482, which has been licensed from DRIVE, a not-for-profit biotechnology company wholly owned by Emory University. The FDA in April approved DRIVE’s IND application to begin human clinical trials of what was EIDD-2801 in the U.S., after another Ridgeback candidate, EIDD-1931, knocked out SARS and MERS viruses in human cells and also effectively fought coronaviruses that are resistant to remdesivir.
According to Ridgeback, EIDD-2801 had shown broad spectrum activity against influenza, SARS, MERS, chikungunya, Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV).
On April 6, Timothy P. Sheahan, PhD, and Ralph Baric, PhD, both at The University of North Carolina at Chapel Hill, and colleagues from there, Emery, Vanderbilt University Medical Center, and the U.S. Centers for Disease Control and Prevention published a study in Science Translational Medicine reporting that both prophylactic and therapeutic administration of EIDD-2801 in mice infected with SARS-CoV or MERS-CoV improved pulmonary function, and reduced virus titer and body weight loss. The study was published two weeks after the researchers disclosed their results in a preprint.
“The potency of NHC/EIDD-2801 against multiple CoVs [coronaviruses] and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs,” Sheahan, Baric, and colleagues concluded.
Ridgeback and DRIVE announced their collaboration to rapidly advance EIDD-2801 into human trials in March, with Ridgeback agreeing to advance the COVID-19 candidate through clinical development and ensure that it is available during the pandemic. At the time, Ridgeback said, its partners had contracts in place to fund a Phase I study evaluating EIDD-2801’s potential as an influenza treatment. But after pivoting to COVID-19, Ridgeback filed an IND and a clinical trial application for the virus, and self-funded all of Ridgeback’s Phase I activities, with the goal of accelerating development and clinical use.
MK-4482 is being developed for seasonal and pandemic influenza under a contract awarded to Emory Institute for Drug Development by the National Institute of Allergy and Infectious Diseases (NIAID) under contract Nos. HHSN272201500008C and 75N93019C00058; and for VEEV and EEEV by the Defense Threat Reduction Agency (DTRA) under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: