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.
2021 Status: 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: