Merck Advances Molnupiravir into Phase 3 Trial for Mild-to-Moderate COVID-19 Outpatients Amid Global Cases Surpassing 140 Million

April 18, 2021 /BioValleyBIOON/ -- Currently, the COVID-19 epidemic overseas continues to spread rapidly. According to Baidu's "Real-time Updates on the Novel Coronavirus Pneumonia Epidemic"Big DataReport, as of 00:00 on April 18, 2021, the global cumulative number of confirmed cases exceeded 140 million (140.68 million), and the number of deaths exceeded 3 million (3.015 million).

Recently, Merck & Co. and Ridgeback Biotherapeutics jointly announced the latest updates on the clinical program of molnupiravir (MK-4482/EIDD-2801), an oral antiviral drug. Molnupiravir is a potent orally administered ribonucleoside analog that inhibits the replication of various RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19. Molnupiravir has demonstrated activity in several preclinical models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission, and has also shown activity in preclinical models of SARS-CoV-1 and MERS.

Based on two ongoing placebo-controlled phase 2/3 trials evaluating molnupiravir (twice daily for 5 days) in outpatients and hospitalized patients with COVID-19Clinical TrialsBased on the planned interim data analysis of the Phase 2 dose-finding portion (Part 1) of the (MOVe-OUT, MOVe-IN) studies, as well as the data analysis from the previously completed Phase 2a dose-ranging study in outpatients, both parties decided to proceed with the Phase 3 portion (Part 2) of the MOVe-OUT study in outpatients with COVID-19, evaluating molnupiravir at an oral dose of 800 mg twice daily. Data from the MOVe-IN study indicated that molnupiravir was unlikely to demonstrate clinical benefit in hospitalized patients with COVID-19, who typically had a longer duration of symptoms prior to study enrollment. Therefore, both parties decided not to advance this study to Phase 3.

Dr. Roy Baynes, Chief Medical Officer, Senior Vice President, and Head of Global Clinical Development at MSD Research Laboratories, stated: “We continue to make progress in the clinical development of our antiviral candidate, molnupiravir. The data from the dose-finding portion of these studies are consistent with its mechanism of action and provide meaningful evidence of the antiviral potential of the 800 mg dose. Based on the results of this study, we are advancing a Phase 3 trial program in non-hospitalized patients, which strategically leverages our extensive network of clinical sites to enroll eligible patients globally.”

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

Chemical structure of molnupiravir (Image source: scinexx.de)

The MOVe-OUT study is an ongoing Phase 2/3, randomized, placebo-controlled, double-blind, multicenter study evaluating the efficacy, safety, and pharmacokinetics of oral molnupiravir in non-hospitalized patients with polymerase chain reaction (PCR)-confirmed COVID-19. The primary efficacy endpoint of the MOVe-OUT study is to assess the efficacy of molnupiravir versus placebo by measuring the percentage of patients who are hospitalized and/or die from randomization through Day 29.

Part 1 of the MOVe-OUT study enrolled a total of 302 participants who had developed symptoms within 7 days prior to randomization. They were assigned to receive oral molnupiravir at doses of 200 mg (n=75), 400 mg (n=77), or 800 mg (n=76) twice daily, or placebo (n=74). In Part 1 of this study, the combined molnupiravir treatment groups showed a lower percentage of patients experiencing hospitalization and/or death compared with the placebo group; however, the number of reported events was insufficient to provide a meaningful measure of clinical efficacy. Analysis of SARS-CoV-2 in nasopharyngeal and oropharyngeal swabs from patients in the MOVe-OUT and MOVe-IN studies using quantitative and qualitative PCR (an exploratory endpoint) indicated that molnupiravir inhibited viral replication. Compared with placebo, a greater proportion of participants in the molnupiravir groups exhibited a decline in viral RNA from baseline on Days 5 and 10 of treatment, and had undetectable viral RNA on Days 10 and 15 after completion of treatment. The greatest overall antiviral effect was observed with the 800 mg dose compared with the 200 mg and 400 mg doses. These differences in virologic endpoints were more pronounced in participants who presented within <5 days of symptom onset.

In the MOVe-OUT study, among 299 patients who received at least one dose of the study intervention, drug-related adverse events were reported in 6.2% (14/225) of patients treated with molnupiravir and 6.8% (5/74) of patients treated with placebo. In the MOVe-IN study, among 293 patients who received at least one dose of the study intervention, drug-related adverse events were reported in 11.0% (24/218) of patients treated with molnupiravir and 21.3% (16/75) of patients treated with placebo. To date, safety and laboratory data from the MOVe-IN and MOVe-OUT studies have provided no evidence of unexpected findings or trends at any study dose. In these two trials, no deaths were considered by investigators to be related to the drug in patients treated with molnupiravir, and no drug-related adverse events leading to discontinuation were observed. Interim results from the MOVe-IN and MOVe-OUT studies, including virological findings and pharmacokinetic analyses, have been shared with regulatory authorities and will be presented at upcoming medicalMeetingPublished above.

The External Data Monitoring Committee noted that subgroup analyses supported the potential benefits of the treatment and recommended amending the MOVe-OUT protocol to focus enrollment on patients in the early stage of disease course and those at high risk for adverse COVID-19 outcomes (e.g., elderly patients, obese patients, andDiabetespatients). In accordance with these recommendations, MSD will amend the enrollment criteria for the MOVe-OUT study to shorten the allowable duration of symptoms to <5 days and to enroll subjects with at least one risk factor for progression to severe disease. MSD plans to initiate patient enrollment for the Phase 3 portion (Part 2) in late April/early May.

Final data from Phase 3 (Part 2) of the MOVe-OUT study are expected to be available in September/October 2021. Merck currently anticipates that, subject to favorable results from the MOVe-OUT study, it may submit an Emergency Use Authorization (EUA) application for molnupiravir as early as the second half of 2021. Merck and Ridgeback Biotherapeutics plan to share further findings from the ongoing molnupiravir development program with regulatory authorities. Additionally, Merck plans to initiate a clinical program in the second half of 2021 to evaluate molnupiravir for post-exposure prophylaxis. (Bioon.com)

Original Source: Merck and Ridgeback Biotherapeutics Provide Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19