Merck Will Apply for EUA of COVID-19 Antiviral in Wake of Promising Phase III Data

Merck Will Apply for EUA of COVID-19 Antiviral in Wake of Promising Phase III Data

Merck & Co. announced it will seek to gain an emergency use authorization (EUA) from the FDA for the COVID-19 oral antiviral candidate it is developing with Ridgeback Biotherapeutics, molnupiravir, after Phase III data showed a nearly 50% reduction in the risk of hospitalization or death in patients 29 days after treatment.

The company announced results today 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 eight deaths in patients who received placebo.

“This compares nicely to antibodies which have around a 70% reduction in hospitalization but are generally less convenient in IV formulation,” Jefferies analyst Michael Yee wrote in a research note this morning.

Molnupiravir reduced the risk of hospitalization and/or death across all key subgroups, Merck said, adding that efficacy was not affected by timing of symptom onset or underlying risk factor. An analysis of the approximately 40% of patients with available viral sequencing data found molnupiravir to have shown consistent efficacy across the Gamma, Delta, and Mu variants of SARS-CoV-2.

The positive results, Merck said, prompted it to stop recruitment early in, acting upon a recommendation from the study’s independent Data Monitoring Committee and in consultation with the FDA. At the time of the recruitment halt, MOVe-OUT had recruited more than 90% of the intended Phase III sample size of 1,550 patients.

“With these compelling results, we are optimistic that molnupiravir can become an important medicine as part of the global effort to fight the pandemic and will add to Merck’s unique legacy of bringing forward breakthroughs in infectious diseases when they are needed most,” Merck CEO and president Robert M. Davis said in a statement.

Merck said it plans to apply for an EUA for molnupiravir, as well as submit marketing applications to other regulators worldwide.

Molnupiravir’s positive data contrasts with the two COVID-19 vaccine candidates Merck had co-developed with partners (V590 and V591) until halting their development in January, saying they generated weaker immune responses than other unnamed COVID-19 vaccines.

Potential “best option,” $10B in orders

“After swinging and missing on the vaccine front, MRK’s success with molnupiravir could not only unlock over $10b in near-term orders, the pill could also represent the best option for bringing the pandemic under control worldwide,” Daina M. Graybosch, PhD, Managing Director, Immuno-Oncology and a senior research analyst with SVB Leerink, wrote this morning in a research note.

Molnupiravir would be the first oral pill to be approved for treating COVID-19. Other drugs for the disease that have received FDA approval or EUA call for intravenous infusion or injection.

“The oral drugs are likely to be more easily distributed and utilized since antibodies are mostly used in clinics or hospitals,” Yee wrote.

MOVe-OUT was a global randomized, placebo-controlled, double-blind, multi-site study of non-hospitalized adult patients with laboratory-confirmed mild to moderate COVID-19, at least one risk factor associated with poor disease outcomes, and symptom onset within five days prior to randomization.

The trial’s primary efficacy objective was to evaluate the efficacy of molnupiravir compared to placebo based on the percentage of participants who are hospitalized and/or die from the time of randomization through Day 29.

Molnupiravir, also called MK-4482, is an 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.

Merck said in May 2020 that it planned to partner with Ridgeback Biotherapeutics in developing molnupiravir, originally known as EIDD-2801. Miami-based Ridgeback gave Merck exclusive worldwide rights to develop and commercialize the drug and related molecules. In return Merck agreed to pay Ridgeback an undisclosed upfront payment, specified milestones and a share of the net proceeds of EIDD-2801 and related molecules, if approved. Merck agreed at the time to oversee clinical development, regulatory filings and manufacturing.

Molnupiravir suffered a setback in April when Merck and Ridgeback opted not to advance the drug 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.

$1.2M U.S. supply agreement

But in June, Merck inked a $1.2 billion supply agreement with the U.S. government, which committed to purchase approximately 1.7 million courses of Molnupiravir upon an EUA or approval by the FDA. The company said at the time it expected to have more than 10 million courses of therapy available by the end of 2021.

The percentages of patients with any adverse event were comparable in the molnupiravir group (35%) and placebo group (40%). Also comparable was the incidence of drug-related adverse events, which was 12% among molnupiravir patients and 11% in those randomized to placebo. Fewer subjects (1.3%) stopped therapy due to an adverse event in the molnupiravir group compared to the placebo group (3.4%).

Eligibility criteria for MOVe-OUT required that all patients had laboratory-confirmed mild-to-moderate COVID-19, with symptom onset within five days of study randomization. All patients were required to have at least one risk factor associated with poor disease outcome at study entry.

The incidence of any adverse event was comparable in the molnupiravir and placebo groups (35% and 40%, respectively). Similarly, the incidence of drug-related adverse events was also comparable (12% and 11%, respectively). Fewer subjects discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%).

“We are also interested in secondary endpoints not yet disclosed such as reduction in “time to symptom clearance” (i.e., how much faster symptoms are gone; antibodies clear symptoms quicker by around 1–3 days),” Yee of Jefferies added.