Merck announced that the company entered into an non-exclusive voluntary licensing agreement for its experimental Molnupiravir with five Indian generic companies right in the middle of what is perhaps the worst surge of the pandemic yet in India. Molnupiravir is an experimental drug under development with Ridgeback Biotherapeutics. Merck declared to the world that its goal here was to accelerate availability of the drug in India and other low-and middle-income countries (LMICs) should it be approved or authorized under emergency use authorization by local regulatory bodies. TrialSite recently profiled the Merck experimental drug, which was subject to some controversy last year when a whistleblower charged that individuals in the federal bureaucracy were inappropriately trying to secure more taxpayer support for the experimental drug.
Although there have been some concerns with the potential safety of the drug, is was greenlit for human trials, and what follows is a breakdown of research status and demonstrated safety in the Phase 1 trial in the United Kingdom (UK). However, TrialSite notes that this Phase 1 authorship was tightly connected to the ownership and commercial success of the product.
And the stakes for this drug are huge. After all, it’s the early onset, mild-to-moderate cases, roughly 90% of all COVID-19 cases that ivermectin proponents sought after, given the performance of that drug in well over 50 clinical trials now. Of course, Merck is an ivermectin producer and in the past proudly gave away billions of doses for eradication of various parasites in the topics. That program’s been wildly successful, the inventors of the drug won the Nobel Prize yet Merck attacked the developmental candidate for COVID-19 declaring there was absolutely no evidence for efficacy and even raised safety concerns. TrialSite viewed the activity critically, suggesting there was commercial motive.
After all, Merck in November made a move to spend $425 million to buy another COVID-19 experimental drug from OncoImmune, and a month later, reported that the U.S. government gave the company $356 million for ongoing research targeting for that same drug as well as securing up to 60,000 to 100,000 doses. Months later, Merck scrapped that whole program and pivoted to concentrate on Molnupiravir. But what about the taxpayer money that was allocated to the other drug now dropped?
Results of Phase 1 Study
On March 3, 2021, Ridgeback Biotherapeutics reported the results of a Phase 1 clinical trial evaluating EIDD-2801/MK-4482 published in the peer reviewed journal Antimicrobial Agents and Chemotherapy. The sponsor reported that the study met its primary objectives to determine the safety, tolerability and pharmacokinetics of single and multiple ascending oral doses of the study drug also known as Molnupiravir. Overall, the sponsor reported the drug was well tolerated.
With 130 patients, the study (NCT04392219) started in April 2020 and ran through until August, 2020. The study was managed at Covance (part of LabCorp), a contract research organization’s research unit in the United Kingdom. The primary authors of the study do have direct ties to the outcome of the drug. For example, all of the authors either work for the sponsor, the CRO that the sponsor is renumerating for the study, or Emory University’s drug development non-profit organization, which also has an ownership interest. This by no means is indicative of anything other than a well-run trial, but TrialSite notes there is no independence here among authors. Follow the link for the study.
Phase 2/3 Study in Hospitalized Patients Ongoing
In one multi-center and multi-national Phase 2/3 study (NCT-4575584), Merck evaluates the safety, tolerability and efficacy of the study drug (MK-4482) as compared to placebo in hospitalized patients. The sponsor hypothesizes that Molnupiravir is superior to placebo as measurable by the rate of sustained recovery through Day 29.
The top three primary endpoints make the study almost look like a safety study—they include 1) time to sustained recovery, meaning the participant is alive, and not hospitalized or the participant is alive and medical ready for discharge as determined by the investigator; 2) percentage of participants with an adverse event (in a time frame of up to 7 months); and 3) percentage of participants who discontinued study intervention due to an AE.
Secondary endpoints include 1) all-cause mortality rate (up to 29 days); 2) pulmonary score on a scale (up to 29 days); 3) pulmonary + score on a scale (up to 29 days)—this is an ordinal scale, which is a 7-category assessment that captures the range of disease severity; 4) National Early Warning Score on a scale (time frame here end of treatment –up to 6 days)—note that this measurement assesses a participant’s degree of illness as assessed by clinical risk prediction categories for poor clinical outcomes including mortality within 24 hours of a set of vital sign measurements; and 5) WHO 11-point outcomes score on a scale (time frame up to 29 days). This scale is an 11-point ordinal scale that categorizes clinical progression.
This study commenced in October 2020 and is scheduled to run until June 27, 2021. The full estimated study complete date is December, 2021.
Phase 2/3 Study in Non-Hospitalized Cases Ongoing
Importantly, a multi-center, and multi-country study (NCT04575597) for non-hospitalized cases continues until a planned, final completion date of December 26. This study emphasizes the vast majority of COVID-19 cases, that is those that have early onset, mild-to-moderate cases, representing about 90% of all COVID-19 cases.
In this Phase 2/3 clinical trial, Merck aims to compare the safety, tolerability and efficacy of the study drug to placebo. They hypothesize that the drug will be superior to placebo as assessed by the percentage of participants who are hospitalized and/or die through day 29.
Launched on June 23, primary endpoints include 1) percentage of study participants that become hospitalized and/or die; 2) percentage of participants with an adverse event (time frame up to 7 months); 3) percentage of participants who discontinued study intervention due to an AE (time frame up to 6 days).
Secondary outcome measures include 1) time to sustained resolution or improvement of each targeted COVID-19 sign or symptom (time frame up to 29 days); 2) time to progression of each targeted COVID-19 symptom (time frame up to 29 days); and 3) WHO 11-point outcomes score on a scale (time frame up to 29 days)
Merck Generic Deals
While India goes through what appears to be the worst of the pandemic’s rage, Merck has been negotiating licensing deals with Indian firms, much like Gilead accomplished with remdesivir once that drug was under emergency use authorization.
Merck positions this move by making the drug more available once it’s authorized—either formally or via some emergency use mechanism.
The deals were put together with the following generic firms:
· Cipla Limited
· Dr. Reddy’s Laboratories Limited
· Emcure Pharmaceuticals Limited
· Herero Labs Limited
· Sun Pharmaceutical Industries Limited
Merck notes in their recent press release that these firms are all qualified with the World Health Organization (WHO) via the Pre-Qualified Manufacturing facilities. Merck has negotiated a license for these firms to produce and sell in India and over 100 LMICs. The terms of the licenses were not disclosed. Merck shared that they are also in discussions with the Medicines Patent Pool to “explore the potential for additional licenses.”
Donation to India
Merck reported that it has donated over $5 million worth of oxygen-production equipment, masks, hand sanitizer, and financial aid to support relief efforts in India.
Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment and prevention of transmission, as well as SARS-CoV-1 and MERS. EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University. Since licensed by Ridgeback, all funds used for the development of EIDD-2801 by Ridgeback have been provided by Wayne and Wendy Holman and Merck.
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