Merck’s quest for the development of treatments targeting COVID-19 has increasingly disappointed all, but the big bet stands right before them—and all of society. If this great American pharmaceutical company can successfully bring Molnupiravir (EIDD-2801) to market under emergency use authorization (EUA) by second half of 2021, they will own what could be a $5+ billion per annum market in America alone. That’s because there is no safe and efficacious treatment recognized by authorities for early onset, mild-to-moderate COVID-19—representing 90% of all coronavirus cases. Merck’s trials and tribulations during COVID-19 could be rectified, with investor praise and consumer thanks, should they ultimately prove success. But it’s been a tortious process, and they are by no means close to the Land of Oz—the yellow brick drug development road is perilous, too. They have done much for humanity from the development of incredible cancer drugs to inspirational humanitarian acts, such as the donation of billions of doses of ivermectin (Stromectol/Mectizan) to the developing world, which was a great gift fighting tropical-based parasite disease. Merck notes that their ivermectin program “reaches more than 300 million people in the affected areas annually, with more than 4 billion treatments donated since 1987.” After failing at a COVID-19 vaccine effort, the company rightly moved to develop COVID-19 therapies. In the quest for a big hit (and to redirect the billions currently going to Gilead for remdesivir), they opted to not only ignore growing clinical trial data indicating some considerably notable positive ivermectin trial data targeting COVID-19 but actually go on the attack against their own drug. Existing ivermectin human-based studies use comparable dosage schemes as to current indications. TrialSite showed how Merck had to avoid ivermectin because of at least a two-prong strategy involving both the acquisition of a biotech firm called OncoImmune for $425 million targeting a treatment for COVID-19 called CD24c as well as a partnership with Ridgeback Biotherapeutics to develop a controversial experimental antiviral drug. A month after the OncoImmune purchase announcement, Merck boasted that they received $356 million from the government (taxpayers) to support COVID-19 research involving CD24c (MK-7110). TrialSite wrote that it was understandable from a business perspective that they had to avoid ivermectin: but they most certainly didn’t have to disseminate misinformation to the public, an indicator of the values of at least some in leadership. Now just five months later, the company announced it dropped the $425 million drug known as CD24c (MK-7110). But what about the $356 million Merck received to develop MK-7110? Did they secure permission from the feds to take that money and use it for the development of Molnupiravir? Remember this was one of the controversial experimental products that whistleblower Rick Bright complained about as crony-capitalism permeated the world of drug politics and power. The pandemic has exposed a lot of issues in the world of drug development that necessitate reform.
$425m for What?
Despite receiving $356 million of U.S. taxpayer money to develop MK-7110, Merck recently dropped the drug. That’s right—they just received an infusion in December and its own $425 million allocation just months ago as reported in their 10K to the U.S. Securities and Exchange Commission (SEC) in February of 2021. So, what happened?
The company acknowledged that the FDA required additional data for the company to secure an Emergency Use Authorization (EUA). What did they think—they could just buy the company and secure the EUA? Rather, the FDA required that for Merck to obtain the EUA, they would need to sponsor more clinical trials as well as research concerning the manufacture at scale and that the drug now known as MK-7110 couldn’t make it to the EUA finish line until the second half of 2022. Merck came to the conclusion that the timeline combined with technical, clinical, and regulatory “uncertainties” and the existing availability of medicines for patients with COVID-19 led them to discontinue MK-7110 for COVID-19. Rather, they would focus on producing Molnupiravir and on producing the Johnson & Johnson COVID-19 vaccine, which itself has run into some challenges.
Transition to Focus only on Molnupiravir
TrialSite suggested that when Merck inked a deal with Ridgeback Biotherapeutics back in July 2020 to access the orally available Molnupiravir (originally developed by Emory University and known as MK-4482 or EIDD-2801) that the company was after a massive market that Gilead’s remdesivir had essentially to itself. TrialSite reflected that 90% of the COVID-19 cases are in fact mild-to-moderate and never end up in hospitalization. With over 140 million COVID-19 cases worldwide and over 32 million in America alone, a solid, safe, and effective treatment for early onset would secure many billions of dollars per annum and, in fact, could reduce hospitalizations, hence eating into Gilead’s COVID-19 revenues. The upside was massive and hence another reason why the ivermectin debate had to go away. The stakes were far too rich. Now it’s not clear what strings are on the $356 million in government money but the company recently shared with the world its plans to go after the ultimate COVID-19 prize.
Studies Moving Forward
The company recently announced in a press release that based on a planned interim analysis of data from the Phase 2 dose finding portion (Part 1) of two ongoing placebo-controlled Phase 2/3 trials evaluating the study drug administered twice a day for five days in outpatients (MOVe-OUT) and hospitalized patients (MOVe-IN) with COVID-19, and from a previously completed Phase 2a dose-ranging study in outpatients, the decision was made by the company’s leadership to proceed with the Phase 3 portion of Part 2 of MOVe-OUT in outpatients with COVID-19, evaluating the 800 mg dose of Molnupiravir twice daily.
This, of course, made economic sense as TrialSite has educated the TrialSite Community this is where the vast market opportunity is for therapeutics and hence repurposed drugs such as ivermectin, fluvoxamine, colchicine, favipiravir and others have moved to the back of the bus so to speak in American society (including the ivory tower academics, regulators, and of course industry interests).
As it turns out, data from MOVE-In suggests a flop of a study. Sharing the decision, Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, stated, “We continue to make progress in the clinical development of our antiviral candidate Molnupiravir. Data from the dose-finding portion of these studies are consistent with the mechanism of action and provide meaningful evidence of antiviral potential of the 800 mg dose.” He continued, “Based on the findings of this study, we are advancing a Phase 3 trial program in non-hospitalized patients that strategically leverages our large network of clinical sites to enroll appropriate patients globally.” Merck summarizes the recent studies in the latest press release published by TrialSite. But actual metrics are still lacking.
Data Monitoring Committee for MOVe-OUT Protocol
Merck reported recently that the MOVe-OUT study Data Monitoring Committee noted that the subgroup analyses support potential benefit of treatment and suggested amendments to the study protocol to focus on enrollment on patients early in the course of disease and those considered high risk for poor COVID-19 outcomes (e.g. older patients, those with diabetes and obesity). Merck will add to their protocol as a consequence to include these other demographic cohorts in the Phase 3 study. Moreover, Merck will amend the inclusion criteria for the study by reducing the allowable symptom duration or enrollment to < 5 days and by enrolling participants with at least one risk factor for progression to severe disease. Merck will commence enrollment of patients in the Phase 3 portion (part 2) of MOVe-OUT by late April to early May.
The company estimates they can generate sufficient data in September or October 2021 to use positive results from this study to make their move for the EUA—the needed milestone to start monetizing the drug. Hence an aggressive projection they share to investors: by the second half of 2021, they may be in a position to file for the EUA. They, of course, are doing this in partnership with Ridgeback Biotherapeutics. Merck also plans on sponsoring a clinical program to investigate Molnupiravir for post-exposure prophylaxis in the second half of 2021 to compete in some capacity with AstraZeneca’s AZD7442, a dual long-acting monoclonal antibody however currently under investigation for prophylaxis (PrEP) and post-exposure prophylaxis (PEP).
Molnupiravir Results Thus Far
Merck reported in MOVe-OUT is an ongoing Phase 2/3, randomized, placebo-controlled, double-blind, multi-site study evaluating the efficacy, safety, and pharmacokinetics of orally administered Molnupiravir in non-hospitalized participants with COVID-19 confirmed using polymerase chain reaction. The primary efficacy objective of MOVe-OUT is to evaluate the efficacy of Molnupiravir compared to placebo as assessed by the percentage of patients who are hospitalized and/or die from the time of randomization through Day 29. Part 1 of MOVe-OUT enrolled a total of 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).
The percentage of patients who were hospitalized and/or died in Part 1 of the MOVe-OUT study was lower in the combined Molnupiravir-treated groups versus the placebo arm; the number of events reported are not sufficient to provide a meaningful measure of clinical effect. The sponsor hasn’t shared more detailed metrics, however.
Analysis of SARS-CoV-2 in nasopharyngeal and oropharyngeal swabs from patients in both MOVe-OUT and MOVe-IN using quantitative and qualitative polymerase chain reaction, an exploratory endpoint, indicated that Molnupiravir inhibits replication of the virus, as demonstrated by a greater decrease from baseline in viral RNA compared to placebo at Day 5 and Day 10, and by a larger proportion of participants with undetectable viral RNA at Day 10 and Day 15 following the end of treatment. The largest overall magnitude of antiviral effect was observed in the 800 mg dose compared with the 200 mg and 400 mg doses. These differences in virology endpoints were more pronounced in participants enrolled < 5 days following symptom onset reports the company in its press release.
Among 299 patients who received at least one dose of study intervention in MOVe-OUT, 6.2% (14/225) of those receiving Molnupiravir and 6.8% (5/74) of those receiving placebo reported drug-related adverse events. In MOVe-IN, of 293 patients who received at least one dose of study intervention, 11.0% (24/218) of those treated with Molnupiravir and 21.3% (16/75) of those receiving placebo reported drug-related adverse events. To date, the safety and laboratory data from MOVe-IN and MOVe-OUT provide no evidence for unexpected findings or trends observed at any of the doses studied. In both trials, no deaths were considered drug-related by the investigators, and there were no drug-related adverse events that led to discontinuation in participants who received Molnupiravir. Interim results from both MOVe-IN and MOVe-OUT, including virology findings and pharmacokinetic analyses, have been shared with regulatory authorities and will be presented at an upcoming medical meeting.
Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally administered 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 against coronaviruses in several preclinical models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission, as well as SARS-CoV-1 and MERS. Molnupiravir was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University.
The drug has demonstrated in preclinical research led by coronavirus experts at University of North Carolina and Vanderbilt University that in these animal studies involving two distinct coronaviruses (SARS-Cov1 and MERS) that EIDD-2801 (now Molnupiravir) can improve pulmonary function, decreased body weight loss, and reduce the amount of the virus in the lung.
Moreover, the drug shows promise against seasonal bird influenza, respiratory syncytial virus, chikungunya virus, Ebola virus and more. This drug has received considerable public funds, including money from the National Institute of Allergy and Infectious Diseases (NIAID) under contract numbers HSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA) under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075.
TrialSite notes below that experts involved with this preclinical research actually developed a coronavirus with a spike protein in the lab back in 2015 and that no therapies or vaccines were successful against the lab-created pathogen, in what read as a scary sci-fi picture, so we conclude that this particular compound (EIDD-2801) wasn’t involved back in the 2015 testing against the lab-produced coronavirus.
Crony Capitalism or the Status Quo?
Molnupiravir (EIDD-2801) was at the center of controversy when a whistleblower for the U.S. government challenged the ever growing handouts of money for previous POTUS’ Operation Warp Speed initiatives, also funding the NIH’s ACTIV-based studies, as he shared with authorities that he received what he considered unethical and improper requests in what was to him clearly a compromised environment. As reported in Science back in May 2020 titled “Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug,” previous POTUS officials asked insiders to expedite the approval of $300 million or more to fund the development of an experimental, investigational product under consideration for COVID-19. That drug was Ridgeback’s EIDD-2801 (now Merck’s Molnupiravir). Joffrey Benford wrote in an email, “We are uncomfortable with rushing forward,” noting it “Impossible due to acquisition processes and procedures that are required for the size of its acquisition.”
This incident and others were at the heart of the whistleblower Bright’s complaints who was subsequently and more than likely punished for speaking out. He was removed on April 20 as head of BARDA or the Biomedical Advanced Research and Development Authority—part of the Department of Health and Human Services of the federal government. Whistleblower Bright suggested “crony-capitalism” was alive and well as comfortable and connected bureaucrats were improperly handing out what could ultimately amount to billions of taxpayer dollars. Any rational government would perform an audit of exactly what has transpired here.
Bright’s scrutiny was on Ridgeback Biotherapeutics’ effort to win that $300+ in federal funding. While the drug had shown some antiviral promise targeting COVID-19, Bright was against funding the drug. He suggested that the drug was already receiving taxpayer dollars in the form of existing government support. But he also raised the specter of safety issues.
Apparently in some earlier studies, according to Jon Cohen and Charles Piller writing for Science, the experimental compound caused some genetic mutations. Although at the time assistant secretary for preparedness and response (ASPR) at BARDA’s parent agency, U.S. HHS, was purportedly pushing to get the small biotech the money, apparently the whistleblower action thwarted the effort.
Moreover, Bright had to go up against some powerful backers behind the scenes. When he filed his whistleblower complaint against the HHS in the U.S. Office of Special Counsel, he included a number of exhibits of which only some were made available to the public. He alleged that the then administration was driven by “cronyism over science” and that politics over sound principles and science led the discussion. So this meant that not only was Wright shaking things up with the political leadership—all the way to the office of the POTUS—he was also shaking the wrong therapeutic bushes with EIDD-2801. While he declared the drug included dangers, the drug was previously supported by the powerful NIAID director Dr. Anthony Fauci and the Department of Defense (DOD). Taking on POTUS, Fauci, and the DOD’s interest….is probably a losing proposition.
Interestingly, in a meeting to discuss funding with the drug’s maker, Emory Institute for Drug Development (EIDD) and their head George Painter, coupled with a high-level drug development lobbyist and consultant named John Clerici, cautioned to Mr. Bright (the whistleblower) that this drug could be a great American national security asset and threatened to take the drug to a different country if BARDA wouldn’t offer funding. This declaration is purportedly in the whistleblower complaint. If this is true, clearly pecuniary interests trumps national conviction in this age of cronyistic tendencies.
Any Molnupiravir Concerns?
According to Science, EIDD-2801 is a four-decade old antiviral drug that never made it out of the lab, reports Science. Interestingly, however, with Merck’s securing of $356 million for the other drug that’s now ceased in development and its partnership with Ridgeback Biotherapeutics, perhaps that taxpayer funded tranche found its way to Molnupiravir?
EIDD-2801 (Merck’s Molnupiravir) represents all that Merck has left targeting COVID-19 along with supporting manufacturing of the Johnson & Johnson vaccine, which TrialSite has reported must be reviewed for safety considerations.
With over 50 clinical trials, ivermectin’s story didn’t appeal to Merck management and investors (and frankly the rest of industry and much of the academy), hence the crushing of the story. The company’s boondoggle with the $425 million OncoImmune acquisition went nowhere; just months later, the company killed the whole project but perhaps that was serendipitous as the company could maybe use the $356 million in taxpayer originated funds to fund Molnupiravir? TrialSite cannot verify this statement, so we cannot be certain how that funding is used at this point.
In the Science piece, the authors shared that whistleblower Bright noted that “similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls.” Bright shared that during a meeting with Emory Institute for Drug Development (EIDD), lead George Painter, and a drug development lobbyist and lawyer named John Clerici, that the latter presented EIDD-2801 as a “ viral cure-all” and a “miracle cure.”
Bright had noted that Emory had already received $26 million from NIH and the Department of Defense to advance this drug. Why should it get more, given its early state and the negative safety data associated with preclinical research? Bright wanted to see investment in early stage safety studies prior to any major government funding, wrote Jon Cohen and Charles Piller.
The Science authors shared that Molnupiravir does act as a defective RNA building block when confronting an enzyme known as a polymerase to replicate its genome. In this way, the drug works similar to that of remdesivir; however, the latter approved drug is controversial, works in a modest manner, and the World Health Organization (WHO) now recommends against the drug due to the findings in the Solidarity trial.
Drugs Politics & Power: Ominous Intersections
In a study published in Science Translational Medicine, a group of researchers led by the brilliant Ralph Baric (he and team actually developed a coronavirus with a spike protein in the lab back in 2015) found that in April 2020, the drug (EIDD-2801) evidenced considerable possibility in mice. Ironic, some could ponder that a team developing lab-based, spike-protein-enabled coronaviruses were also just a few years later working on the actual cure to a purportedly natural born coronavirus in preclinical studies.
But this is how the world of drugs, power, and politics can unfold as influential government, scientific and industry social networks and circles dictate a close and intricate network of research endeavors, deal making and potentially for the lucky commercialization.
In regards to EIDD-2801, Merck sensed an opportunity to catch up with Gilead by late spring and made their move in the summer, announcing the partnership with Ridgeback Biotherapeutics to secure rights to EIDD-2801 on July 1, 2020.
FDA Greenlight for Phase 1
By April 2020, the U.S. FDA gave the greenlight for the study of EIDD-2801 in humans—the study would be sponsored by Ridgeback Biotherapeutics and Emory University’s Drug Innovation Ventures (DRIVE), LLC. TrialSite emphasized back then that the lab of Baric (again working on studying coronaviruses since 2015 along with Vanderbilt) had uncovered potential efficacy in preclinical research animal studies. With the FDA greenlighting a phase I safety study, Ridgeback Biotherapeutics commenced a safety trial (NCT04405739) centering on EIDD-2801 in connection with COVID-19. Involving 80 participants, the study is scheduled to conclude May 28, 2021.
Market Cleared of Any Discussion of Alternatives
Conveniently, any and all mention of repurposed drugs from ivermectin to fluvoxamine and favipiravir are silenced. In fact, even mentioning that ivermectin was approved by Slovakian health authorities gets one completely censored on Facebook and YouTube—both key communication platforms of this era.
Despite no publicly available data, the FDA issued a warning not to use ivermectin despite the NIH’s COVID-19 Treatment Guidelines Panel updating their recommendation on ivermectin to neutral from negative only for research. TrialSite suggested powerful forces were “circling the wagons.”
The European Medicines Agency (EMA) followed with their downplay as did the World Health Organization (WHO) interpreting a key meta-analysis quite differently than many of the ivermectin proponents.
A treatment was and is desperately needed targeting early onset mild-to-moderate COVID-19 cases—the great majority of all coronavirus cases. This is especially the case in low-and middle-income countries (LMICs) that will have slow vaccination rates. Some doctors believe that hundreds of thousands of lives could have been saved if an early onset mild-to-moderate treatment was available, stopping the progression of the disease to more severe states. Perhaps Merck will be the first across the finish line. The financial windfall will be historical yet at a societally relevant cost.