Scientists Question Safety of Merck’s New COVID “Wonder Drug” Expensive Molnupiravir is about to be authorized for millions of people based on a trial involving 500 patients

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Here we go again with another questionable new COVID drug developed with our tax dollars and sold back to us at massively inflated prices. First, there was the insanely expensive remdesivir and now there’s molnupiravir, an oral pill set to make Merck more billions.

With splashy headlines, media outlets trumpeted molnupiravir, produced by Merck and Ridgeback Biotherapeutics, offering “the promise that COVID-19 could soon be treated by a pill.”

The pharmaceutical companies have requested FDA emergency use authorization after an interim analysis from Merck’s non-peer-reviewed phase 3 clinical trial found the antiviral medicine reduced the risk of hospitalization or death by approximately 50%, with 7.3% of patients who received the experimental drug hospitalized or subsequently died by Day 29, compared to 14.1% of patients who were randomized to receive a placebo. Merck halted the trial early because of its success.

 Yahoo! News reported: “Federal regulators will not scrutinize the results of those trials closely before granting approval for distribution. That approval will be initially made on an emergency-use basis, as it was for the coronavirus vaccines.”

“They will do it as quickly as they possibly can,” Dr. Anthony Fauci told CNBC. “We really look forward to the implementation of this and to its effect on people who are infected.”

The Yahoo report neglected to mention a different Merck molnupiravir study on 304 hospitalized patients, which was  “terminated for business reasons,” according to ClinicalTrials site. It failed to help hospitalized patients.

In contrast, a study by researchers at George Washington University found low-dose aspirin likely works better, reducing the risk of mechanical ventilation by 44%, ICU admissions by 43%, and overall in-hospital mortality by 47%.

Back to the new “wonder drug” molnupiravir, which works by integrating into the genetic makeup of the virus, causing a large number of mutations to destroy the virus.

Our government has such confidence in it, that in June, a $1.2 billion contract was signed with Merck to supply 1.7 million courses of the medication at the price of $712 a course.

“An easily administered oral antiviral drug would be an important part of our therapeutic arsenal that would complement the great success of our vaccine efforts,” said Dr. David Kessler, chief science officer for the Biden administration’s Covid-19 response, in a statement. “Our Administration is going to harness the power of American ingenuity to spur the creation and development of these drugs that can save lives both here in the United States and around the world.”

Produced with public funds amounting to $29 million, Molnupiravir could potentially earn Merck $7 billion by the end of 2021. The company has promised to have more than 10 million courses of the treatment available by the end of the year.

“This would make it, in only a few weeks, one of the 10 most lucrative drugs ever,” noted Quartz’s Annalise Merelli.

The Intercept reported Merck’s molnupiravir was developed using funding from the National Institutes of Health and the Department of Defense.

Molnupiravir costs $17.74 to produce, according to a report issued by drug pricing experts at the Harvard School of Public Health and King’s College Hospital in London. Merck is charging the U.S. government $712 for the same amount of medicine, or 40 times the price.

Activist Heidi Chow decried the exorbitant price the U.S. government paid for molnupiravir as “another example of Big Pharma reaping billions from public investment into research by charging extortionate, rip-off prices for lifesaving Covid drugs.”

Knowledge Ecology International (KEI) obtained the government contract as part of its Freedom of Information Act lawsuit against the Department of Health and Human Services and the Army related to COVID-19 contracts executed by the U.S. government.

The contract, with relevant parts redacted, No. W911QY21C0031, was awarded by the Army on June 7, 2021. It has an upper limit of $3.7 billion. The agreement includes options to purchase additional courses of the drug, but quantities for those possible future purchases are redacted.

KEI notes: “The operative provisions in Section H.12 are not only redacted in full, but the title is also redacted, making it impossible to know if or how any other provisions are modified.”

 

So how safe is molnupiravir?

Depends who you believe. There were no major safety concerns in the Phase IIa study, but it was too small to draw definitive conclusions, said Dr. J Stone Doggett, an infectious disease expert at Oregon Health & Science University. In a phase IIa study of 202 patients, headache, insomnia, and increased alanine aminotransferase were the only adverse events that occurred in four or more participants, according to a preprint manuscript.

The Daily Mail reported “side effects were reported by both groups in the Merck trial, but they were slightly more common among the group that received a dummy pill. The company did not specify the problems.”

In India, two drugmakers sought to end late-stage trials of their generic versions of molnupiravir to treat moderate COVID-19, a week after Merck said its own trial had succeeded for mild-to-moderate patients.

A Drug Controller General of India spokesman revealed molnupiravir had not shown “significant efficacy” against moderate cases, but was successful against mild cases.

A Merck spokesperson said that Merck and the Indian companies had defined “moderate” disease differently.

Some scientists have raised safety questions. Compared to intravenous monoclonal antibodies, which are authorized to treat mild-to-moderate disease, small molecules like molnupiravir are less specific and run a higher risk of off-target side effects, suggests University of North Carolina immunology and infectious diseases researcher Dr Sam Lai.

The lack of long-term safety data concerning molnupiravir could be an obstacle for skeptical patients. Merck has yet to present detailed safety data on molnupiravir. Due to the need for longer-term safety data, molnupiravir may need to be limited to patients at high risk of developing severe disease.

There are “persistent side-effect concerns with mutagenic molnupiravir,” a Clinical Trials Arena article observed. Ron Swanstrom, a professor at the University of North Carolina, Chapel Hill, in January questioned “whether molnupiravir could be metabolized into a precursor of DNA,” and then “enter the host cell nucleus, leading to oncogenesis.” Oncogenesis is the complex, multi-step process by which normal cells turn into cancerous cells.

Molnupiravir is an oral ribonucleoside analog that inhibits RNA virus replication. The drug has certain mutagenic characteristics whereby human cells can also be targeted so there is a theoretical potential for causing genetic alterations, or potentially cancers, noted research professor Dr. Luis Menendez Arias, research professor at Consejo Superior de Investigaciones Científicas (Spanish National Research Council) in Madrid.

Concerns include that molnupiravir could insinuate into viral mRNA, causing errors in replication and transcription, and it could insinuate into nuclear RNA, and into mitochondrial RNA.

TrialSiteNews published a critique by Leo Goldstein, “Merck Ignores Molnupiravir’s Cytotoxicity.” Goldstein argues that molnupiravir is a mutagenic nucleotide analogue. It increases the rate of mutations in the coronavirus’ RNA and in human DNA. He writes: “The consequences of molnupiravir’s DNA mutagenesis, such as cancer or birth defects, take months or years to develop. The 24 days of patient observation after 5 days treatment is obviously not enough to detect anything,” and added, “No results have been published in peer reviewed journals.”

In theory, mutagenic drugs can cause either birth defects or cancer. The inclusion criteria for the Phase 3 study of molnupiravir required males to refrain from donating sperm and either agree to abstain from sex or use contraception.

Females were required to not be pregnant or breastfeeding. Women who were of child-bearing age had to agree to use a highly effective contraceptive method or be abstinent for 28 days from the start of the study intervention. Women of childbearing age also had to have a negative highly sensitive pregnancy test within 24 hours before receiving the first dose of the medicine. Merck excluded vaccinated people from its phase 3 study.

Prof. Luis Menendez Arias published the paper “Decoding molnupiravir-induced mutagenesis in SARS-CoV-2” in the Journal of Biological Development in July 2021. He wrote: “The biochemical mechanisms involved in molnupiravir-induced mutagenesis had not been explored. In a recent study, Gordon et al. demonstrated that NHC can be incorporated into viral RNA and subsequently extended and used as template for RNA-dependent RNA synthesis, proposing a mutagenesis model consistent with available virological evidence. Their study uncovers molecular mechanisms by which molnupiravir drives SARS-CoV-2 into error catastrophe.”

Error catastrophe refers to the cumulative loss of genetic information in a lineage of organisms due to high mutation rates.

“Available evidence suggests that molnupiravir could become a paradigmatic example in the use of lethal mutagenesis as an antiviral strategy. However, there are inherent risks in this approach. NHC can be metabolized by the host cell to the 2′-deoxyribonucleoside form by the ribonucleotide reductase and then incorporated into the host cell DNA. The mutagenic effect of NHC has been shown in animal cell cultures, raising concerns on the potential risk of molnupiravir-induced tumorigenesis (the production of tumors) and the emergence of detrimental mutations in sperm precursor cell generation and embryo development.”

An August 2021 paper published in the Journal of Infectious Diseases found that β-D-N4-hydroxycytidine (NHC, the initial metabolite of molnupiravir) “displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.”

The authors warned: “Evaluating the utility of this drug should be done in those likely to receive the greatest benefit with monitoring provided to assess potential long-term genotoxic side effects.”

Science magazine reported in 2020, the former Head of U.S. Biomedical Advanced Research and Development Authority (BARDA) Dr. Rick Bright opposed granting additional funding to develop the drug, partly over safety concerns related to the drug. In a complaint summarized in Science, Dr. Bright wrote 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.

Dr. Bright filed a whistleblower complaint, suggesting federal officials inappropriately tried to steer U.S. money to an unproven treatment for the coronavirus. He said senior Trump administration officials had asked him to rapidly approve funding that would help a small pharmaceutical firm further develop a still-experimental drug. The federal outlay could have ultimately amounted to $300 million or more.

Molnupiravir was originally developed by researchers at Emory University in Georgia, initially for Venezuelan equine encephalitis. At a meeting on November 1, 2019 with Emory University officials, EIDD-2801 (molnupiravir) was presented as “cure-all” for influenza, Ebola, and nearly every other virus, Bright reported in his whistleblower complaint. He asked whether Emory had conducted a reproductive study for toxicity and was told they had not.

Ridgeback licensed molnupiravir from Emory University in 2020 and then sold the license to Merck two months later. As the Washington Post reported: “Ridgeback Biotherapeutics had no laboratories, no manufacturing facility of its own and a minimal track record when it struck a deal in March with Emory University to license an experimental coronavirus pill invented by university researchers.” Ridgeback’s owners, Wayne and Wendy Holman, will receive a share of the massive profits.

Bright said officials illegally retaliated against him for objecting to what he saw as improper and unscientific efforts to steer taxpayer dollars to certain firms run by “cronies” or “for political purposes.”

In 2019, Wendy Holman, chief executive of Ridgeback Biotherapeutics, and a former hedge fund manager, was named to President Trump’s advisory council on HIV/AIDS. Last year, Holman submitted a request for approximately $100 million in federal funding for molnupiravir, without, according to Bright, any supporting documentation for its funding request.

In the Washington Post article headlined, “Hedge fund manager stands to profit on ‘flip’ of taxpayer-funded coronavirus drug,” Dr. Aaron Kesselheim, a professor at Harvard Medical School commented on Emory’s agreement to license molnupiravir to Ridgeback: “I would think that universities … would not normally transfer products to basically a house-flipper. I wouldn’t think they would have to engage with speculators, like it appears that Ridgeback Biotherapeutics is.”

Knowledge Ecology International’s director James Love, described Ridgeback’s two-month ownership of the license to molnupiravir as “molecule-flipping.”

Very early in the pandemic, Dr. Bright reported how he tried to warn Trump administration officials of the emerging threat and was stonewalled. He was blocked from gaining virus samples and attempting to ramp up counter-measures like securing masks.  “Dr. Bright and his team feverishly emailed health officials and laboratories in Australia, Thailand, the United Kingdom and France to try to obtain samples because the CDC had refused to provide information or virus samples to them.”

After he was removed as Director of BARDA in April 2020, and involuntary transferred to the NIH, he released a statement: “I believe this transfer was in response to my insistence that the government invest the billions of dollars allocated by Congress to address the COVID-19 pandemic into safe and scientifically vetted solutions, and not in drugs, vaccines and other technologies that lack scientific merit.” He subsequently faced a smear campaign and filed the whistleblower complaint. A settlement with financial compensation was reached in August 2021.

The New York Times reported that Bright received further compensation for “distress associated with the disparaging comments and threats” made by administration officials,” including then-President Trump.

Emory School of Medicine chemist Prof. Raymond Schinazi has advised caution with widespread use of molnupiravir until more data is available, due to its potential harm to young people of reproductive age or those who are pregnant.

Quoted in the Science article, Schinazi stated that his previous pharmaceutical company, Pharmasset, abandoned a similar drug in 2003 after discovering its mutagenic properties. He said the small chemical tweaks made to increase the ingredient’s bioavailability and transform it into EIDD-2801 (molnupiravir) were unlikely to change its mutagenicity.

“Thank goodness someone is raising the red flag,” said Schinazi. “You don’t develop a drug that’s mutagenic. Period.” Schinazi suggested reproductive harm could happen with short-term treatment.

“Proceed with caution and at your own peril,” Prof. Schinazi wrote in an email to Barron’s published in the article “Merck’s Covid Pill Could Pose Serious Risks.”

As far as molnupiravir’s possible debilitating side effects, drug makers have immunity under the Public Readiness and Emergency Preparedness (PREP) Act, which provides “substantial liability protections for makers and distributors of pandemic, epidemic, and bioterrorism countermeasures.”

One of the authors of the paper published in August in the Journal of Infectious Diseases, Dr. Shuntai Zhou, told Barron’s: “There is a concern that this will cause long-term mutation effects, even cancer.” Dr. Zhou stated that he is certain that the drug will integrate itself into the DNA of mammalian hosts. “Biochemistry won’t lie,” he said. “This drug will be incorporated in the DNA.”

Nathaniel Landau, a professor in the Department of Microbiology at New York University School of Medicine suggested, “Given the possibility that the drug could be incorporated into cellular DNA, it will be very important to demonstrate a lack of cancer in animal models and in humans.” It should not be rushed for clinical application before ensuring that it will “not cause cancer even at very low frequencies.”

Merck said it ran two tests in animals in which it gave molnulpiravir at higher doses, and for longer, than it would in humans. The company reported that in ferrets, molnupiravir significantly reduced the upper respiratory tract load in infected models and suppressed spread to noninfected models. It’s worth noting that ferrets cannot develop large viral loads or severe disease.

The company reported the tests showed that molnupiravir is not mutagenic. Merck also said data shows molnupiravir is not capable of inducing genetic changes in human cells.

There are caveats to extrapolating animal model data to humans, reported Ashley Brown, associate professor at the Institute for Therapeutic Innovation, University of Florida. With molnupiravir, it needs to be converted into its active triphosphate form in the cell, and enzymes responsible for such conversion may be different between animal models and humans, she said. Dosing data in animals do not relate to humans, as plasma concentrations do not correlate to activity within animal and human cells, she explained.

Dr. Robert Malone, who helped pioneer mRNA technology, sarcastically tweeted on Oct. 5, a photo of Merck’s molnupiravir pills with the caption “This is the reason for all of the ‘horse drug’ propaganda.” Merck also makes ivermectin.

Dr. Elizabeth Duke, a researcher overseeing the molnupiravir trial, told Kaiser Health News in September: “You could give it to everyone in a household, or everyone in a school. Then we’re talking about a return to, maybe, normal life.”

The Bill and Melinda Gates foundation announced in late October it will donate $120 million towards the distribution of  molnupiravir across the developing world. “To end this pandemic, we need to ensure that everyone, no matter where they live in the world, has access to life-saving health products,” Melinda Gates said in a statement. “Today’s commitment will ensure that more people in more countries get access to the promising drug molnupiravir.” There was no mention of possible toxicity.

 

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Jon Woodhouse

Jon Woodhouse is the Managing Editor of The Maui Independent. Moving to Maui 36 years ago, he feels blessed daily to live here. He writes weekly for The Maui News and has worked for the Department of Education since 2001.

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