Scientists continue to share their concerns over the potential mutagenic side effects of the candidate COVID-19 drug molnupiravir, as Merck apply for Emergency Use Authorization for the drug. As part of the efficacy and safety research on molnupiravir, Merck has set criteria for both male and female participants related to reproduction, fueling questions about the drug’s safety in patients of reproductive age. However, despite the potential risks, Merck has continued to ink deals worldwide.
Concerns for Impact on New Life?
Participants in Merck’s molnupiravir trials must agree to stringent criteria related to reproduction both during and up to 4 days after the end of the trial. Males must abstain from heterosexual intercourse or use contraception. Women of childbearing potential (WOCBP) must either use a highly effective contraceptive method or abstain from sexual intercourse, and should have a negative pregnancy test result within 24 hours before taking the first dose. Female participants should not be breastfeeding while taking the drug.
The detailed criteria have resurrected queries over the safety of molnupiravir. As the U.S. Food and Drug Administration (FDA) prepare to consider the application for Emergency Use Authorization (EUA) for molnupiravir at the end of November, TrialSite takes a closer look at the science surrounding this pharmaceutical.
Mutagenic By Design
Molnupiravir disrupts the viral replication by introducing mutations during viral RNA replication. William A. Haseltine, an American scientist, Harvard Medical School professor, and businessman discussed how the drug halts SARS-COV-2 through lethal mutagenesis.
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The drug tricks the virus into replicating.
When replicating, errors are inserted into the genetic code assuming the nucleotide uracil and cytosine
Once re-replicated, mutations are developed (changing of nucleotides from U to C and C to U)
Once more faulty codes are copied, the virus is killed, shortening replication and infection period, and transmission.
However, there are two potential negative consequences of this method of action: one to the virus, and one to the patient.
Firstly, it is imperative that the optimal dose is delivered. Use of a suboptimal dose would increase the mutations occurring during viral replication, without ensuring the virus is killed. The result would not only be ineffective treatment, but the potential to produce new variants of the virus itself. These new variants could potentially be more virulent than the original strain.
The second issue of concern is the potential for host DNA to be subject to the same mutagenesis as the viral DNA.
Abandoned Trials
As reported previously on Trialsite, Dr. Raymond Schinazi, an organic medicinal chemist specializing in antiviral agents, pharmacology, and biotechnology, and his scientist colleagues states that NHC, the initial metabolite of molnupiravir, may result in ‘animal cell culture mutations’. Research into the drug was abandoned in 2003 when they found out about its mutagenic properties.
A study published in August 2021 found that NHC is mutagenic to mammalian cells as well as to the COVID virus. Their research on SARS-CoV-2 showed antiviral and mutagenic effects at concentrations as low as 0.3 μM. Using a cell line that allows detection of mutation in a single gene, the scientists reported that doses of rNHC did not inhibit cell growth, but induced mutagenesis in a dose-dependent fashion.
The paper clarified that the experiment involved exposing the cells to the drug for 32 days. The doses of NHC tested were between 0.3 μM up to 3 μM. While all tests involving NHC had greater levels of mutations than the negative control, the values were not statistically significant when NHC concentrations were below 3 μM. The authors specified that these changes would be limited to dividing cells where synthesis of DNA precursors is ongoing.
Merck scientists responded to the publication stating that because the mutation observations were based on lab cell culture, they were “not relevant to how the drug would affect an entire animal.”
However, the scientific community is not convinced. Dr. Rafael R. Castillo, a member of the Board of Medicine in the Philippines, discussed the ability of mutagenic drugs to cause cancer or congenital defects. He stated that although a five-day course should not cause lasting side effects, it should not be recommended for longer courses. He also suggested that the FDA issue precautions and warnings to patients, especially those of reproductive age.
Scientists also raise concerns that the effects of mutations at the molecular level, including cancer and birth defects, may present later in life, meaning it may be hard to prove the causal link with molnupiravir.
Profit Over Safety?
Dr. Haseltine wrote in a Forbes article that two prices are going to be paid: when taking molnupiravir: the cost of the drug and its side effects.
Merck secured funding to conduct research on molnupiravir as a potential drug against the COVID-19 virus. Of course the $356 million was thanks to the taxpayer. Rick Arthur Bright, an immunologist, vaccine researcher, and former director of the Biomedical Advanced Research and Development Authority (BARDA), raised his concerns about funding the research of the drug using taxpayers’ money given its mutagenic property. Mr. Bright states that an unauthorized $20 million fund for molnupiravir was given from BARDA’s money.
Despite the questionable funding and questions raised concerning the side effects of the drug, Merck conducted a Phase 3 trial, finding positive results.
Trialsite reported on Merck’s planned tiered-pricing approach for molnupiravir after closing a deal with the US government. Research on molnupiravir pricing showed a calculated cost of about $18-$20 per course of treatment, while it will be sold for 35 times more at about $700 per course. Merck also applied to the FDA on October 11, 2021 for molnupiravir’s emergency use based on their unfinished trial results.
Up to old tricks?
This is not the first time Merck have pushed a drug to the front lines despite evidence for its dangerous side effects. Vioxx (rofecoxib) was a pain relief drug targeting arthritic patients, which was approved by the FDA in May 1999 but had to be withdrawn in 2004 for fatal cardiac side effects.
That may sound simply unfortunate, but the facts point to a more sinister unfolding of events. In November 1999, just six months after the FDA’s approval of the drug, interim results of Merck’s clinical trial drew attention to the fact that twice as many recipients of Vioxx had experienced serious heart problems or died, compared with the control group taking naproxen. The data and safety monitoring board voted to continue the study, named Vioxx Gastrointestinal Outcomes Research study (VIGOR), re-evaluated the data the following month and requested that Merck make a plan to analyze the cardiovascular effects of the drug.
However, when the results of the VIGOR study were published in November 2000, no such analysis was included. Not only that, but several scientists involved in the study raised warnings about data related to cardiovascular adverse events that had been left out of the publication. Even when cardiologists published a re-analysis of the complete dataset in August 2001, raising “a cautionary flag about the risk of cardiovascular events”, Merck did not move to withdraw its drug.
Only in September 2004, after another study highlighted an increased risk of heart attacks with long-term use, did Merck finally withdraw Vioxx from the market. By this time, it had been taken by an estimated 20 million Americans, of whom 88,000 were estimated to have had heart attacks because of the drug and 38,000 died.
In the court cases that followed, it emerged that Merck had drawn up a list of doctors and scientists that it “wanted to neutralize and discredit” during its marketing of Vioxx.
In light of this history of disinformation strategies, Merck’s apparent confidence in the safety profile of molnupiravir should be scrutinized. The fact that they are loudly discrediting the safety profile of their own ivermectin, has led to speculation that they are clearing the way for their profitable, patented alternative.
On November 4, TrialSite reported on the UK’s decision to authorize molnupiravir. This follows its use in parts of Vietnam, and other deals being struck around the world. TrialSite will be watching the FDA’s evaluation of molnupiravir with interest, and will continue to report on these unfolding events.