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The trial that led to MRK’s dropping MK-8507 was testing the combination of MK-8507 and Islatravir. Although MRK says Islatravir did not play a role in the observed safety problem, it sounds like GILD is not fully convinced.
It’s baffling that Molnupiravir efficacy dropped precipitously from the interim analysis to the final analysis; during the post-interim portion of the trial, patients in the Molnupiravir arm actually did worse than those in the placebo arm.
Moreover, in a trial such as this one with a very short treatment period (5 days), it’s unlikely that crossover from the placebo arm to the Molnupiravir arm after unblinding could have had a material impact on efficacy.
The FDA advisory panel for MRK’s EUA request is next Tuesday. Perhaps we’ll have a better understanding of what happened after the meeting.
MRK’s presenter at the FDA adcomm just said that he has no valid explanation for the observed fall-off in Molnupiravir’s efficacy relative to placebo in the portion of the trial following the interim analysis other than that the placebo arm overperformed (LOL).
Merck's COVID-19 pill significantly less effective in new analysis
Nov 26 (Reuters) - Merck & Co said on Friday updated data from its study of its experimental COVID-19 pill showed the drug was significantly less effective in cutting hospitalizations and deaths than previously reported.
The drugmaker said its pill showed a 30% reduction in hospitalizations and deaths, based on data from 1,433 patients. In October, its data nL1N2QX0QJ showed a roughly 50% efficacy, based on data from 775 patients. The drug, molnupiravir, was developed with partner Ridgeback Biotherapeutics.
The lower efficacy of Merck's drug could have big implications in terms of whether countries continue to buy the pill. Interim data from 1,200 participants in Pfizer Inc's trial for its experimental pill, Paxlovid, showed an 89% reduction in hopsitalizations and deaths.
Merck's shares fell 3.5% to $79.39 in morning trading.
Merck released the data before the U.S Food and Drug Administration published a set of documents on Friday intended to brief a panel of outside experts who will meet on Tuesday to discuss whether to recommend authorizing the pill.
The agency's staff did not make their own recommendation as to whether the pill should be authorized.
FDA staff asked the panel to discuss whether the benefits of the drug outweigh the risks and whether the population for whom the drug should be authorized should be limited.
They also asked the committee to weigh in on concerns over whether the drug could encourage the virus to mutate, and how those concerns could be mitigated.
Pills like molnupiravir and Paxlovid could be promising new weapons in the fight against the pandemic, as they can be taken as early at-home treatments to help prevent COVID-19 hospitalizations and deaths. They could also become important tools in countries and areas with limited access to vaccines or low inoculation rates.
EASIER TREATMENT
The Merck and Pfizer pills are cheaper to produce and easier to administer than existing treatment options such as antibody therapies from Regeneron and Eli Lilly, which are mostly administered as intravenous infusions.
The two experimental drugs have different mechanisms of action. Merck's is designed to introduce errors into the genetic code of the virus. Pfizer's drug, part of a class known as protease inhibitors, is designed to block an enzyme the coronavirus needs in order to multiply.
Merck filed for a U.S. authorization of molnupiravir on Oct. 11, following the interim data, and submitted the updated data to the FDA this week.
The molnupiravir arm of the study had a hospitalization and death rate of 6.8%, according to the updated data. The placebo group had a hospitalization and death rate of 9.7%.
One patient in the molnupiravir arm died, versus nine in the placebo group.
The United Kingdom conditionally approved molnupiravir, branded as Lagevrio, earlier this month.
Merck expects to produce 10 million courses of the treatment by the end of this year, with at least 20 million set to be manufactured in 2022. It has a contract with the U.S. government to supply as many as 5 million courses at a price of $700 per course. Several other countries have already secured millions of courses of the pill.
Merck has said data shows molnupiravir is not capable of inducing genetic changes in human cells, but men enrolled in its trials had to abstain from heterosexual intercourse or agree to use contraception. Women of child-bearing age also had to use birth control.
Still, the FDA said in its briefing document that there are safety concerns about potential birth defects from the drug and asked the panel to discuss whether the drug should be available to pregnant women.
Merck’s new COVID drug, Molnupiravir, is dangerous and unproven
OP-ED DANIEL HOROWITZNovember 22, 2021
First it was lockdowns, then masks, then a series of failed shots and boosters, with a side-dish of remdesivir killing people in hospitals while blocking lifesaving treatments. Now, the same forces within big pharma are about to unleash their first outpatient drug on us. Are we really to believe that this will suddenly be the first pristine COVID product from big pharma that actually helps rather than harms us? Color me skeptical, especially based on what we know about Merck's supposed wonder drug, Molnupiravir.
First, it's important to note that the medical establishment has made it clear they will not touch a repurposed drug so long as it's off-patent. However, they have no problem using repurposed drugs that are expensive and unsafe as they did with remdesivir (which was repurposed from the Ebola virus) after it killed so many people and had to be pulled from trial. Well, Molnupiravir is also a repurposed drug. Wait for it … Molnupiravir is actually repurposed from a horse drug!
Merck's Molnupiravir, also known as (EIDD-2801), was originally co-developed by Ridgeback Biotherapeutics LP and a biotech company owned by Emory University in 2003 to treat equine encephalitis and was later purchased by Merck to be used for coronavirus. There is nothing novel about the drug. It is a nucleotide analogue that introduces errors in the viral RNA at the time of replication after to cause mutations. The problem with mutagenic drugs is that they are known both to cause side effects, such as cancer and birth defects, in the individual, as well as spawn mutations in the virus — not coincidently similar to the leaky vaccines currently being used.
The reason drugs like ivermectin that work "accidentally" against viruses are so much safer is precisely because they don't attempt to go after the virus in an offensive way, running the risk of damaging good cells and causing mutations. It's actually a good thing that they are not traditional anti-virals and work in a defensive way. The reason we have so few anti-virals in the first place is because they are dangerous to the patient, sort of like chemotherapy.
Merck is asking for federal emergency use authorization at the same time the federal government has signed a $1.2 billion contract with them based on a single safety study conducted by ... you guessed it ... the very entity itself. Interestingly enough, the study participants were bizarrely told to abstain from "heterosexual intercourse" during the trial, a rare and interesting distinction for a trial protocol in an anti-viral therapeutic. But, in fact, they understood that this technology, which works similar to chemotherapy, is not safe for women of childbearing age who want to have children in the future. As Dr. Simon Clarke, associate professor in cellular microbiology at the University of Reading, said, the specific instructions on heterosexual sex "suggests that the drug has the potential to cause birth defects should someone become pregnant."
Much like vaccines, anti-viral agents have to be formulated perfectly. If they fail to fully kill the virus, they run the risk of having the virus mutate and becoming more virulent, akin to shooting at the king and missing.
Also, in the same way anti-virals attack the genetic makeup of the viruses, they have the potential to damage the hosts as well, just like we see with anti-cancer drugs. "Proceed with caution and at your own peril," wrote Raymond Schinazi, a professor of pediatrics and the director of the division of biochemical pharmacology at the Emory University School of Medicine, who has studied NHC for decades, in an email to "Barron's" last month.
After the body ingests Molnupiravir, it produces a compound called NHC (N-hydroxycytidine). Schinazi, who works at the university that originally developed the drug, co-authored a paper in the Journal of Infectious Diseases a few months ago warning that NHC caused mutations in animal cell cultures. Schinazi used to own a biotech company that once attempted to pursue this drug, but abandoned it in 2003 once it was discovered it's mutagenic tendencies.
Barron's also interviewed Dr. Shuntai Zhou, another author of the study and a scientist at the Swanstrom Lab at UNC, who claims he warned Merck last year about their initial findings.
"There is a concern that this will cause long-term mutation effects, even cancer," Zhou says.
Zhou says that he is certain that the drug will integrate itself into the DNA of mammalian hosts. "Biochemistry won't lie," he says. "This drug will be incorporated in the DNA."
What impact it will have when it's there is unknown, given the various systems human cells use to limit the impact of mutations. Well, that sounds like a drug we want to dive into headfirst while we have safe, cheap, and effective alternatives.
Merck disputes these claims and suggest their studies show otherwise. But are we really to once again place our blind trust in a company that stands to make billions when known molecular biological principles should caution us against proceeding forward with this technology? Why would we spend billions on an untested drug with a dangerous mechanism of action when safe, off-patent, repurposed drugs already work better without the risk?
In another violation of informed consent, Merck was given $356 million in taxpayer funding at the beginning of the pandemic to develop this already-developed drug, despite opposition at the time from former director of the Biomedical Advanced Research and Development Authority (BARDA) Rick Bright. He warned 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."
It is simply indefensible to pursue a drug like this when we already have established, effective, less expensive drugs that are actually safe. Even on side of efficacy, it's becoming harder to take Merck's press released "study" at face value. Two Indian companies that contracted with Merck have already pulled out of the deal because they believe it has no efficacy against moderate COVID-19 infections. Merck had already suspended its trials on Molnupiravir for hospitalized COVID patients, but in October, Aurobindo Pharma Ltd and MSN Laboratories pulled their studies after the drug failed to yield positive results with those who already had a moderate version of the virus.
The fact that Merck is seeking approval to make this drug a standard of care after their trial only followed up on safety data for 29 days in the human trials is unprecedented. The results of their human "trial" were never published in a peer-reviewed journal, the same as a press release released only on their website. "Merck says" their drug is safe and effective is in line not just for approval in the free market, but for government purchases of over a billion dollars' worth of doses.
In the preprinted results of the study by Ridgeback employees last December, they made mention of toxicity in the bone marrow found in the dogs that were part of the animal trial. Interestingly enough, when the study was published in an actual journal several months later, the reference to toxicity in the bone marrow disappeared. However, in the approval paper from the U.K.'s Medicines and Healthcare Products Regulator Agency, they mention, "Reversible, dose-related bone marrow toxicity affecting all haematopoietic cell lines was observed in dogs at ≥17 mg/kg/day (0.4 times the human NHC exposure at the recommended human dose (RHD))." That is not a large enough dose to achieve toxicity.
Shockingly, the U.K. regulator also concedes that "Carcinogenicity studies with molnupiravir have not been conducted," even though long term cancer risks are always a concern with nucleotide analogues. The agency also revealed that "No clinical interaction studies have been performed with molnupiravir."
Sadly, from everything we have seen with the shots and with remdesivir, the less safety data that is available, the more likely the FDA is to approve the drug — in violation of 100 years of standard protocols for drug approval.
FDA to meet with MRK for its COVID antiviral pill, on 11-30-21 --
The committee will discuss Emergency Use Authorization (EUA) 000108, submitted by Merck & Co. Inc., for emergency use of molnupiravir oral capsules for treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalization.
AS I SAID BEFORE "Cancer causing Molnupiravir is a FLOP, Merck should pull this toxic poison from the market immediately before too much damage is done. Massive class action lawsuits are coming Merck's way if they don't."
SHAME ON MERCK FOR PUSHING THIS DANGEROUS DRUG ON THE UNSUSPECTING PUBLIC!!!!
ACIP also endorsed MRK’s V114 for the same patient pool—but only if followed by Pneumovax. Requiring only one shot—and having broader serotype coverage—is a clear marketing edge for PFE in what will be a very large market.
Ten days have passed since Merck dropped its bombshell announcement about Molnupiravir, its "revolutionary" anti-viral that purports to lessen severe COVID and death by half in vulnerable unvaccinated patients.
But as scientists warn about potential unexamined safety issues with molnupirvavir, analysts at Goldman Sachs are reminding clients that Merck is hardly alone in the race to produce an effective antiviral that could function like the Tamiflu of COVID.
Looking ahead to Q42021 and on to Q12022, Goldman is looking forward to drug readouts from Roche, Pfizer, Shionogi and others developing oral antivirals. Goldman's discussions with clients about the potential influence of antiviralls "...indicate that key questions about oral antivirals largely center on: 1) clinical differentiation among the various programs; 2) data and approval timelines, supply, and pricing; and 3) the potential for pediatric and prophylactic use. Within, we size up the market potential and TAM with our market model and frame key upcoming readouts for the late stage programs. We also provide a list of upcoming catalysts in the category."
For investors seeking "exposure to the antiviral theme", Goldman recommends 1) Roche, as preclinical data for its AT-5227 suggest "differentiation" vs. molnupiravir, 2) Shionogi, whose S-217622 represents an alternative to RNA polymerase therapies, and 3) Divi's Labs, which will ride molnupiravir's coattails.
Cancer causing Molnupiravir is a FLOP, Merck should pull this toxic poison from the market immediately before too much damage is done. Massive class action lawsuits are coming Merck's way if they don't.
Molnupiravir is a prodrug of nucleoside analogue ß-D-N4-hydroxycytidine (NHC), which could potentially be incorporated in mammalian DNA.
One study determined there was evidence that the drug could potentially drive mutagenesis in both viral RNA and mammalian DNA. “It seems unlikely that a short course of therapy would spare the host from this exposure because both RNA precursors that affect the virus and DNA precursors that would affect the host pass through the common ribonucleoside diphosphate intermediate,” concludes an article in the Journal of Infectious Diseases.
SVB Leerink analyst Dr. Geoffrey Porges predicts that FDA would restrict who has access to the drug over safety concerns, according to Barron’s.
In the Phase 3 trial of the drug, the side effects of COVID-19 are apparently worse than that of molnupiravir as patients in the placebo group were more likely to withdraw early than recipients of the drug.
An August article published in the Journal of Infectious Diseases found that ß-D-N4-hydroxycytidine (NHC, 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.”
Last year, the former Head of U.S. Biomedical Advanced Research and Development Authority (BARDA) Rick Bright opposed granting additional funding to develop the drug, partly over safety concerns related to the drug. In a complaint summarized in Science, 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.”
The Science article also quotes the Emory University chemist Raymond Schinazi who stated that his previous pharmaceutical company, Pharmasset, abandoned a similar drug in 2003 after discovering its mutagenic properties.
“When someone is infected by a virus, it makes the cells in their body produce copies of itself. This drug works by causing the machinery that reproduces Covid-19’s genetic material to make mistakes, thereby stopping effective replication. That mode of action could cause problems with our own cells, and while reports are that the drug is well tolerated, we still don’t have full details of any side effects. It’s worth noting that people involved in the trial were instructed to abstain from heterosexual sex or use contraception. While this is routine practice with some other medicines, such as cancer chemotherapy, it suggests that the drug has the potential to cause birth defects should someone become pregnant.
“This news is positive, but we must not be carried away. It would be good for the 50% of patients that it could save from getting seriously ill, but not so much for those who are still hospitalised, despite taking it. There’s currently no way of knowing which group someone will be in. It’s worth remembering that another drug, dexamethasone, was found to save around a third of people who would have died with severe Covid-19, but its clinical introduction did not prevent nearly 100,000 deaths in the UK in the past twelve months.
"Proceed with caution at your own peril, said one scientist who studied the primary ingredient in molnupiravir. Another warned that "biochemistry won't lie": "there is a concern that this will cause long-term mutation effects, even cancer."
Anyone who is dumb enough to take this shit will find themselves staring in the mirror in a few years after getting a cancer diagnosis asking themselves "What was I thinking"?
It isn't even like this is a theory... it WILL happen to many people!
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