At best, molnupiravir (MOV) is a useless drug we’re wasting $$ on. At worst, it could accelerate the emergence of novel variants with unpredictable characteristics. First I’ll explain why MOV is useless. Later, I’ll present evidence I’ve found that it could be dangerous. 1/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
The phase 3 clinical trial for molnupiravir took place in 2021 & had two parts: 1st half from May-September, 2nd half from Sept-Nov. They showed opposite results. (I’ll be using the superb paper by @GidMK below throughout this thread.) 2/ https://t.co/WH0NRORrJ6
— Ryan Hisner (@LongDesertTrain) October 4, 2022
All subjects were unvaccinated. In part 1, molnupiravir reduced hospitalization/death by about 50% compared to placebo. In part 2, MOV *increased* hospitalization risk by ~35% compared to placebo. 3/ pic.twitter.com/V1SHu7iRY7
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Unsurprisingly, Merck only wanted pt 1 of the trial considered for their EUA application. They argued only the 1st half of the trial should be considered because….reasons. Luckily, their attempt to end the study halfway through was thwarted by quick recruitment. 4/ pic.twitter.com/QiYNg4NJw0
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Unsurprisingly, Merck only wanted pt 1 of the trial considered for their EUA application. They argued only the 1st half of the trial should be considered because….reasons. Luckily, their attempt to end the study halfway through was thwarted by quick recruitment. 4/ pic.twitter.com/QiYNg4NJw0
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Merck’s attempt to erase the negative—indeed, harmful—results of the second half of the molnupiravir clinical trial is utterly farcical, yet brazen distortion of data is so common in the industry that this hardly excited any attention or censure. 5/ pic.twitter.com/WlHwdELVVT
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Furthermore, of the ~20% of study subjects with evidence of prior infection, outcomes were *worse* for the MOV group than placebo group. Outcomes were also worse for those with diabetes. 7/ pic.twitter.com/9FGqEalq0k
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Here is our situation: The evidence shows molnupiravir is either useless or harmful in those not Covid-naïve, i.e. who’ve been infected, vaccinated, or both—a description that now fits ~100% of the population. Yet MOV is still FDA-approved & widely used. 8/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
FDA is complicit in Merck’s plundering of the public. This is all unsurprising in a system based on patent monopolies, which provide enormous incentives for fraud & corruption. Until they’re abolished, nothing will change. 9/ https://t.co/wyaNKAJI46
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Much else about the MOV clinical trial is sketchy. The deck seemed slightly stacked in favor of the treatment group in almost every way. MOV group had a lower % than placebo group in both part 1 & the full study for most risk factors. 10/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Apart from serious heart condition, all the most serious risk factors were overrepresented in the placebo group, the difference then being made up by the least serious risk factor, a BMI ≥ 30, which describes about half of US adults. 11/ pic.twitter.com/JS6iq5cfcA
— Ryan Hisner (@LongDesertTrain) October 4, 2022
The >3-fold difference in COPD% for pt 1 is striking. Disparities were largest in the part 1 sample, as one would expect, as part 1 was crucial for narrative-setting & PR purposes & with pressure for successful results at its most intense. 12/ pic.twitter.com/3a9jZYFgG4
— Ryan Hisner (@LongDesertTrain) October 4, 2022
This risk-factor bias in favor of the molnupiravir group would probably not have a huge effect on overall outcomes, but it likely mattered here: One less hospitalization in the placebo group would’ve rendered overall MOV benefit statistically non-significant. 13/ pic.twitter.com/UvXXRWtBTI
— Ryan Hisner (@LongDesertTrain) October 4, 2022
In fact, the # of placebo-group hospitalizations *was* 1 less than reported, but peculiarly, any patient lost to follow-up was counted as hospitalized. How hard do you think they tried to find that last placebo group subject, on whom the study’s results depended? 14/ pic.twitter.com/r8vuxzjyYL
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Moreover, if you simply adjust for the underrepresentation of males in the molnupiravir treatment group, the trial results become nonsignificant, as the study authors were kind enough to inform us, though they try to put a positive spin on it somehow. 15/ pic.twitter.com/Xsd4kEAztA
— Ryan Hisner (@LongDesertTrain) October 4, 2022
All this is trivial next to other molnupiravir red flags. For example, three trials were done which found no benefit for molnupiravir over placebo—including one trial that was stopped early due to a higher death rate in the MOV group. 16/ pic.twitter.com/b6EBat1ifS
— Ryan Hisner (@LongDesertTrain) October 4, 2022
These negative studies simply weren’t published in journals, and the FDA, instead of demanding an explanation from Merck, simply pretended they never happened, making the whole EUA approval process a farce. The FDA is a subsidiary of Big Pharma. 17/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Another suspect aspect of the trial: the hospitalization rate in the placebo group was extraordinarily high in part 1 of the trial—14.1% compared to 3-7% for similar mAb trials & 4.7% in pt 2 of the MOV trial—for no apparent reason. 18/ https://t.co/TAFTQ5CGBy
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Merck later announced a different “successful” trial that was obviously fraudulent. The authors weren’t even competent frauds. They barely attempted to disguise the scam. Merck pretended not to notice & touted the results. We’ve entered farce territory. 19/ pic.twitter.com/G7Csh4BN8n
— Ryan Hisner (@LongDesertTrain) October 4, 2022
More statistical chicanery & other Merck malfeasance is described in the @GidMK paper “Making Statistical Sense of the Molnupiravir MOVe-OUT Clinical Trial,” which I highly recommend you read. 20/ https://t.co/cbPdLuXz98
— Ryan Hisner (@LongDesertTrain) October 4, 2022
But molnupiravir is more than just a crap drug. It works by causing random mutations throughout a virus’s genome. Potentially, this could accelerate the evolution of SARS-CoV-2 variants. See this @michaelzlin thread for more details on this aspect. 21/ https://t.co/bMmRjfw2te
— Ryan Hisner (@LongDesertTrain) October 4, 2022
But is there evidence molnupiravir is causing increased mutations, potentially fostering novel variants with unpredictable characteristics? AFAIK, no one is monitoring MOV use or even trying to determine its safety in this respect—regulatory negligence. 22/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
However, I’ve recently come across multiple hypermutated SARS-CoV-2 sequences that have every sign of having been created by molnupiravir. First, let’s review what some of these telltale signs are. 23/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Instead, we see mutations highly concentrated in spike, which makes up a relatively small portion of the SARS-CoV-2 genome. ORF1ab, OTOH, makes up about 2/3 of the genome. If mutations were randomly distributed, we’d expect ~60-70% to occur in ORF1ab. 25/ pic.twitter.com/vsH6JoJzjd
— Ryan Hisner (@LongDesertTrain) October 4, 2022
This is almost never the case with hypermutated sequences, where ORF1ab mutations are usually pic.twitter.com/hefE3qecrM
— Ryan Hisner (@LongDesertTrain) October 4, 2022
The nucleotide mutations induced by molnupiravir are of a specific type called transitions (as opposed to transversions). More on this below. 27/ pic.twitter.com/kJWXwVIh6C
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Transitions are T—>C, C—>T, A—>G, and G—>A. Everything else is a transversion: G—>T, T—>G, C—>G, G—>C, A—>C, C—>A, A—>T, and T—>A. (T = U for our purposes. Some diagrams/lists use T, some U.) 29/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Various nucleotide mutations occur at very different frequencies. Here are the relative frequencies of the 12 possible nuc mutations in SARS-CoV-2; bottom compiled by @alchemytoday & top based on @richardneher‘s data here. 30/ https://t.co/ceHuPkeh92 pic.twitter.com/fKnzsoUmjS
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Using the Neher numbers (which I converted into percentages—any mistakes are my own), the ratio of transitions to transversions (Ts/Tv) is 2.03:1, meaning we should expect to see twice as many transitions as transversions on average. 31/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Finally, nucleotide mutations can be synonymous or nonsynonymous. Synonymous nuc mutations change the amino acid (AA) coded for. Synonymous nuc mutations do not cause an AA change & therefore have little to no effect on the virus. 32/ pic.twitter.com/AM97uSSudU
— Ryan Hisner (@LongDesertTrain) October 4, 2022
In hypermutated, chronic-infection sequences, we see an unusually high percentage of nonsynonymous nuc mutations, usually >80%, indicating that these nuc mutations result from strong selection pressure. 33/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
So what would a molnupiravir-created sequence look like compared to other hypermutated genomes?
— Ryan Hisner (@LongDesertTrain) October 4, 2022
• Mutations more randomly distributed, with >50% in ORF1ab
• Ts/Tv ratio of much higher than the typical 2:1
• Lower % of nonsynonymous nuc changes, probably <70% 34/
I’m going to present few examples of sequences that fit this description. To save space, they will all be given in picture form. One was collected in late August, the others in September. Here’s sequence #1, a BA.5.2.1. 35/ pic.twitter.com/9bMSWcI2wt
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Sequence #2, a BA.2.3. By the way, all these sequences come from countries that have approved molnupiravir for use (though I’ve heard unlicensed generic use is widespread in some countries as well). 36/ pic.twitter.com/9PJhspbaWr
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Sequence #3, a BA.1.1 37/ pic.twitter.com/zluTLxmYV6
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Sequence #4, a BA.4.1.1. This sequence has many more mutations than is listed here, but it was a low-coverage sequence, so many are not visible. In particular, there are likely >2x as many spike mutations as the ones listed. 38/ pic.twitter.com/pmWFwfixwV
— Ryan Hisner (@LongDesertTrain) October 4, 2022
Could there be other explanations? Maybe? I’m not an expert, and these are very complex matters. If anyone has alternative explanations for these bizarre sequences, please comment. 40/
— Ryan Hisner (@LongDesertTrain) October 4, 2022
