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The Extraordinary Hypocrisy of Molnupiravir
The Representation of Merck's Molnupiravir as a "Game Changer" Only Underscores a Bias - And Merck Has Other Data It Is Not Sharing
Trigger alert: This article may upset those who care about other human beings.
Molnupiravir (mull-noo-’peer-aveer) is the talk of the town, belle of the ball in the press. “Game changer” is the word on the street, according to a message to Science Insider:
“Molnupiravir is unquestionably a game changer! The large effect size, and the ease of administration change the paradigm of mild COVID-19 treatment with a potential to reduce COVID-19 death rates.” See: Science Magazine
The hype even included Fauci going on in an interview about how the idea that molnupiravir is so effective that the vaccine won’ t be needed.
“That’s such a false narrative” Fauci aped at the camera.
What’s all the excitement & hype about?
Well for one, Merck reported no deaths in the molnupirvir group, but there were eight deaths in the placebo group.
Great news, right?
Hold on there. This is an interim analysis. On non-hospitalized patients. (See the Phase 3 MOVe-OUT trial record at ClinicalTrials.gov)
Why, when the litany of studies have been published on the efficacy of off-label use of hydroxychloroquine and ivermectin, has the media been silent or hostile to the published studies? When meta-analyses find that the studies - both randomized clinical trials and observational studies - spanning the range of prophylaxis, mild, moderate and severe COVID-19 support immediate adoption for early treatment using ivermectin especially - why in the world is Merck’s molnupirvir interim analysis given the spotlight?
Slow Down, People. The Molnupirvir Study is ONE Study (And It’s Not Even a Study) In Non-Hospitalized People Without HIV, Hepatitis or Liver Disease. And the Hospitalized Patients - They’re Found in A SECOND, BURIED Study.
Before we get too excited about molnupirvir, let’s remember that there are 29 studies on ivermectin and 32 studies on hydroxychloroquine totaling over 26,000 and 54,000 patients combined, respectively.
Merck’s non-peer-reviewed molnupirvir interim analysis report study? Only 775 patients.
According to the US press, with 775 patients in the Merck study, 7.3% of patients given molnupiravir were either hospitalized or died 9 days after treatment, compared to the 14.1% of placebo patients.
None died, but 7.3% were hospitalized.
And 14.1% on placebo died.
Placebo? Died? When there is a vast amount of published research on clear winners are the early treatment protocols as described by the medical authorities on the matter? (See “Who Are the World’s Leading Authorities in COVID-19 Treatment?”)
Merck and NIH allowed 14.1% of people in the control arms to develop severe COVID-19 and die with no treatment. None. Just placebo. How did the NIH and the FDA let this happen in the face of the evidence of efficacy of early treatment? How could they?
Because that’s the standard of care for early COVID-19: go home, incubate, get sick, and die if you must. But don’t call us until you are seriously ill.
Related: Stat News: NIH Director Francis Collins to step down
But Wait, There’s More
There’s a few other issues with the molnupiravir study the public should know about - and they should let their legislators and regulatory agency regents know that we know about as well.
Like, for example, it’s not clear if Merck actually had 775 patients. According the ClinicalTrials.gov entry, it was a Phase 2/Phase 3 combined phase trial with six arms, and an enrollment of 1450 patients. It’s bad enough that combining Phases 2 and 3 prevents the development of knowledge confirming adverse events. But where are the rest of the patients?
Why the difference between 775 and 1450? The “study” (actually a press release) was an ‘interim analysis’. The problem is the data are in for all 1450 patients. So why and how was this “interim analysis” allowed? When will we see the rest of the data?
Two Studies, One of Which Merck Didn’t Report in Their Press Release
Recall that the study was in non-hospitalized patients so they could study hospitalization rates and deaths. Got it.
Fine, but there’s also an entirely different study on hospitalized patients that appears to have been - get this - “terminated for business reasons”.
According to the US government’s official record of the trial at ClinicalTrials.gov, THAT study is “Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001”).
The study aims are “to evaluate the safety, tolerability and efficacy of molnupiravir (MK-4482) compared to placebo. The primary hypothesis is that molnupiravir is superior to placebo as assessed by the rate of sustained recovery through Day 29.”
The intended number of patients was 1300. The number of patients in the terminated study of hospitalized patient? 304.
The reason given why the study was terminated? “Business Reasons”.
Study Changes on the Record
According to a comparison of the initial study protocol, the following change were made to the hospitalized study protocol since it was initially submitted to the NIH database:
(1) Completion date of Oct 18, 2021 (Anticipated) WAS CHANGED TO August 11, 2021 (Actual)
Why did the study terminate early, with no (not even interim) results?
(2) Study enrollment: 1300 [Anticipated] WAS CHANGED TO 304 [Actual]
With all of the hospitalizations and deaths from COVID-19 around the world, clearly they could have accrued patients more easily?
(3) Percentage of participants with an adverse event (AE)
[ Time Frame: Up to 19 days WAS CHANGED TO Up to 7 months ]
Was this an attempt to hide rapid-onset adverse events with the “fog of COVID-19” to allow morbidity and mortality to “even out” among study arms?
(4) EXCLUSION CHANGE: “Has an active diagnosis of hepatitis due to any cause” WAS CHANGED TO “Has history of Hepatitis B or Hepatitis C infection with any of the following: 1) cirrhosis 2) end-stage liver disease 3) hepatocellular carcinoma 4) aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal at screening. Has a history of acute pancreatitis within 3 months prior to randomization or a history of chronic pancreatitis”
(5) EXCLUSION CHANGE: “participants with a recent history of mechanical ventilation not associated with COVID-19, or participants with conditions that could limit gastrointestinal absorption of capsule contents” WAS CHANGED TO “participants with a recent history of mechanical ventilation, or participants with conditions that could limit gastrointestinal absorption of capsule contents”
The clinicaltrials.gov entry lists an astonishing 89 performance sites; with 304 patients, that’s an average of 3.4 patients per performance site.
Was this even a serious attempt at a study?
Notably, none of the actual data from the trial is posted to ClinicalTrials.gov (See Science.org: FDA and NIH let clinical trial sponsors keep results secret and break the law ).
What does this all mean?
Under Merck’s own data, if everyone took the drug in the early phases, we’d still see half of the patients hospitalized. So the study certainly could have continued. In a basic analysis, it means that somehow 304 hospitalized COVID-19 patients in the care of physicians accruing patients for Merck for the studies of molnupiravir were, in fact, enrolled in a study - but the results not mentioned by Merck in their press release. It also means that the study was having a hard time finding and enrolling COVID-19 patients that did not have to be excluded from the trial. These criteria include (wait until you read the last one):
Has critical COVID-19 with any of the following: respiratory failure (including endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (flow rates >20L/min with fraction of delivered oxygen >= 0.5), noninvasive positive pressure ventilation, or extracorporeal membrane oxygenation (ECMO))
Is on dialysis or has reduced estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 by the Modification of Diet in Renal Disease (MDRD) equation
Has any of the following conditions: human immunodeficiency virus (HIV) with a recent viral load >50 copies/mL or cluster of differentiation 4 (CD4) <200 cell/mm^3; chemotherapy required within 6 weeks before randomization; a neutrophilic granulocyte absolute count <500/mm^3; autologous or allogeneic hematopoietic stem cell transplant recipient
Has history of Hepatitis B or Hepatitis C infection with any of the following: 1) cirrhosis 2) end-stage liver disease 3) hepatocellular carcinoma 4) aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal at screening
Has a history of acute pancreatitis within 3 months prior to randomization or a history of chronic pancreatitis
Is taking or is anticipated to require any prohibited therapies
Is unwilling to abstain from participating in another interventional clinical trial through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics
Is anticipated to require transfer to a non-study hospital within 72 hours
Has a baseline heart rate of < 50 beats per minute at rest
Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization
Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator
Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to: participants who are not expected to survive longer than 48 hours after randomization or participants who are expected to require mechanical ventilation within 48 hours after randomization or participants with a recent history of mechanical ventilation or participants with conditions that could limit gastrointestinal absorption of capsule contents”
So did Merck’s study of molnupiravir in hospitalized patients fail in spite of attempts to give the drug its best chance at success? That is, did they terminate the study due to lack of efficacy in late-stage COVID-19? If so, the public has the right to know under the rules governing clinical trials. “For Business Reasons” is not a scientific or medical reason to terminate the study.
Did Merck cherry-pick their results and cherry-pick one of two studies for their press release. Who knows? Seems they left out some critical information.
Translational Failure Seems Assured
When a patient tests positive for COVID-19, they and their doctor (if their doctor is even involved) do not know if they are going to be hospitalized. And clinical practice is sporadic - a patient might be given a treatment the day of the test or five days after, depending on their aggressiveness for pursuing care. A central tenet of translational science is that clinical studies that are conducted on a restricted population, the inferences made about the efficacy and safety of the drug is restricted to that population, and generalizations cannot be made to populations that are excluded.
To make unwarranted generalizations to untested populations is a type of translational failure.
If, by any stretch of reason, FDA approval is made using the one interim analysis of (potentially) cherry-picked data in a cherry-picked study published as a press release without peer review, ignoring the data from the study not mentioned at all- their guidance should carry restrictions disallowing the use of the drug on or by patients in all of the excluded groups, including those who are hospitalized.
To avoid translational failure, the drug is (at best) for mild to moderate cases of COVID-19 and has not been shown to be effective in late-stage COVID-19. It has also not been shown to be effective in people who have renal failure, HIV, Hepatitis or any liver disease, or those who require “prohibited therapies” (whatever those are), in people who have low platelet count, or in anyone who is expected to have severe COVID-19 or expected to die from COVID-19.
And the drug, of course, would, in a consistent world in which all other treatments, even those with strong, reproducible evidence of efficacy have been denied to COVID-19 patients, only be permitted for use on non-hospitalized patients, because the data on that group is not published… yet.
Of course, the terminated-for-business-reasons study could have results that actually show promise. We’ll never know that though, because publication is per Merck’s discretion (in spite of rules about hiding negative or unsuccessful results).
I am not saying Merck ran an extra trial to bury hospitalized patients to improve the efficacy of their drug in the first trial, but some might consider that possibility.
It is unlikely that the data on the efficacy and safety of molnupiravir on hospitalized patients will ever see the light of day.
Unless, of course, the rules in place are enforced, as NIH and FDA has promised.
But don’t hold your breath. Biden has a new plan to create a new agency known as ARPA-H, which would fund “ambitious research projects too risky for private investors to back them” (StatNews).
If by some miracle the rules on full reporting are enforced for the buried molnupiravir trial, the identified data from the trials need to be audited to make sure patients with an undesirable outcome under one trial were not excluded because they were enrolled in another trial focused on studying that same outcome.
That would point to more scientific chicanery, and we’ve all had more than enough of that.
James Lyons-Weiler, PhD
Translational Scientist/Senior Policy Analyst
October 5, 2021
FDA Ups the Ante and Sends First Notice of Noncompliance for Failure to Submit Clinical Trial Results https://www.jdsupra.com/legalnews/fda-ups-the-ante-and-sends-first-notice-7392067/
FDA Takes Action For Failure to Submit Required Clinical Trial Results Information to ClinicalTrials.Gov https://www.fda.gov/news-events/press-announcements/fda-takes-action-failure-submit-required-clinical-trial-results-information-clinicaltrialsgov