New study OBLITERATES Paxlovid and Molnupiravir justification

Paxlovid barely does anything; Molnupiravir may make things WORSE.

Most long-time readers of this Substack will know I have been incredibly pushy about my open disdain for Molnupiravir, which I believe does nothing — at best — while posing unacceptable risks.

But I will do a very concise backgrounder for those who are interested. Scroll down to the section 2 if you have heard these rants on this before!

1. Backgrounder on Molnupiravir

Frankly, the “randomized” control trials were a joke. The interim results showed a strong benefit for the drug; however, the second leg of the trial clearly showed a large negative effect. The trial was stopped early “for ethical reasons”. In other words, the argument was that we can no longer deny this fantastic drug to the public!

Of course, the main problem in the trials was poor randomization. Prior to the interim analysis, individuals with the worst comorbidites were disproportionately found in the placebo group. I am curious if the trial runners did not have their hand slapped because in the post-interim period, the randomization was better (though, not weighted in favor of the placebo group to make up for the pre-interim period). And yes, I am implying this may be a classic case of the researchers not actually being blinded.

When the trial ended, the results were barely statistically significant. It may have even been a case where a single extra hospitalization in the drug-arm of the trial would have wiped out any statistical significance. Another reason I suspect the researchers were not blinded. Despite the trial being ended early, and fair randomization never achieved, the researchers did not adjust the analysis to account for the disproportion in comorbidities probably because there was no way to actually do so in a way that makes the drug look good.

There were also two subsequent trials out of India that ended early because no benefit from the drug could be found, though they never published the results (quite common in pharmaceutical research and an abhorrent practice in my opinion).

Yet, regulators still approved the drug. Absolutely nothing was mentioned about the poor randomization in the approval process. The regulators were aware of the ridiculous mechanism through which Molnupiravir is supposed to act — by inducing mutagenesis in the virus. Yet, they dismissed it as a non-factor. In fact, the biggest push-back in the approval process was from a woman who said she wouldn’t want to take this drug when pregnant. Shit. Fair enough. But I wouldn’t want to take this drug when not pregnant.

That’s the basic concerns I have with Molnupiravir, but if pressed I could find many more. I do not have a similar rant for Paxlovid. However, if you are interested, may I suggest reading some Igor Chudov?

Paxlovid, "Snake Oil" of the 21st Century?

2. Hong Kong study design

The study is a retrospective cohort study of 93,883 patients in Hong Kong with an observation period between February 16th and March 31st. In totality, there were 83,154 individuals that did not receive antiviral treatment; 5,808 received Molnupiravir; and 4,921 received Paxlovid. Individuals were identified in clinic settings through testing and were excluded from the evaluation if they were hospitalized on the same day as testing positive. Finally, characteristics of individuals in the different cohorts were then matched using propensity scores to adjust for in-group differences like underlying health conditions.

It should be noted that the main limitation of propensity score matching is potentially excluding important covariates. Building on this limitation, the researchers offer two potential explanations for Molnupiravir’s lack of effectiveness:

(1)

“The apparent lack of effectiveness in reducing hospitalization by molnupiravir might partly be related to its availability in earlier days when our local guideline limited its use to patients at highest baseline risk, namely advanced age (70 years old or above) and unvaccinated status".

(2)

“In addition, molnupiravir was preferentially prescribed to more frail patients with multiple comorbidities and polypharmacy than those who received nirmatrelvir/ritonavir, perhaps because of the multiple DDIs associated with the latter".

Both arguments against the results are weak if you believe the researcher’s choice in propensity score covariates. For what it’s worth, the researchers point out that there was no evidence to suggest that either point is a large concern.

Generally, I believe the researchers did not leave much out in the way of important covariates except, perhaps, those which they could not have observed due to the nature of the analysis. I do wonder if there could have been a justification for adding societal status/income level in this particular set of propensity scores. My reasoning would be that individuals with higher social status would be better cared for at home and would receive better treatment at hospitals. They would also be more likely to receive expensive antivirals.

In theory, this would make the antivirals appear more rather than less effective; however, my argument would be pure speculation. There is a wide literature of health economics that would suggest people higher in the societal ladder have better health outcomes, something that seems like it would be heightened in a place with a huge disparity in living standards, but I do not have case-specific proof of relevance. I am certain that the authors did not have that data available in any case.

3. Results

The results are, well, pretty devastating for both antivirals.

Molnupiravir in both the general population and those aged over 60 or under 60 with comorbidities did not reduce the risk of hospitalization or death even after weighting. In fact, the chance of hospitalization or ICU admission/IMV (invasive mechanical ventilation) use/death increased after using the antiviral. While the increase was not statistically significant, the best that can be said about the drug is that it did nothing at all.

For Paxlovid, the results were slightly better. The antiviral did result in a small reduction in the risk of hospitalization and a slight but not statistically significant reduction in ICU admission/IMV use/death; furthermore, the reduction in hospitalizations was significantly lower than in the randomized control trials. The inherent problem with most drugs is a small benefit is never enough due to side effects. In this case, one has to question whether the benefit is even enough to cover the risk of doctor mistakes, misconduct, or patient misuse of the drug (ie., not accounting for drug to drug interactions).

Below are visualizations taken from the study. First is cumulative incidence of hospitalizations:

And the second is cumulative incidence of ICU admission/IMV use/death.

Again, not a pretty picture for either drug, and a far cry from what the randomized control trials claimed.

4. What’s next?

We are currently waiting on the results of two more trials for both drugs, which will be some of the largest trials ever run on antivirals: RECOVERY and PANORAMIC. I am hopeful that these trials will bring forward a justification to outright revoke emergency use authorizations for Molnupiravir everywhere.

For Paxlovid, I am less hopeful. There is simply too much regulatory capture when it comes to Pfizer products and even a tiny amount of efficacy coming out of these trials will be enough to keep this drug on the market unless the Paxlovid rebound story gets enough negative publicity.