FDA Votes on Molnupiravir

While Paxlovid Remains Illegal and is expected to remain illegal for at least several weeks, the FDA did manage to finally meet to discuss whether or not to legalize the other Covid-19 treatment pill, Merck’s Molnupiravir. While later data reduced effectiveness estimates from 50% to 30%, that’s still much better than 0% and it uses a unique mechanism that can probably be profitably combined with other treatments, so one might naively think that after sufficient stalling for appearances this would be easy.

One would be wrong. The vote was 13-10, was restricted to those at high risk, and could easily have failed outright.

I may want to later refer back to this, so it’s splitting off into its own post.

High Level Summary

Usually we get live-blogs from Helen Branswell and Mattew Herper. They held off and only issued a summary post later on this time, perhaps because the meeting was too painful. Luckily, my commenter Weekend Editor is excellent at summarizing such meetings, so I’ll quote their summary in full, link goes to their full post. After the summary, I’ll note the salient other details in the full post.

Today the FDA’s AMBAC meeting voted to recommend molnupiravir get an emergency use authorization. But just barely: 13 yes, 10 no, 0 abstentions. And with a lot of caveats among the yes votes.

Some issues:

(a) The efficacy vs hospitalization was “wobbly”: the interim report had 48.3% (CL: 20.5% – 66.5%) efficacy, but when they added the rest of the data it was only 30.4% (CL: 1.0% – 51.1%). People thought this might mean there were responder/nonresponder populations, and nobody knew a biomarker to distinguish them.

This is an interesting mix of good and bad thinking. Yes, it’s possible that the 50% vs. 30% thing wasn’t random, but why is that an issue here?

If you have a drug with 30% efficacy, that’s good. If you have a drug that is 50% effective half the time and 10% effective the other half, depending on who it is used on, and you can’t tell who is who, then you still have a 30% effective drug.

The difference is that because of the way you are now stacking your coin flips, it feels like you are now giving a 10% effective drug to some people without knowing it? Or there’s the ‘problem’ that if you knew more you could differentiate between the two populations, so now you have an imperfect procedure and it wouldn’t be ‘ethical’ somehow to proceed, or you’re blameworthy when the drug doesn’t work in a particular case?

I’m glad this didn’t cause a veto for enough voters, but consider that if this wasn’t an emergency situation, it might have caused one, despite being good news since it opens up the possibility of doing better once we know more.

Then again, perhaps the argument is that experiments are illegal except for getting drugs approved, so if we approved the drug we’d never run the experiment? Which has a certain kind of dystopian logic to it, I suppose.

Of course, same as it ever was, we stopped the study when the early results looked so good, and now we’re saying the results are at most barely good enough…

(b) While the mechanism and efficacy calculations from Merck were quite convincing, the FDA showed there were some issues with mutagenicity, particularly in the first trimester of pregnancy. (And I have to apologize: I got bored, and went grocery shopping at this point, stocking up in case the Omicronomicon gets loose. So I missed most of this, and am too tired to go back and listen. Maybe tomorrow.) Any woman will only get Molnupiravir after a negative pregnancy test.

Points for Omicronomicon, that’s great, and given the timing I hope it was all dry goods that will keep for a long time. In any case, a pregnancy test is quick and cheap, and damaged babies are considered quite bad, so I have no issue with this requirement, even though in practice it’s going to be painfully dumb a large percentage of the time. Given this is a treatment for those already sick, it would take a very large concern to make taking this a bad idea otherwise.

(c) One point in favor was that people thought the efficacy of monoclonal abs will fade with Omicron, so they want an alternative. OTOH, they also said if there’s “another oral medication” with higher efficacy with less side effects (think Paxlovid!), then the FDA should reconsider Molnupiravir. So Molnupiravir may get approved for like a month or so until Paxlovid blows it away? They so carefully didn’t mention Paxlovid that I wonder if there was some legal constraint.

This is of course completely crazy and illustrates how twisted their frameworks have become. Molnupiravir and Paxlovid are probably complements because they have different mechanisms, and the existence of a life saving medicine (that is currently illegal, thanks to you murderous madmen) is no reason to then make a different lifesaving medicine illegal because there’s a better option. If Paxlovid is legal and available and so is Molnupiravir, are they worried people who could have been given Paxlovid won’t be given Paxlovid?

Then there’s the crazy of the monoclonal abs argument and the ‘need’ for this new treatment as a justification. Once again, these treatments are complements, and also I can’t help but notice that a lot of people are dying of Covid-19 and we’re worried about a lack of hospital capacity and all that? It’s like the FDA thinks you only get one treatment (because who would dare use more than one without a Proper Scientific Study and a Standard of Care, or something) and therefore they have to ban all but the best treatment no matter the issues of cost and supply? The hell?

(d) Listening to the voting statements was almost painful: the AMDAC members were clearly conflicted.

So the recommended EUA only for high-risk individuals, mostly the unvaccinated or those who had suboptimal response to vaccination.

Pending FDA administrative action, Molnupiravir is EUA’d… sort of.

When they tried this insanity with boosters, limiting who can have access without legal liability to life saving medicine and thus allowing people to die, in order to satisfy arcane ‘ethical’ requirements, the states increasingly overruled the FDA. I very much hope that they do this again. But I fear that given the ‘mutagenicity’ issue doctors will rightfully fear lawsuits from people who claim nonsensical ‘mutations’ happened to them, and so won’t be able to give Molnupiravir to a lot of their patients, resulting in a bunch of people dying and hospitals filling up faster.

Seems like the most important action is to hurry along to the Paxlovid hearings, no?

Yes, still true, although they now have a distinct downside. They may lead to a lifesaving medicine, that is currently on track to be at least sort of legal, becoming illegal once more.

And it’s only on track to be legal rather than legal, with substantial doubt, because the FDA administer has to sign off, then the CDC advisory committee has to meet and then the CDC management has to approve. Given what we’ve seen so far, all of these steps are at risk.

However, it’s also important to note this concern, even if it didn’t make the comment summary and seems like it wasn’t considered too important:

There was also some concern that the induction of high mutation rates in the virus might, if it doesn’t go far enough, create a troublesome new variants.

This does seem like a real concern if it’s even slightly well-founded, and a good reason to consider not approving the drug. The downside of doing this could be very, very high. If this was the reason given for rejection, I might even accept it. Here’s what the Stat news summary had to report about that.

Panelists also worried about data showing that use of molnupiravir might, in theory, lead to new variants of the SARS-CoV-2 virus through its mechanism, which works by causing viruses to make mistakes in copying their genetic material.

“With all respect, I think it’s incumbent upon you to make some effort to make an estimate of what is the likelihood of escape mutants occurring as a result of your drug,” said James Hildreth, a panelist and the CEO of Meharry Medical College.

However, other panelists, including John Coffin, a Tufts molecular biologist, argued that the overall risk of such mutations due to the drug was small.

It seems appropriate here to have some amount of model error, and to actually do the calculation.

That’s the high level result.

Key Facts

There’s always a lot of good information at these meetings. What is it important to know?

Here’s the protocol:

The drug is administered 2ce per day for 5 days at a dose of 800mg (in the form of 4 capsules of 200mg each, so the dose can be titrated down, perhaps?).

Treatment must start within 5 days from symptoms. That’s empirically important, as shown here. The reduction in viral load over time is dramatic for intervention before 5 days past symptoms (left), but it is an order of magnitude weaker for intervention after 5 days of symptoms (right). That means we need to have a testing system which is widely available, cheap or free, and fast!

This also means that if you catch the problem quickly, we would probably see much better than 30% efficacy. This effect has to be continuous, there’s nothing special about five days in particular.

There were 10 subject deaths during the trial, but 9 were in the placebo arm. As a crude indication of safety, that’s pretty good. There were a lot of other safety studies, both in vitro, in animals, and in surveillance of the trial population. The trial seemed pretty safe, with adverse events in the placebo arm about the same as treatment. There is some worry about mutagenicity, particularly during organogenesis in pregnancy when messing with human RNA could be a bad idea.

The safety profile definitely more than passes my bar of ‘if this is unsafe then it’s nowhere near as unsafe as not using it so give it to me.’ If I get sick, I want treatment, and yet they are intending to make it illegal for me to get it, even outside issues of ‘delay.’

For a drug with 30% efficacy against hospitalization, that’s a rather good ratio. Sample size is small, but I suspect that the 30% is an underestimate.

There is no doubt this improvement is due to virus clearance, since they measured SARS-CoV2 RNA at baseline, day 3, and day 5. The reduction, as measured by log of mean difference and its 95% CL, is significant as shown here. It’s not just making people feel better, it’s doing so by a mechanism that makes sense and is related to the disease process.

It works. Weekend Editor notes this graph.

Weekend Editor suggests Molnupiravir might reduce everyone’s risk down to a similar baseline, based on this graph, which is interesting. Then again, have we considered that these sample sizes are too low and that’s why everything’s so noisy ? Still it is suggestive, and it is suggestive that the effective reduction in hospitalization and death could be much higher than 30% in practice.

This is the de rigeur Kaplan-Meier plot. It shows hospitalizations versus time, for the treatment arm and control arm. There’s a log-rank statistic that shows this difference is significant, i.e., the spread between the 2 curves is real.

The logistical difficulties of getting the drug to people within 5 days of symptoms looked daunting to some AMDAC members.

If five days is daunting, how are we going to get Paxlovid to people within three? Also, seriously, five days is an insanely long amount of time, if it’s not enough then FIX IT.

The Actual Decision

It’s good to have a reference handy of how everyone voted, to compare with other votes in the future, or for other reasons.

From the Stat news summary, some insight into what some people were thinking.

“I think we need to stop and acknowledge that the whole reason we’re having this discussion is because the efficacy of this product is not overwhelmingly good,” said W. David Hardy of Charles Drew University School of Medicine and Science during a discussion about the drug’s use during pregnancy. “And I think that makes all of us feel a bit uncomfortable about the fact whether this is an advance therapeutically because it’s an oral medication, not an intravenous medication.”

Then again that seems to directly contradict this summary viewpoint from the same article:

In the end, panelists narrowly voted that the benefits of having an oral Covid treatment to keep people out of the hospital outweighed their questions and concerns. But the FDA may write a far narrower authorization for the drug than observers would previously have expected.

This suggests that being an oral treatment was (correctly, I’d presume) considered an important advantage?

It also suggests that this decision was indeed very close and another similarly effective drug could easily have been rejected in this spot.

What is ‘overwhelmingly good?’ I’m guessing that if it were standard of care, and someone were suggesting not using it, the 30% would be enough to make this seem completely crazy and unacceptable. It’s all about framing.

It has to be ‘an advance’ because one does not simply use it in addition to other tools, and it’s a disadvantage that it is an oral medication in the context of whether it is ‘an advance’ in this other sense, even though in terms of usefulness it is a rather big advance, and the process is looking at a bunch of veto considerations rather than doing a cost-benefit analysis.

Takeaways

  1. When you stop a trial early, you sometimes don’t get enough data.
  2. This lack of data can then endanger approval. We have a concrete example.
  3. The vote was 13-10 and at best we’re likely to get a narrow authorization. If many of you want Molnupiravir, you won’t be able to get it, and it’s possible no one will be able to get it.
  4. The FDA is even more willing to deny us life saving medicine than we previously expected. We should worry more about this, not less.
  5. Pregnant women probably shouldn’t take Molnupiravir, and pregnancy tests will be required before the drug is given out.
  6. There is one other real potential worry about Molnupiravir, that it could create new variants. This does not seem to have been a major consideration, nor does a probability or cost-benefit assessment seem to have been done here, and the 13-10 vote was due mostly or entirely to other reasons.
  7. Chances seem good that this can be a >30% effective treatment in practice, among those who get it in time and are allowed to get it. I’d be far more surprised by substantially lower than 30% than by substantially higher.
  8. Paxlovid remains so illegal the FDA can’t even say its name in meetings.
  9. FDA Delenda Est.

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26 Responses to FDA Votes on Molnupiravir

  1. lunashields says:

    “High risk” means everyone can get it in practice. “former smoker” and boom

    • Matty Wacksen says:

      Exactly. If covid-19 has taught me anything, it is that a surprisingly large number of people think of themselves as “high risk” because they have some kind of medical condition. Given the fact that lots of people – and also doctors – think covid-19 is far more dangerous than it is, I’m not sure whether “drug that may or may not help against covid, but also may or may not cause cancer in 10 years” is something obviously positive.

      I mean I don’t think the FDA should exist, but if you start with the premise that the FDA is morally responsible for the effects of drugs people take, then I don’t know if they should approve this one.

  2. samjlord says:

    I am sympathetic to the claim that the FDA is overly conservative. However, this example seems weak. The effectiveness is dropping like a rock, and there are serious potential side effects, including cancer, birth defects, and viral mutation. Meanwhile, there are affective vaccines and monoclonal antibody treatments, Both of which have proven to be highly effective and very safe.

    There seems to be only minor benefits (above the other treatment options) and some very terrible potential risks of this treatment. To me, it doesn’t seem egregious that the advisory panel is hesitant.

    That said, I think that having a lower bar for emergency situations makes sense. Let docs decide. But in the real world, when the FDA authorizes something, they know that means that in many many people will get the treatment. So I understand their hesitation

  3. amac78 says:

    Weekend Editor: “Panelists also worried about data showing that use of molnupiravir might, in theory, lead to new variants of the SARS-CoV-2 virus through its mechanism, which works by causing viruses to make mistakes in copying their genetic material.”

    This ought to be a significant concern. There is a well-known precedent: treating Hepatitis C virus (HCV) with interferon plus ribavirin. For lack of something better, this was the Standard of Care up until c. 2015, when Direct Acting Antivirals (DAAs) such as Epclusa and Mavyret first became available.

    Ribavirin has multiple mechanisms, among them is induction of RNA virus mutagenesis that drives HCV to an abnormally high error rate. (Ribavirin is also teratogenic.)

    To my knowledge, this increase in HCV mutations has not been shown to accelerate the evolution of more pathogenic or infectious variants of the virus. (Please correct me if this is in error.)

    According to UpToDate (paywalled), ribavirin is still used in certain cases, as a supplement to DAA therapy.

    As an aside, the FDA was extremely cautious and slow in approving the first DAA. Debate raged as to whether it could be trialled alone, or had to be combined with interferon/ribavirin. I can’t come up with an estimate of how many deaths would have been averted, had approval been advanced by a year — but clearing a deadly virus in ~98% of patients is better than doing so in ~60% of patients.

    • That sounds about right to me.

      The probability of making a new variant as a function of the induced mutation rate is likely a downward-facing U-shaped function. Too little induced mutations, no problem. Too much induced mutations, also no problem because the virus can’t replicate. Middling induced mutations, problem.

      I’m a little disappointed mutations inducing new variants was not a major point of discussion.

      But only a little, because I didn’t think of it in advance either! So let’s all afford each other a bit of epistemic humility and forgiveness on that subject. At least it got brought up at the right place and time.

  4. H.P. says:

    The idea of letting a regulator pick the “best” product is bonkers. And, as far as I know, that isn’t the FDA’s purview. They are supposed to tell us whether a drug is safe, not whether it is better than another drug. The panel seems to feel entirely free to consider whatsoever they choose. This is a problem.

  5. Dan Elton says:

    From what I am seeing they didn’t take the results from Hetero’s trial into account at all https://www.heteroworld.com/images/Press_Release_Molnupiravir_Interim_Clinical_Results_Final_090721.pdf

    (Hetero is an Indian company that has a license agreement with Merck to produce the drug for India and other low-income countries.) As I summarized it previously, Hetero did an “N=741 trial way back on 9 July this year. They reported that after 14 days Molnupiravir reduced hospital admissions by 70% (7 hospitalized who got the drug vs 23 in the control group, p < 0.0001)."

    The treatment was given to patients with "mild" COVID-19 within five days of symptom onset. Pfizer's Phase III trial was described as having been performed using patients with "mild to moderate" COVID-19. I wonder if that difference in wording is relevant to understanding the difference between the two trial results — it seems the drug works better when given earlier before more serious symptoms have time to manifest.

  6. 50% vs 30%:

    This is an interesting mix of good and bad thinking. Yes, it’s possible that the 50% vs. 30% thing wasn’t random, but why is that an issue here?

    Several reasons:

    (a) The first tranche of the data got 50%, and the second got 30%. Charitably assuming they are of equal size, that means the efficacy in the second tranche was around 10%. (If the second tranche was smaller, then the second tranche efficacy was even lower.) This is a serious decrease. Also, the lower confidence limit on efficacy was 1%, i.e., if you force me to be really skeptical I might have to admit the effect was marginal. That is a serious drawback.

    Hence “wobbly” is pretty accurate, at least to me.

    (b) The trial was supposed to be randomized, so there should have been no difference between the two tranches. Obviously, that is false. Maybe some sites reported later, and were testing a different population? Why is that population different? Can we discover a predictive biomarker for the difference? Was there a randomization leak?

    Something hinky happened, and nobody will calm down until we know what that was.

    (c) If there were only a few mild side-effects, this would be ok: “we don’t know exactly who’s going to respond, but some people will, and the ones who don’t respond have wasted only their time, not their health.” However, now that we have the complete safety data, the latter part of that statement is not the case: the side-effects are serious enough that we want to give it, as much as we can, only to people likely to benefit. But we can’t tell who those people are ahead of time, aside from avoiding pregnant women. (Also there was some discussion about effects on spermatogenesis, thinking that men should use birth control for at least a couple months after exposure to molnupiravir, because some of the mutagenic effect can happen in sperm.)

    The side effects, particularly mutagenesis, are worrisome. Not as worrisome as getting COVID-19, but we don’t know in advance who will benefit and who will not.

    Points for Omicronomicon, that’s great, and given the timing I hope it was all dry goods that will keep for a long time.

    Omicronomicon: I’ve been reading Charlie Stross novels. I just wish they weren’t quite so on the nose. On his blog, he says exactly that, too: it’s hard to satirize the world when it becomes outrageous beyond the point of satire.

    Groceries: Lentils, pasta, powdered milk, flour, frozen foods, dry cat food, in addition to the usual produce. Also, batteries. I’ve been thinking there might be lockdowns, but hoping to avoid power cuts from total collapse, hence reliable refrigerator & freezer. And my portfolio is positioned pretty defensively even in normal times, because basically I don’t need a lot of growth.

    Monoclonal abs:

    Then there’s the crazy of the monoclonal abs argument and the ‘need’ for this new treatment as a justification. Once again, these treatments are complements… because who would dare use more than one without a Proper Scientific Study…

    Oddly enough, I am already aware that they are complements. :-) (Yes, I know you weren’t snarking at me personally; it was just fun to pretend so for a moment.)

    The AMDAC folk were speaking less about mechanism of action than about pragmatics: what can I do for the next patient who walks through my door with early COVID-19? Monoclonals are certainly one thing. But if Omicron makes those less effective or even ineffective, then… what? It’s good to have several early-stage treatments.

    Bonus points if they’re different mechanisms, as is the case here, because many docs, especially at the big-time research hospitals, will try combination therapy on their own in advance of a trial (“pilot study” or “observational study”, with the excuse that the results will help design and set power for a real combination trial). But if molnupiravir has severe side-effects or limited response in a population we can’t identify, then the enthusiasm for combinations goes down.

    Until yesterday, I was chomping at the bit to get somebody to start a monoclonals + fluvoxamine + molnupiravir + paxlovid combination trial in various subsets, to uncover response synergy. After reviewing some of the tox stuff this morning, while carefully not grocery shopping, I’m more biased toward monclonals + fluvoxamine + paxlovid. Still pretty disjoing MoA’s there.

    But I fear that given the ‘mutagenicity’ issue doctors will rightfully fear lawsuits from people who claim nonsensical ‘mutations’ happened to them, and so won’t be able to give Molunpiravir to a lot of their patients, resulting in a bunch of people dying and hospitals filling up faster.

    While they do worry about malpractice suits and insurance misfeasance, most of docs are really good at thinking about the benefit to their patients. (Sometimes too much: they ignore evidence-based medicine’s treatment guidelines, and tailor treatment to each patient thinking they can outsmart the Bayesian reasoning behind EBM. They almost never can.)

    So the risk of mutagenicity, particularly in pregnancy, hits them hard in the primum non noceres.

    Chance of approval/EUA:

    And it’s only on track to be legal rather than legal, with substantial doubt, because the FDA administer has to sign off, then the CDC advisory committee has to meet and then the CDC management has to approve. Given what we’ve seen so far, all of these steps are at risk.

    A fair worry. But I’d put it at about 75% – 80% that it will be EUA’d and in practice guidelines by sometime this month. (Gaack: how did it get to be December already? Just a few minutes ago it was July!)

    Re generating new variants:

    This does seem like a real concern if it’s even slightly well-founded, and a good reason to consider not approving the drug. The downside of doing this could be very, very high.

    Yes, it is a risk. I have no idea how much risk. The risk of a new variant is probably a downward-facing U curve as a function of the rate of mutation: too little mutation, and you don’t make any new variants; too much mutation, and the virus dies without making functional new variants. Clearly the molnupiravir strategy is to be on the upper end of that curve.

    I don’t feel especially bad that it was only mentioned by, I think, 2 or 3 of the AMDAC members because I didn’t think of it either, and am now kicking myself (gently) for that. OTOH, they did say a lot of “I agree with the previously mentioned concerns, and &hellip” so they could be agreeing about new variants.

    But sounds like we both thing this should have been A Big Deal.

    Re 3 days, 5 days, and cutoffs:

    This effect has to be continuous, there’s nothing special about five days in particular.

    Maybe. But if the viral load vs time follows something like a logistical curve (the “S curve” much beloved of venture capitalists), then it’s pretty dang steep at the point of inflection. If that’s at 5 days (I have no evidence, but that’s what the prescription guidelines are), then it makes partial sense.

    Re Patient risk tolerance:

    The safety profile definitely more than passes my bar of ‘if this is unsafe then it’s nowhere near as unsafe as not using it so give it to me.’ If I get sick, I want treatment, and yet they are intending to make it illegal for me to get it, even outside issues of ‘delay.’

    Actually, there was a lot of discussion about this. They want docs to have a careful conversation with their patients, in which the risk and benefit tradeoffs are carefully explained, and then the patient makes a choice. You, having higher risk tolerance, would probably choose to take molnupiravir if offered (until paxlovid is online). Others would choose otherwise. Docs often hate this, because it takes time, it’s kind of squishy and emotional, and easy to bias a patient one way or the other withing intending to.

    They would much prefer drugs with clear guidance about who gets them under what circumstance. Molnupiravir is apparently a situation where they will not get what they want in that regard.

    Logistics of catching pts for early treatment:

    If five days is daunting, how are we going to get Paxlovid to people within three? Also, seriously, five days is an insanely long amount of time, if it’s not enough then FIX IT.

    The KM curve shows time since the start of treatment, not since the start of symptoms. Most of the subjects in the trial were probably starting treatment around day 5, except for somestragglers who helped show on a previous graph that they had lower virus reduction than the early patients.

    The 3-5 day early treatment window is why so many people are screaming about the lack of rapid tests in the US: they’ll need to be free, fast, and stacked high on the shelves of every drugstore in order for early treatment to work. And people will have to take the test and abide by the result, not feel penalized for having a negative result.

    So some of that is social and practical, not just the underlying science.

    Oral vs IV:

    This suggests that being an oral treatment was (correctly, I’d presume) considered an important advantage?

    Yes, oral delivery is a huge advantage over IV delivery.

    For an IV, the patient has to come into the clinic or hospital (home health nurses are a thing, but a rare thing). It takes maybe an hour, end-to-end. There may be facility charges from a hospital. You have to have skilled RNs standing around looking smart but doing nothing (mostly, you hope), just in case something goes wrong with the IV and they can save somebody’s life. Having highly skilled people mostly standing around is both expensive and essential.

    Taking 4 pills twice a day at home is much easier. Especially if you stock the pills in doctor’s offices, so the patient doesn’t even need to go to the pharmacy: “Here’s 40 capsules of molnu-mumblety-mumble. Take 4 in the morning and 4 in the evening for the next 5 days. STAY HOME, don’t go out at all unless it’s to go to the hospital. Call me if you get worse. Drop off your co-pay on your way out.” Easy.

    Then there’s insurance: in the completely wedged US healthcare system, insurance often calls the shots, and they will call for oral over IV if that’s ever a choice (sensible, if the treatments are equivalent). The only way to get them off this is to show in a combination trial that an oral anti-viral PLUS monoclonal ab infusion has a positive efficacy synergy. They’ll complain and try to intimidate docs away from that, but the docs can win by waving the study at them like a talisman to repel vampires. (Actual words used by my PCP, in another context.)

    Not saying “paxlovid”:

    8. Paxlovid remains so illegal the FDA can’t even say its name in meetings.

    I hope you’re joking here (p ~ 80%?). There’s probably some liability constraint about mentioning other drugs by name. Even by the generic name, such as paxlovid. They can probably talk about other approved drugs, but if they mention something coming up for approval, every word they say will likely be evidence in the upcoming drug’s hearings? That… probably makes one tread carefully.

    __Summary:__

    (1) There was something hinky about the trial: the interim results were bright and sunny, while the full results were dark and stormy. Were there distinct populations in spite of randomization? Was there a randomization leak? Based on the interim result, stopping the trial to hurry approval makes sense, but based on the full result it does not. That should not happen.

    Nobody likes a trial where things that shouldn’t happen, happen anyway. What else might be wrong?

    (2) After reviewing the tox stuff this morning (groceries already in the pantry, you know), I wonder why the interim result with its wonderful 50% efficacy didn’t show the tox data? Why are we only finding out about it now? Did some scientist report the tox data late, or did some Merck manager do a “damn the torpedoes, full speed ahead?” Either way, at Merck somebody’s gettin’ yelled at right now. I can’t quite hear it indoors, because my house is well insulated with high R-value windows, but then I haven’t stepped outside yet this morning.

    Let’s hope paxlovid has a smoother path with fewer negative surprises.

    • TheZvi says:

      How much do you know about the Paxlovid timeline? Can we do that by end of year? Any knobs anyone can turn?

      • Not much, just like everybody else. I just looked at the AMDAC meeting schedule, and it’s not there. Yet.

        Here’s what I can figure out:

        (1) Pfizer applied for an EUA for paxlovid on 2021-Nov-16. They’re doing “rolling submissions” in other countries, meaning they update as new data becomes available, a common practice.

        For comparison, Merck applied for an EUA for molnupiravir on 2021-Oct-11.

        So on the dicey heuristic that they both might take the same amount of time, paxlovid is about a month behind molnupiravir.

        (2) According to the New York Times (yeah, I know you don’t like them; just like the FDA hearings I’ll read it so you don’t have to), the FDA hasn’t yet said whether it would convene an outside committee of experts (likely the AMDAC). This can happen for one of 2 reasons:

        (2a) Bad case: The drug candidate is so bad, they’re pulling a WC Fields and saying “Go away kid, ya bother me.” This is unlikely, given the interim readout of paxlovid. (OTOH, that’s what I said about the interim readout of molnupiravir, and look at all this egg on my face today.)

        (2b) Good case: The drug candidate is so good, they decided they don’t need the backup of outside experts. This is good, but it comes at the cost of transparency provided by the AMDAC hearing process (which is how I get to poke my nose in and watch).

    • Thomas says:

      “The first tranche of the data got 50%, and the second got 30%. Charitably assuming they are of equal size, that means the efficacy in the second tranche was around 10%”

      That’s not true – you can calculate the efficacy in the second tranche by subtracting the “Interim Analysis” from the “Full Dataset”. In the Molnupiravir group, the hospitalization rate in the second tranche was 6.2% (20/324), but in the placebo group it was 4.7% (15/322). So the efficacy in the second tranche was -32.5%.

      • Ohmigosh, Thomas: you are absolutely, completely, positively and totally correct! I was just winging it, trying to make the point that the second tranche of patients must have had pretty poor efficacy. That turns out to be true, but I guessed incorrectly using the average.

        Mea culpa: I have tattooed 1,000 times on the inside of my eyelids, “Efficacies Do Not Average!”

        To say proper thanks to you, and to work out the details properly so I won’t forget, I posted today a slightly more proper analysis of combining efficacies across patient groups.

        Summary: I agree with you, that the efficacy in the second tranche of patients was -32.5% (95% CL: -151.6% – 30.1%).

        Thanks again, for (a) giving me the opportunity to correct a mistake and do better, and (b) making the point even more strongly that there were vast differences in efficacy, rightly called “wobbly” at the FDA AMDAC meeting.

  7. Dan Elton says:

    I think we can say with pretty high confidence that Molnupiravir is at least as good as Remdesivir, but without requiring IV administration. Remdesivir has been in widespread use for months but is currently in very short supply. (See Phase III trial results on Remdesivir here: https://www.nejm.org/doi/full/10.1056/nejmoa2007764)

    • The study you cited for remdesivir (thanks!) uses days to hospital release as its outcome (10 on remdesivir vs 15 on placebo). The molnupiravir study used hospital admission within 29 days vs not as its outcome. I have no idea how to compare those, but both do show improvement.

      Remdesivir (a) has milder side-effects comparable to placebo, and (b) is for late-stage (or later-stage, anyway) therapy.

      Molnupiravir is (a) side-effects reported weirdly late to the AMBAC, and (b) is for early-stage therapy.

      But… yeah, maybe similar efficacy?

      Dexamethasone is pretty good for late-stage therapy too, not to mention cheap and safe and widely available. Maybe paxlovid will eclipse molnupiravir, just as dexamethasone at least competes with remdesivir in later stage therapy?

      I guess my bottom line is that molnupiravir wasn’t the magic bullet I was hoping for. It might still be useful as an ordinary bullet, if that’s an acceptable analogy.

  8. L.T. says:

    Small typo in various places (including the title): It’s Molnupiravir, not Molunpiravir. I guess it suffers from the same problem as Comrinaty/Comirnaty/Comniraty…

  9. Michael B says:

    Hold up. Is it really possible to deadlock drug approvals like this?

    You can have a drug that’s so effective against a serious illness that they’ll stop the trial early because it would be “unethical” not to, sacrificing the opportunity to strengthen the evidence by letting it run to completion, then! then! have a scientific panel later decide the drug can’t be approved because the evidence isn’t strong enough to suit them?

    What. The. Fuck.

    Does every pharma company just have to accept that after man-centuries of work and millions to billions of dollars spent on a drug that may have amazing efficacy, the FDA might incompetently implode your drug trial on you and render your drug unapprovable?

    If Merck had been denied, what were they supposed to do, exactly? Just run yet another trial and hope this time the ethics committee and science advisory committee would randomly agree with each other next time?

    To rip off Kelsey Piper a bit, this seems like a system designed to turn the smartest people in the world into supervillains.

    • Alsadius says:

      From everything I know of the FDA, this isn’t even surprising. These guys make Kafka seem like a pleasant dream.

  10. Fred says:

    Hi Zvi,

    This convo is taken from a Synairgen SNG001 bulletin board.
    It doesn’t make Molnupiravir look good if true.

    I just did some calculation of the results from MOVe-OUT Study of Molnupiravir, they just say the first 762 participants efficacy is 50%, and the whole study 1433 participants efficacy is 30%.
    I wanted to see what is the second half (646 participants) of the study efficacy,
    hxxps://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-results-from-move-out-study-of-molnupiravir-an-investigational-oral-antiviral-medicine-in-at-risk-adults-with-mild-to-moderate-covid-19/

    So the the second half (646 participants) the efficacy is -32.51%.

    15 Hospitalization/death from Placebo group,
    20 Hospitalization/death from Molnupiravir group

    Hospitalization/death 15/322 Placebo, 20/324 Molnupiravir

    hxxps://i.redd.it/eh6f4ntjg9281.png — This is the excel file I made

    I might be wrong, if anyone have time please double check for me, the News release is here
    hxxps://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-results-from-move-out-study-of-molnupiravir-an-investigational-oral-antiviral-medicine-in-at-risk-adults-with-mild-to-moderate-covid-19/
    helen38
    27 Nov ’21 – 23:29 – 58371 of 58821
    0 4 0
    From the news release, it said for an absolute risk reduction of 3.0% (95% confidence interval [CI]: 0.1, 5.9; nominal p-value=0.0218) and a relative risk reduction of 30% (relative risk 0.70; 95% CI: 0.49, 0.99).

    an absolute risk reduction of 3.0% and a relative risk reduction of 30%, can anyone know what does it mean? What is the difference?
    helen38
    27 Nov ’21 – 23:52 – 58372 of 58821
    0 4 0
    One last thing, the reason why the result is so difference is not because of Molnupiravir, they actually did better on the second part of the trial, Hospitalization/death 1st part 7.27%, 2nd part 6.17%,
    the reason is the Placebo group Hospitalization/death 1st part 14.06%, 2nd part only 4.66%.

    The Placebo group Hospitalization/death on the 2nd part dropped 66.85%.

    Meaning Placebo group 1st part has over 3 times more Hospitalization/death than 2nd part of the trial.

    waterloo01
    28 Nov ’21 – 07:54 – 58374 of 58821
    0 8 0
    Helen38 good analysis. You might recall when they 1st put out the initial results the huge outlier was the placebo rate (14% I seem to recall) was out of whack with every other trial and looked wrong, which we discussed briefly here.

    Their updated results, as you have highlighted are at best, so so.

    Edit: Which is one reason Vallance was suggesting that they will have to ‘relook’ at the data from both antivirals in the light of Omicron (although the review of Molnupiravir should be reconsidered in the light of the full and disappointing results as you highlight).
    timbo003
    28 Nov ’21 – 09:19 – 58375 of 58821
    0 6 0
    >>>>Helen/Waterloo (re Merck’s molnupiravir clinicals)

    • I did a check on the efficacy in the interim cohort, the full cohort, and the difference between them, i.e., the completion cohort. (Thanks to fellow commenter Thomas for pointing out that I needed to do that to correct my earlier blunder.)

      The result agrees with your numbers above (though the numbers reported on the Merck slides at the FDA were for only 709 subjects):

      Full cohort: 30.4% (CL: 1.0% – 51.1%)
      Interim cohort: 48.3% (CL: 20.4% – 66.5%)
      Completion cohort: -32.5% (CL: -151.6% – +30.1%)

      This doesn’t use Cox-regression-like methods to account for people dropping out of the trial. But they didn’t release those data, so this is as close as we can get.

      And, yeah… the second half of the trial, something’s wrong there. But you, Thomas, and I have all independently gotten to the estimate of -32.5% efficacy.

  11. Nika says:

    You’re misspelling molNUpiravir as molUNpiravir in the title and a few other places.

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