Emergency Use Authorization (EUA) from the FDA is the exception, not the rule. Except for COVID therapies. Three vaccines and one drug have EUA in the US. Merck is now seeking EUA for its antiviral drug molnupiravir. Should it be granted?
There are now two direct-acting antiviral drugs that have been shown to decrease the severity of COVID, Gilead's remdesivir and Merck's molnupiravir. Both are nucleotide analogs that inhibit the reproduction of viral RNA—an oft-used mechanism of fighting viruses.
Remdesivir was granted EUA in October 2020 for hospitalized COVID patients with severe disease – not the time when the drug is most effective – because there was no alternative. Remdesivir's efficacy was modest when used this way.
But a recent study showed that, when given intravenously to people with mild-to-moderate COVID on three consecutive days early in the infection, the drug decreased hospitalization by 87 percent. While these results are impressive, the notion of setting up infusion centers all over the country where a whole bunch of infectious people will have to wait to be treated is far from ideal. And IV drugs, partly because of stricter manufacturing standards, are usually more expensive than pills, so I would expect a three-day course of IV remdesivir to be quite pricey (this is why I wrote in 2020 that a remdesivir pill is needed). Furthermore, this approach won't be feasible in countries without adequate healthcare infrastructures.
Merck has been developing molnupiravir, formerly EIDD-2801, on an oral antiviral, which could be dispensed as a pill. The company recently announced that, based on Phase-3 clinical data, it would be seeking Emergency Use Authorization (EUA) from the FDA. Should the request be granted?
Shortcuts vs. Cutting Corners
Under normal circumstances, a drug cannot be sold until it receives FDA approval—a long and torturous process designed to ensure that a new drug is both safe and effective (1). Many (most?) of us who have done pharmaceutical research realize that this can be slow and maddening but necessary. Few people would be comfortable taking a new medicine that hasn't been properly evaluated.
But we aren't in normal times and the rules have been bent. Even working at "lightning speed," it took the FDA nine months from the time the agency granted EUA to the Pfizer vaccine to grant it full approval. The use of the EUA as a shortcut was a no-brainer in this case. Making the vaccines available sooner undoubtedly saved tens/hundreds of thousands of lives.
What About Molnupiravir?
Since mid-2021, when the COVID vaccines began to give the world a break (2), life has been very different than it was during the bleak winter of 2020. Despite the unwelcome (and unexpected) appearance of the evil Delta variant, life in much of the world has returned to something approaching "normal." The need for drugs like molnupiravir isn't as critical as it was in the pre-vaccine days. Should the FDA still be handing out EUAs for experimental drugs with clear Phase-3 benefits?
What Do the Data Show?
Merck's MOVe-OUT (clinical trials are given acronyms, often stupid) Phase 3 trial showed a clear benefit of molnupiravir in keeping people healthier (NCT04575597). Highlights include:
- The study was a double-blinded, randomized clinical trial with defined endpoints.
- Data (non-peer-reviewed, unpublished interim data) were derived from 775 non-hospitalized patients having mild-to-moderate COVID and at least one risk factor known to make them more vulnerable to COVID (obesity, diabetes etc).
- The treatment cohort received 800 mg capsules twice a day for five days.
- After 29 days 53/377 (14.1%) of those who received placebo needed to be hospitalized; eight died.
- After 29 days 28/385 (7.3%) of those who received the drug needed to be hospitalized; none died.
- The cohort receiving molnupiravir was half as likely to required hospitalization.
- The occurrence of adverse effects of the two groups was the same (35% for drug-treated, 40% for placebo.
- Adverse effects resulting in withdrawal from the trial: 1.3% in the drug-treated group, 3.4% for placebo group (this should tell you something).
- The drug was effective against the Delta, Gamma, and Mu variants (3).
- Long-term safety is unknown, but molnupiravir is a known mutagen – a drug or chemical that damages DNA. This is normally a no-no for drugs. I will be writing soon about why this is probably not an important concern here (with the exception of pregnant women).
Should Molnupiravir Be Granted EUA?
In my opinion, this is an easy decision—yes, it should, provided that there are no unpleasant surprises in the meantime, such as unanticipated manufacturing or quality control issues or previously unseen side effects or toxicity.. Even with the infection seemingly in retreat, as of mid-October, there are still more than 100,000 new cases and about 1,500 deaths daily in the US. Even people who have been fully vaccinated still become ill, albeit not as ill as those who are not vaccinated. And Merck plans to supply the drug to low-income countries where vaccination is not a viable option.
Perhaps most convincing is that not only did molnupiravir reduce the need for hospitalization by half, but it did so without side effects. Recall that the drug-treated group had fewer side effects than the placebo group, suggesting that the drug made them feel better.
My bet is that the FDA will act swiftly and grant the EUA for this vitally important drug.
(1) The FDA is far from perfect, but no matter what, they can't win. There will always be those who argue that it takes too long for new drug approval and others who argue that new drugs are not studied sufficiently and are unsafe.
(2) The Delta variant had other plans. See Don't Shoot The Messenger RNA: Blame The Virus, Not The Vaccine
(3) The fact that the drug handles the variants is not surprising, since it blocks viral RNA synthesis and is thus not impacted by changes in the viral spike that formed the variants.