Merck’s Covid Drug Will Do for Now, Just in Time for Omicron

(Bloomberg Opinion) -- If vaccines are the bazookas in the fight against SARS-CoV-2, antiviral drugs could be the artillery that helps save lives, especially among those who have a higher risk of developing serious illness. Now that they’ve arrived, health authorities have to decide how best to deploy them. 

Last month, the U.K. became the first country to approve molnupiravir, a treatment for Covid-19 produced by Ridgeback Biotherapeutics and Merck & Co. On Tuesday, an advisory panel convened by the U.S. Food and Drug Administration voted in favor of allowing emergency use authorization of the antiviral drug, too. But between these two approvals, Merck released some data showing the drug has a lower efficacy level than initially thought, and is much lower than a rival drug by Pfizer, which is also applying for emergency-use authorization. 

The new treatments are cheaper and easier to take than existing treatments such as remdesivir. If used within days of infection and according to the treatment guidelines, they should make hospitalization with Covid increasingly rare, allowing us to better live with the virus.

Bloomberg Opinion’s Therese Raphael speaks to Bloomberg Intelligence pharmaceutical analyst Sam Fazeli about how these treatments work and what the risks are. 

Therese Raphael: Merck’s Covid drug didn’t exactly get a ringing endorsement from the FDA. Why was the vote so close? 

Sam Fazeli: It was, indeed, not a ringing endorsement: 13-10, so quite a borderline judgment. Some of the panel members who voted “yes” also noted that once “another drug” is approved, the FDA should revisit the emergency-use authorization for molnupiravir. The issues were numerous, including uncertainty about efficacy, side effect questions and worries about the development of variants as the drug mutates the virus.

TR: How does Merck explain the disparity between the higher efficacy levels in the earlier “interim” part of the trial and the more disappointing later results from the “full analysis”? 

SF:  Actually Merck did not really explain the odd split in efficacy between the two parts, but provided some potential reasons for why the data was so massively different in the second part of the trial, during which the efficacy against hospitalization or death basically disappeared.

The possible causes of loss of efficacy in the second part of the trial include the older age of the population, more diabetic patients (in which the drug seemed to struggle to show significant efficacy), more female participants, a higher percentage of subjects showing signs of prior Covid infection (and thus having antibodies), more patients based in Europe, and, most interestingly, the possibility that the patients recruited in the second part were most likely infected by the delta variant.

But none of this makes any difference to the fact that in some or several situations, the drug struggled to show efficacy.

TR: There are several risk factors often mentioned with the molnupiravir. One of them, mutagenicity (or the risk that it will cause cancer), didn’t seem to overly concern the panel. What are the other concerns and can they be addressed through restricting the way the drug is prescribed?

SF: While mutagenicity is not a major worry, the ability of the drug to cause mutations in the virus did generate a lot of discussion among the panel members. The problem is whether the drug’s use in the real world — for example with people potentially not completing their full five-day course of therapy — will increase the risk that the virus develops into new variants of concern.

There was also data suggesting that the drug interferes with normal bone development in young animals, which is why it will likely not be authorized for people under 18. Lastly, there is a risk of embryofetal problems due to mutations in the growing fetus, which is why female patients will have to ensure they are not pregnant when being treated.

TR: The FDA has another option: Pfizer’s anti-viral Paxlovid, which had much higher efficacy rates in its recent trial. How does this drug work differently?

SF: Paxlovid has an entirely different mechanism of action. Molnupiravir causes the accumulation of mutations in the virus as it makes copies of itself, making the resulting viruses unable to function normally. It’s this action mechanism that causes many of the issues around mutagenicity.

Paxlovid works by inhibiting the molecule that the virus needs to assemble itself — its protease. This  is an enzyme that chops up other proteins, which the virus needs to replicate in the cell. It cuts the all-in-one protein that is initially made from the viral genome into the 29 individual proteins needed to assemble a viable viral particle. Pfizer’s mechanism is similar to some drugs used to treat HIV and hepatitis C. So it will not have issues similar to molnupiravir, though it could have side effects of its own. We need to see the detailed data from Pfizer.

TR: Is there a similar risk that Pfizer could revise down its earlier results?

SF: There is always a chance that efficacy data gets worse when a larger patient population is analyzed. But the incidence of hospitalizations or deaths are already so low in the Pfizer trial for those treated with Paxlovid that the risk of it losing a large amount of efficacy is low. Even if there some efficacy loss, going down from 85% efficacy would still leave a high level of protection.

TR: One risk of anti-viral pills is that the virus develops resistant strains, leading to loss of efficacy. Is either the Merck or Pfizer formulation more likely to have that risk? Is there a way to reduce it?

SF: The best way to reduce the risk of resistance to an antimicrobial drug is for it to be used exactly as instructed. This is easy to do in a clinical trial, but in real life things can get very messy. People may take the drug for less than five days, especially given the pill burden for both drugs, or at a later time in the course of their disease onset vs. in the first five days of symptoms.

But I am not overly worried about resistance given the drugs are only used for a short period of time. Nevertheless, one way to reduce the risk is to combine the different mechanisms, but I don’t think that’s likely with these first products because of the number of pills that would be required.

TR: Now that we have the omicron variant, how do you expect these treatments to fit into the arsenal of responses?

SF: It depends on two factors. First is whether omicron is actually more resistant to immunity derived from vaccination and prior infection, as its mutational pattern suggests. If that’s the case and the virus is as pathogenic as existing variants, then the pills become very important. That’s especially so if monoclonal antibody treatments such as Regeneron’s prove less effective against the new variant.

We also need to understand how the omicron mutations affect the drugs. We know that there are single mutations in the protein targets for each of the two drugs. Currently the thinking is that these should not cause much of a headache for them, but we need data to be sure.

TR: These antiviral approvals are a treatment, but there has been some discussion of deploying them (as well as the monoclonal antibody treatments we talked about) as preventative. What’s your view on that?

SF: Prophylaxis is entirely possible, but remember you will be giving the drug to otherwise healthy people so the risk-benefit calculation changes, creating a much higher bar. Also, some of the monoclonal antibody treatments are quite long-acting, giving at-risk individuals a good degree of protection for periods of over six months. So I see them as better suited in this setting to antivirals.

This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.

Therese Raphael is a columnist for Bloomberg Opinion. She was editorial page editor of the Wall Street Journal Europe.

Sam Fazeli is senior pharmaceuticals analyst for Bloomberg Intelligence and director of research for EMEA.

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