What Merck’s Experimental COVID Pill Can and Can’t Do

Posted by on October 6, 2021 2:22 pm
Categories: Everything Else

Two years into the pandemic, we’ve gotten a lot better at tackling the coronavirus at the extremes of infection. We have preventives—including masks, distancing, ventilation, and our MVP vaccines—that can be deployed in advance of a viral encounter. We have regimens of last resort: drugs, such as dexamethasone, that do their best, lifesaving work in hospitals with trained health-care workers, in patients whose disease has already turned severe. But in the chasm that sits in between—the hazy period after infection and before severe illness—decent tools that can derail COVID’s progression have been sparse.

We now have a new candidate aiming to fill that crucial niche: the experimental antiviral molnupiravir, developed by Merck and Ridgeback, which comes in an easy-to-swallow pill. According to a company press release posted this past Friday, the drug can halve rates of hospitalization among people recently diagnosed with mild or moderate COVID-19. Molnupiravir hasn’t yet been given emergency clearance by the FDA, and won’t be available for at least a few months, but Merck and outside experts have said they expect a formal green light soon. With the Delta variant still ravaging the world’s unvaccinated, a pill such as this one could ease the burden on overtaxed health-care systems—which most other COVID treatments have struggled to do. “To have something to take by mouth the minute you’re diagnosed, that reduces your chances of getting severely sick … that’s kind of the dream,” Nahid Bhadelia, the founding director of Boston University’s Center for Emerging Infectious Diseases Policy and Research, told me.

But in that middling stretch of the COVID timeline, molnupiravir might be able to stake out only limited territory. The drug is meant to be taken within the first five or so days of illness, “the earlier, the better,” George Painter, a pharmacologist at Emory University and one of molnupiravir’s early developers, told me. That’s a punishingly tight window, especially in nations short on diagnostics to detect the virus—as well as access to health workers and infrastructure to prescribe and provide the drug. “Rolling out an oral medication is hugely important,” Erin McCreary, a clinical pharmacist and COVID-treatment expert at the University of Pittsburgh, told me. But a pill, she said, has to be “paired with access”—of which a drug itself is no guarantee.

Despite its experimental status, molnupiravir is a pretty familiar face to the antiviral-research community. In the pre-COVID era, the drug generated some buzz when scientists found that it could stamp out a menagerie of viruses, including influenza. Its modus operandi is pretty similar to that of remdesivir, the only COVID-19 drug with full FDA approval. Both mimic building blocks of SARS-CoV-2’s genetic code, allowing them to mess with the fastidious self-xeroxing process that the virus uses to generate copies of itself inside human cells.

The two antivirals are slightly different agents of chaos, though. To make more of itself, SARS-CoV-2 deploys a scribe-like enzyme called a polymerase to scan and duplicate its genome letter by letter. When the polymerase spots a stray remdesivir molecule, it stumbles, as if flustered by a bad typo. Molnupiravir is more insidious still. It’s such a good mime of the letters in the viral alphabet that the polymerase often overlooks the interloper, making genome copies riddled with mistakes. “An analogy might be gross misspellings,” Painter said. The drug’s sabotage is so extensive that experts call it an “error catastrophe”: Dangerous viral particles have essentially no shot of emerging out the other end.

Molnupiravir’s packaging might give it another leg up. Researchers have long known that a bad case of COVID-19 tends to unfurl in two stages—one dominated by the virus, and a second by the immune system’s overzealous reaction. The point of antivirals is to act early, and fast—to nip a growing virus population in the bud, before it can wreak havoc on our tissues, or trip too many of the body’s hypersensitive alarms. These drugs are largely useless once people have descended into the second phase. Remdesivir has to be delivered intravenously, over several days—usually in a hospital, after most patients are pretty sick. (This might explain why remdesivir studies in these settings have produced mixed or underwhelming results.) Molnupiravir, meanwhile, was designed as a pill so it could be “easily administered in the outpatient setting,” Daria Hazuda, Merck’s vice president of infectious-disease discovery, told me. The drug is easily shipped and stored, and can be taken pretty much anywhere.

Merck’s recent trial, which has yet to be documented in a peer-reviewed scientific study, used the drug in people who had at least one risk factor for developing severe COVID-19 and had just begun to feel ill. Only 7 percent of them ended up getting hospitalized, compared with 14 percent in a placebo group, and none of them died. “That’s hugely clinically significant,” Ilan Schwartz, an infectious-disease physician at the University of Alberta, who wasn’t involved in the drug’s development, told me. The pill also, so far, appears to be playing nice with human cells, dealing its deathly blows only to viruses—no serious side effects have been reported yet, though Merck’s final data are expected to provide more details upon publication. And there’s been little sign that SARS-CoV-2 can evolve to skirt molnupiravir’s effects, which should make the drug relatively variant-proof. The trial’s results were so promising that an independent panel of experts evaluating the data decided to halt the study early so the company could move forward with its product.

Realistically, molnupiravir might be better compared to monoclonal antibodies—the only treatments for COVID’s early-infection phase that have gotten emergency authorization from the FDA so far. Across trials, monoclonals have proved highly effective at stopping mild and moderate cases of COVID-19 from ballooning into serious ones; one formulation has even been okayed for use in people who have recently been exposed to SARS-CoV-2 but haven’t yet developed symptoms. But monoclonals have weaknesses, too: They still need to be infused or injected by professionals, viruses can adapt to resist them, and skyrocketing demand has seriously strained supply. Molnupiravir, if it pans out, could expand the therapeutic options for this stage of disease. In a best-case scenario, the people who take it would be able to stop themselves from getting seriously sick, while also shortening the length of time the virus lingers in their body—potentially making them less of an infectious threat. Treated people could end their disease earlier in the COVID timeline.

Molnupiravir’s name, however tough to pronounce, has a story behind it. The drug’s been packing such a punch in trials, Emory’s Painter said, that it inspired him and his collaborators to name it after Mjölnir, the mythical hammer of the Norse god (and Marvel Avenger) Thor. “All we wanted was something that carried the idea of potency,” he told me, referencing Arthur C. Clarke’s The Hammer of God, a novel about a human mission to deflect an asteroid on course to collide with Earth. “That it can stop something.”

The Mjölnir reference might work in another way too. Wielding a hammer effectively requires impeccable timing. A powerful tool still needs to hit its mark.

Treatments are, by definition, reactive; a drug, no matter how early it’s dosed, can’t undo an infection, or a prior transmission event. It can only contain the fallout. The 50 percent reduction in hospitalizations noted in Merck’s press release is stellar, but some participants “still did get hospitalized,” Bhadelia pointed out, and without public data, outside researchers can’t yet identify who benefited most, or least, from the pills. Drugs such as this one might not block other outcomes, including long COVID. And Merck has yet to test the pill in pregnant people and kids. Experts also pointed out the paucity of data on the drug’s performance in vaccinated people, most of whom remain at very low risk of severe disease but could still benefit from early treatment, especially if they’re in high-risk groups. Molnupiravir won’t ever replace tools that can exert their effects before the virus even shows up. “I’m really hoping people don’t look at this as a reason to not get a vaccine,” Elizabeth Campbell, an expert in COVID antivirals at the Rockefeller University, told me.

Also, Molnupiravir is going to be used by humans, not gods. Which means it’s going to be subject to some very human limitations. For the pill to work, people will need to realize they’re sick and confirm that with a test; they will need to seek care from a health-care provider and successfully nab a prescription; they will need to access the drug and have the means to obtain it. Then they will need to take the drug successfully, which, according to Merck, means swallowing four capsules twice a day for five days—a total of 40 pills.

Molnupiravir’s been billed as a cheaper alternative to remdesivir and monoclonal antibodies, which can carry price tags of up to about $3,000 and $2,000, respectively, for the drugs alone. But at a projected $700 per course of treatment, molnupiravir still “isn’t very affordable,” Bhadelia said, especially in lower-income countries, where vaccination rates have been low and drugs like these are desperately needed. Merck has pledged to set up tiered pricing that could cut the pill’s cost abroad, and has partnered with several other manufacturers in other parts of the world to speed the timeline of availability “in maybe 100-plus countries,” Hazuda, of Merck, told me.

Even if pills were free and abundant, their effects could still be constrained by a diagnostic bottleneck. Since the pandemic’s early days, access to timely, accurate testing has been woefully inadequate, an issue that’s been exacerbated by the structural barriers faced by communities of color, Utibe Essien, a health-equity researcher at the University of Pittsburgh, told me. If a result comes too late, or a test seems out of reach, then the sick person can easily miss that crucial early-infection window—a big loss, considering that molnupiravir has essentially “no effect on patients once they’re in hospitals,” Campbell told me. “If treatment is contingent on diagnosis, we need to make sure testing is more readily available,” Essien said, or risk widening equity gaps. In this arena, in particular, molnupiravir might stand to be a bit less like its namesake: accessible only to those deemed worthy enough to wield it.

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