Vaccines are key to ending the pandemic, experts say, but vaccinations alone will not be sufficient. Pharmaceutical companies have been racing to find new life-saving therapies to treat COVID, which could also help break the chain of viral transmission in the population. Now two powerful new “game-changing” antiviral drugs will help accomplish that, according to researchers. Clinical trials of both drugs were halted early because they were so much more effective than a placebo.
Molnupiravir, developed and manufactured by Merck and Ridgeback Biotherapeutics, and Pfizer’s new drug Paxlovid both work by stopping viral replication in different ways—a huge leap from currently available treatments. “Anything specifically targeted to actual viral enzymes involved in pathogenesis is much more exciting than nonspecific treatments like monoclonal antibodies,” says Monica Gandhi, an HIV and infectious disease doctor at the University of California, San Francisco.
That is not the only reason for enthusiasm, Gandhi says. Importantly, the new drugs are pills, so they can be taken at home at the earliest signs of COVID. That is in contrast to remdesivir, the only other available antiviral treatment for the disease, which must be given as an infusion in the hospital (although a pill form is currently in the works). Patients already hospitalized with COVID are far less likely to benefit from antiviral drugs. “The oral availability is just thrilling, as is the incredible effectiveness,” Gandhi says. And both drugs require only five days of treatment to work.
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Both Merck/Ridgeback Biotherapeutics and Pfizer have applied to the U.S. Food and Drug Administration for an emergency use authorization (EUA). An FDA advisory committee voted Tuesday to recommend authorizing molnupiravir for high-risk adults, although the vote was close. Some members raised concerns over the drug’s efficacy and potential risks in pregnant people. With the new omicron variant of SARS-CoV-2 rapidly spreading around the globe, the antiviral drugs’ arrival comes not a moment too soon–although it remains to be seen whether they’ll be as effective against the new viral variant.
In the latest data from its phase 3 trial, Merck reported, molnupiravir given within five days of symptom onset cut the rate of hospitalization or death by 30 percent, from 9.7 percent of those who received a placebo to 6.8 percent of those who took the drug (an earlier analysis had reported a drop of 50 percent). One person on molnupiravir died, whereas nine of those who received the placebo did. Pfizer’s trial showed that Paxlovid given within three days of symptoms reduced the risk of hospitalization or death by 89 percent. Fewer than 1 percent of patients who received the drug were hospitalized, and none died, compared with 7 percent of patients hospitalized and seven deaths among those who got the placebo. (Similar results were seen among those who received Paxlovid or a placebo within five days of symptoms: 1 percent of patients who got the drug were hospitalized, compared with nearly 7 percent hospitalized and 10 deaths in the control group.) In both trials, participants had an underlying health condition, such as diabetes or heart disease, that put them at greater risk for severe illness.
While the two drugs appear highly effective, they work in distinct ways to hijack the virus’s ability to copy itself in host cells.
Molnupiravir is known as a nucleoside analogue: it masquerades as one of the building blocks of the RNA that makes up SARS-CoV-2, the virus that causes COVID. Once inside cells, the virus uses an enzyme called a polymerase to grab those building blocks and assemble them into new copies of viral RNA. “The virus needs a template to guide construction of new versions of itself,” says Timothy Sheahan, a virologist at the University of North Carolina Gillings School of Global Public Health, who worked on molnupiravir’s development. The drug gums up the works, causing “catastrophic errors,” so the virus basically mutates itself to death, he says. “At the end of the day, it ends up making viruses with defective genetic materials, rendering them noninfectious,” Sheahan says.
Paxlovid, by contrast, is a protease inhibitor, much like those developed to combat HIV. Once SARS-CoV-2 has replicated its RNA many times over, it hijacks the host’s cellular machinery to make a huge protein containing all of the virus’s parts. That “polyprotein” must be chopped up into manageable bits by a viral enzyme called a protease. By blocking that enzyme’s activity, the drug prevents the production of new, functional viral particles.
But the new Pfizer compound is quickly broken down in the body, Gandhi says, “so it needs a [stabilizing] booster, essentially,” in the form of a second drug called ritonavir to keep it around longer. “We’re really familiar with [this approach for] protease inhibitors in HIV. Almost all of them require ritonavir, too,” she says.
Development of the new antivirals against SARS-CoV-2 was surely sped along by work in HIV, Gandhi says. “The history of medications in HIV is such an incredible success story. It was an evolving process of targeted antivirals developed specifically against enzymes in the life cycle of HIV.”
In addition to preventing severe disease and death, the new drugs might also help stop people exposed to SARS-CoV-2 from getting COVID. That idea is supported by work in ferrets that was led by Richard Plemper, a virologist at Georgia State University. Ferrets treated with the drug that would become molnupiravir did not contract the virus despite being housed for several days with untreated ferrets infected with SARS-CoV-2. Based on another part of that work, the authors also predict that people with COVID who are treated with the drug could become noncontagious within 24 to 36 hours. “In humans,” Plemper says, “it is realistic to have a confirmed case, initiate treatment and start everyone [in a household] on a drug regimen.” And judging from the trial data from Merck, he says, “the results in ferrets are highly predictive of what happens in humans, which is highly encouraging.”
Sheahan agrees, adding, “Those results [in ferrets] are predictive of the power of antivirals in people for sure.” But ultimately, demonstrating the medications’ ability to stop transmission in people will require clinical trials, which are currently underway.
New antiviral drugs are also likely to protect us against future pandemics, which are surely coming down the pike, Sheahan says. “Both remdesivir and molnupiravir have broad activity against lots of different coronaviruses seen in bats, pigs, people, mice—they work similarly against coronaviruses found in all these animals,” he says. That suggests “it’s likely they will work against future viruses as well. So the work we’re doing to address the current pandemic will be useful against future pandemics.”
Making Drug Access Equitable
In order to change the global pandemic game, though, the antiviral drugs will need to be available not just in high-income countries but in those without access to vaccines. When it comes to making the medications available globally, Pfizer said in a statement to Scientific American, “low and lower-middle income countries will pay a not-for-profit price,” and high-income countries will pay a higher but discounted price. (Other outlets have reported that the U.S. government will purchase Paxlovid at a price of about $530 per course, compared with $700 for a course of molnupiravir.) In addition, the statement said, “Pfizer is exploring potential contract manufacturing options to help ensure access across low- and middle-income countries, pending regulatory authorization.” Pfizer expects to manufacture 180,000 courses of Paxlovid by the end of this year and another 50 million doses in 2022, according to public statements.
Merck has taken a more proactive strategy to making its drug widely available, Gandhi says. “I’m really impressed with them. They’ve already arranged to put this ability [in place] for low-income countries to manufacture it, essentially,” she says.
According to Paul Schaper, Merck’s executive director of global pharmaceutical public policy, in July 2020 Merck began strategizing about how to make molnupiravir rapidly available—should it succeed in clinical trials—“not just in high-income countries but [in] middle- and low-income countries. We aim to do that as quickly as possible, as near to simultaneously as possible, globally.” That strategy included building a global supply chain, establishing tiered pricing and engaging, even before approval, with multiple governments and public health organizations around the world to distribute the drug. As a result, Schaper says, the company will be prepared to make 10 million courses of the medication available by the end of 2021, and he expects that number to at least double in 2022.
Another key part of Merck’s strategy was to set up partnerships with producers of generic drugs around the world, vastly increasing the potential to manufacture more doses quickly. “We were able to enter into our first voluntary license agreement with generic [drug-manufacturing] partners in India even before phase 2 data was available, which is unprecedented so early in the drug-development process,” Schaper adds. Both Merck and Pfizer announced they have entered into licensing agreements with the Medicines Patent Pool, a nonprofit organization that will help speed manufacture and distribution of the drugs globally.
How soon could the drugs become available in the U.S.? An FDA panel is set to review molnupiravir’s application for an EUA on November 30, and a meeting to consider Pfizer’s application may not be far behind. “I can’t imagine that the FDA advisory committee won’t have a meeting before the new year to get these drugs out, given how important they are,” Gandhi says. “It is exciting.”