An FDA advisory panel on Tuesday voted 13-10 to recommend Merck's antiviral pill, molnupiravir, for emergency use, and the agency is also reviewing a separate antiviral pill developed by Pfizer.
In October, Merck and Ridgeback Biotherapeutics released their interim analysis of a Phase 3 clinical trial showing that their oral antiviral drug molnupiravir reduced the rate of hospitalization or death by roughly 50% in participants with mild or moderate Covid-19. The drug was most effective when given early in the course of treatment—within five days of symptom onset—and was effective regardless of whether patients had the delta or other coronavirus variants.
Separately, Pfizer's antiviral pill, Paxlovid, is a protease inhibitor that blocks a key enzyme that the coronavirus needs to replicate. In a trial of more than 750 people, Paxlovid was found to reduce the risk of hospitalization and death from Covid-19 by 89% when given within three days of symptom onset. According to Pfizer, Paxlovid was also found to be active against multiple variants of the coronavirus, including the delta variant, in lab testing.
On Tuesday, an FDA advisory committee reviewed molnupiravir for possible emergency use in the United States. According to the New York Times, the drug could receive emergency use authorization (EUA) this week—and Pfizer's antiviral treatment may not be far behind.
Ahead of the vote on Tuesday, FDA staff released an addendum to its original briefing of Merck's drug that highlighted that "the review issues and benefit/risk assessments may [...] differ from the original assessments provided in the briefing document which was based on the interim analysis." Specifically, the agency cited Merck's full results from its Phase 3 clinical trial, released last week, which showed that in over 1,400 adults, the drug reduced the combined risk of hospitalization and death by 30%—a decline from the 50% reduction initially reported by Merck in the interim analysis submitted with its EUA request.
The FDA briefing also evaluated risk management strategies regarding the types of patients who could see the most benefit from the drug, MedPage Today reports. Specifically, FDA suggested that high-risk patients could be identified using the same CDC criteria used for monoclonal antibody treatments. FDA staff also suggested that vaccination status should be considered since unvaccinated individuals have a higher risk of hospitalization and death.
Further, according to ABC News, FDA scientists in the briefing identified several potential risks in the review of the drug, including potential toxicity to developing fetuses and birth defects that were identified during studies of molnupiravir in animals. In addition, FDA staff highlighted the potential risk of viral mutation associated with molnupiravir, specifically "an increased rate of amino acid changes in the SARS-CoV-2 spike protein." However, they concluded that these mutations did not appear to be connected to clinical outcomes, like hospitalization or death.
Ultimately, however, FDA reviewers concluded, "[W]hile the clinical safety data base was small, there were no major safety concerns identified."
FDA's advisory panel voted 13-10 in favor of the treatment for use in adults with mild to moderate Covid-19 who are at risk for severe disease or hospitalization, NBC News reports. According to the panel's chair Lindsey Baden, those who voted in favor of the drug thought its efficacy was "apparent, albeit with issues that have to be weighed." However, those who voted against the recommendation weren't convinced by the data and cited concerns about potential risks, including potential harm to fetuses and DNA damage, he said.
While FDA isn't required to follow the committee's advice, it generally does. If authorized, Merck has agreed to provide the U.S. government 3.1 million courses of the drug for about $2.2 billion, the Wall Street Journal reports. The federal government is expected to allocate the pills to states to filter among pharmacies, hospitals, and doctors' offices for dispensing.
But even after the treatments are widely distributed and available for use, some experts worry it will be difficult to test and treat patients quickly enough for the drugs to be effective, the New York Times reports.
According to the Times, since these antiviral pills are intended to be taken within days of when symptoms first present, their success largely depends on early, accurate Covid-19 testing—which the United States has struggled to deliver throughout the pandemic.
And as new variants arise, the already strained testing infrastructure in the United States could be further put to the test. According to the Times, health officials must ensure that timely, affordable Covid-19 testing is available, particularly in communities that have been heavily impacted by the virus.
"People have to want to get tested, and we have to be able to get tests to people quickly," said David Boulware, an infectious disease specialist at the University of Minnesota. "Can that happen?"
According to the Times, it is not yet clear whether officials will require patients to take a certain kind of Covid-19 test before the drugs are prescribed. And there are challenges associated with each: PCR tests, the highly sensitive laboratory-based diagnostics, can sometimes take days to relay results, while rapid antigen tests are quick, but generally less sensitive.
According to Alyssa Bilinski, a public health policy expert at Brown University, "It starts with the public education such that when people start to have mild symptoms, early in the course of their illness, they think, 'This might be Covid-19, and I should get a test.'"
"Then, of course, we have to have access to tests that have to ideally be affordable. Then people need to get their test results backand they need to get them back quickly," she added. "All of this needs to happen within three to five days."
Because of their quick turnaround times, experts say rapid tests will likely play an important role in the rollout of these antiviral pills. And although there have been testing supply shortages, experts expect they will ease soon. "We're optimistic that the production capacity from both the big players, like Abbott and Quidel, as well as some of the newer smaller players are all hitting the ramp up phase at this point," said Nathaniel Hafer, a molecular biologist at UMass Chan Medical School.
Ultimately, "[t]he idea is access," said Michelle Barron, senior medical director of infection prevention and control for UCHealth. "The whole notion of this is, How can we keep people from progressing and ending up in the hospital?" (Robbins/Zimmer, New York Times, 11/30; Walker, MedPage Today, 11/29; Perrone, ABC News, 11/26; Anthes, New York Times, 11/29; Hopkins/McKay, Wall Street Journal, 11/30; Lovelace, NBC News, 11/30)
FDA's advisory panel voted 13-10 to recommend Merck's experimental antiviral pill to treat Covid-19 for emergency use authorization. While FDA isn't required to follow the committee's advice, it generally does, and the treatment may be official authorized in coming days.
In the meantime, there are four considerations that all health care leaders must think about today.
FDA will likely authorize the treatment for the population studied in the trial—adults with mild to moderate Covid-19 who are at risk for severe disease or hospitalization. But other Covid-19 positive patients may demand the treatment, raising difficult questions for doctors and insurers. Although the Biden Administration ordered enough treatment for 3.1 million people, limited supply is expected upon rollout, if approved. Health care leaders should prepare to address these requests and have prescribing protocols in place—especially if existing treatments prove to be less effective against the omicron variant.
Additionally, with the upcoming review of Pfizer's Paxlovid, which is expected to have greater efficacy than molnupiravir, leaders should anticipate adapting their Covid-19 treatment protocols accordingly with new authorizations and information. While speculative, it's possible that over time, molnupiravir could be reserved for lower-risk patients, whereas Pfizer's drug may be reserved for the highest-risk patients. Additionally, emerging real-world data could change our understanding of which subpopulations (e.g., age, demographic, pre-existing conditions, and comorbidities) for which each treatment is most effective.
As previously noted, rapid tests will likely play an important role in molnupiravir's success. But since rapid tests are still difficult to access, more needs to be done. Without testing for Covid-19, these pills could be rendered useless. Health care leaders should continue to prioritize setting up convenient testing locations—like mobile clinics or community popups—to ensure equitable access to testing.
Even though the oral drug is significantly easier to manufacture, distribute, store, and administer than existing treatments, patients may still face barriers to accessing the drug even after getting tested. There's a real risk that urban or wealthier, better-connected patients with greater access to care could benefit more than historically marginalized populations or patients who may not live close to a primary care clinic or urgent care center. Keeping treatment equity at the forefront will be essential to molnupiravir's success.
As previously noted, FDA panel experts expressed concerns over the many open questions about molnupiravir's safety, efficacy, and risk of mutagenesis. Health care leaders should prepare to answer patient questions and explain how the drug works and the relative risks and benefits. They should also prepare for misinformation and be honest when a lack of information exists—such as whether the treatment could theoretically cause new Covid-19 variants.
To better understand the key open questions and determine the future of molnupiravir, it will be essential for health care leaders, manufacturers, and regulators to continue to collect real-world evidence about the drug's safety and efficacy. In particular, one key question remains: will the treatment work in people infected with the omicron variant? Merck has said that they "have every expectation… that it should work against this particular variant," but have not yet run studies to confirm.
We'll continue to watch the data, open questions, and opportunities and challenges. In the meantime, if you're a health care leader, it's time to start thinking proactively about these treatments and their potential impact on your pandemic response.
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