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Our Take: FDA panel votes to authorize Merck, Ridgeback’s molnupiravir, despite lower efficacy in final trial results

Dec 06, 2021
An FDA advisory panel voted 13-10 in favor of recommending authorization of Merck and Ridgeback Biotherapeutics’ molnupiravir last Tuesday.

If the FDA acts in accordance with the panel’s recommendation, molnupiravir could become the first oral antiviral drug available for use at home to treat COVID-19. It is intended to be taken within five days of the onset of symptoms.

Some members of the FDA’s Antimicrobial Drugs Advisory Committee voiced concerns about the drug, including the potential for increased risk of birth defects when pregnant women take the drug — a risk that Merck has acknowledged.

Others on the panel questioned why the drug’s efficacy in preventing hospitalization and death in comparison with placebo dropped 18 percentage points — from 48% to 30% — when Merck reported the final results of the Phase III MOVe-OUT clinical trial on Nov. 26, relative to the interim results reported on Oct. 1. Based on the recommendation of an independent Data Monitoring Committee, Merck halted enrollment in the trial after the interim results became available.

Neither Merck nor the FDA had a concrete explanation for the difference between the two sets of results, Endpoint News reported. The final analysis included more evaluable participants (1,433 vs. 775 in the interim analysis), but that does not appear to explain the difference.

FierceBiotech reported that Jeffries analysts offered a theory that might partially explain the drop in efficacy between the interim and final study results. Although vaccinated people were excluded from participating in the study, those who were seropositive — meaning they had previously been infected — were not excluded. In this subgroup of participants, the rates of hospitalization or death were the same whether they received molnupiravir or placebo.

Only 139 seropositive participants were included in the interim analysis, and the Jeffries analysts speculated that a higher number of seropositive participants may have been included in the final results, causing the efficacy to drop substantially.

The U.K.’s Medicines and Healthcare products Regulatory Agency conditionally approved molnupiravir in early November for use in reducing the risk of hospitalization and death in people with mild to moderate COVID-19 who are at risk of progressing to more severe illness. It will be marketed there under the brand name Lagevrio.

Our Take: We expect the FDA to authorize molnupiravir for two reasons. First, having a pill that, in theory, could be readily available for people to take when they develop symptoms could prove to be a useful tool in the battle against COVID-19.

Second, the emergence of the omicron variant (see the first brief below) seems to be spurring public health officials to take quick but reasonable actions in an effort to keep the variant in check. The FDA may decide that molnupiravir is better than nothing in terms of having a “COVID pill” available for widespread use.

As we reported in early November, Pfizer’s investigational oral COVID-19 drug, Paxlovid, which is a combination of a drug referred to as PF-07321332 and a low dose of ritonavir, reduced the risk of hospitalization or death by 89% in interim results from the Phase II/III EPIC-HR trial. Like Merck, Pfizer halted enrollment in its clinical studies of the drug based on these results. If Pfizer’s drug can maintain its high rate of efficacy in the final analyses, then it will have a clear advantage over Merck’s drug even if it’s not the first to market.

We’ll be watching to see how the antibody treatments hold up against the omicron variant. If their efficacy is diminished, then the oral antiviral drugs could become an even more valuable means of fighting COVID-19 — at least temporarily.

At particular risk are the investigational antibody drugs, such as AstraZeneca’s AZD7442, an injectable, long-acting treatment that combines tixagevimab and cilgavimab. That drug reduced the risk of symptomatic COVID-19 by 83% in one Phase III trial and, when administered within three days of the onset of symptoms in another Phase III trial, reduced the risk of severe COVID-19 or death by 88%.

Since the omicron variant is so new, there’s no way of knowing at this point how well any of the COVID-19 treatments and vaccines developed so far will protect against it.

What else you need to know
Omicron, the latest variant of the coronavirus that causes COVID-19, has been detected in multiple states. The Centers for Disease Control and Prevention disclosed on Wednesday that a case in California had been caused by the newly identified variant, and by Thursday there were also reports of cases in Minnesota, New York, Colorado, and Hawaii. By early Saturday, cases had been reported in a total of 12 states. The World Health Organization has classified omicron as a variant of concern, largely because it has dozens of new mutations in its genes — considerably more than previous variants — which might allow it to more easily skirt the immunity gained from existing vaccines or prior infection. Although early research suggests that omicron may be more transmissible than previously identified variants, that has not yet been confirmed. It also is not known at this time whether omicron causes more severe illness or how well the current vaccines will protect against it.

In response to the emerging variant, vaccine manufacturers are evaluating the effectiveness of their vaccines and several, including Moderna, partners BioNTech and Pfizer, Johnson & Johnson, and Novavax, are working on adapting their vaccines to target omicron if the need arises. In the meantime, public health officials recommend that unvaccinated individuals get vaccinated and that eligible people get a booster. It is believed that the existing vaccines will more than likely provide some protection against omicron and that boosters, which increase antibody levels, may also help reduce the variant’s ability to spread.

The COVID-19 vaccine mandate for health care workers has been temporarily enjoined. Last Monday, a judge in the Eastern District of Missouri granted a preliminary injunction halting CMS from enforcing the mandate in 10 states until a full judicial review can be conducted. Then on Tuesday a judge in the U.S. District Court for the Western District of Louisiana granted a preliminary injunction in a separate lawsuit initiated by lawmakers in 14 other states. In that ruling, the judge said the scope of the injunction was nationwide and acknowledged that “a higher court” would make final decision on the mandate, which requires health care workers to have their first shot by Dec. 6 and be fully vaccinated by Jan. 4. Following the injunctions, several health systems paused their vaccine mandates, including Cleveland Clinic, Intermountain Healthcare, HCA Healthcare, and Ballad Health, Becker’s Hospital Review reported.

Separately, a judge in the U.S. District Court for the Eastern District of Kentucky granted a preliminary injunction on Tuesday blocking enforcement of the vaccination mandate for federal government contractors in Kentucky, Ohio, and Tennessee. That case is also pending litigation.

CMS’ Oncology Care Model “was significantly associated with modest payment reductions” per episode of care in its first three years, according to an analysis published Nov. 9 in JAMA, but the researchers noted that those reductions did not offset the monthly and performance-based payments made under the alternative payment model, which was designed to improve the value of care for Medicare beneficiaries with cancer. The end result was a net loss of $315.6 million to Medicare during that three-year time period. The analysis did not reveal any statistically significant differences “for most utilization, quality, and patient experience outcomes.”

On Tuesday, the Supreme Court heard oral arguments in a lawsuit the American Hospital Association (AHA) filed against the Department of Health and Human Services (HHS). The case centers on HHS’ decision in 2018 to reduce outpatient Medicare drug reimbursements to 340B hospitals by almost 30%. AHA says the cuts resulted in a $1.6 billion reduction in payments to those hospitals and contends that HHS did not have the authority to change the payment rule in 2018 without first conducting a survey to collect data on drug acquisition costs. The high court is expected to make its decision in the case next year.

Executive moves

CoxHealth CEO Steve Edwards will retire at the end of May 2022. Edwards has been with the Springfield, Mo.-based health system since 1992 and was named president and CEO in 2012. The board of directors has appointed a search committee to seek his successor.

Emory Healthcare’s chairman and CEO, Dr. Jonathan Lewin, will step down from those roles and other leadership positions he holds at Emory University. Dr. Lewin also currently serves as the Atlanta-based university’s executive vice president for health affairs and as the executive director for the Woodruff Health Sciences Center, which includes Emory’s medical, nursing, and public health schools. He will transition away from his leadership responsibilities when a successor for the EVP position has been named and will join the university’s faculty.

Dr. Richard Fisher, president and CEO of Fox Chase Cancer Center, left the organization in late November, Becker’s Hospital Review reported. The cancer center is part of Philadelphia-based Temple University Health System. Dr. Robert Uzzo was appointed to serve as interim CEO while a search for a permanent successor is underway.

What else we’re reading
Less Medicine, More Health: 7 Assumptions That Drive Too Much Medical Care, by Dr. H. Gilbert Welch.
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