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COVID-19’s constant mutations have proven nearly impossible for drugmakers to keep up with. Omicron’s newest stepchildren threaten to render the last two antibody drugs on the market ineffective: Eli Lilly & Co.’s bebtelovimab, which is used to treat symptoms, and AstraZeneca’s Evusheld, which helps prevent infections.

When COVID first hit, scientists quickly developed antibody drugs to protect people from the virus’s worst effects. It’s a straightforward premise: a targeted antibody can immediately neutralize a threat inside the body, preventing an infection from even starting.

But with each new round of COVID mutations, various antibody drugs have been deemed ineffective and pulled off the market. And with very little progress in antibody drug development, it’s quite possible doctors will soon have none to choose from.

“Instead of having more options with these new variants, we’re seeing less and less options,” Florian Krammer, a virologist at Mount Sinai’s Icahn School of Medicine said at a Galien Forum panel last month. “That’s a big issue that I see for the coming 12 months.”

The problem is worldwide. U.K. health officials said Wednesday in updated draft guidance that Evusheld isn’t recommended for COVID treatment due to uncertainty about its effectiveness against omicron. The only drugs still recommended for use are Pfizer Inc.’s Paxlovid antiviral; Lilly’s Olumiant, subject to U.K. marketing authorization; and Roche Holding’s RoActemra, according to the National Institute for Health and Care Excellence. The guidance will not be finalized until 2023.

With new variants such as BQ.1 and BQ.1.1 now accounting for the majority of COVID cases in the Northeast and other parts of the country, U.S. regulators say that Lilly’s COVID drug is no longer a reliable treatment option for nearly half of the U.S. That’s a problem heading into the winter as hospitals and doctors have been relying on antibodies to fight or prevent some severe infections.

As a possible winter COVID surge looms, the Biden administration is asking Congress for $9.25 billion to bolster the government’s COVID efforts as part of a broader request for funding. More than half of that — $5 billion — would be used to support development of next-generation vaccines and therapeutics to fight a broader swath of variants.

Antibody therapies are essential for treating and preventing disease in roughly 7 million immune-compromised Americans, for whom vaccines and antivirals don’t always work well. Before omicron’s latest set of changes, just two COVID antibody drugs remained out of the five that have won FDA authorization.

Regulators aren’t nixing Astra’s preventative or Lilly’s antibody altogether, but rather suggesting doctors only use them in areas where older variants remain dominant. The FDA said the decision to administer Astra’s treatment, for example, “should be based on the regional prevalence of the resistant subvariants, the individual patient’s risks, the available resources, and logistics.”

With new subvariants continuing to grow in prevalence across much of the U.S., as Centers for Disease Control and Prevention data show, monoclonal antibody effectiveness could become even further limited.

It’s unlikely doctors will have new antibodies to work with anytime soon. Although some companies have products in various stages of development, none are close to an emergency use authorization that would see them become available this winter, according to Janice Reichert, executive director of the Antibody Society, a nonprofit trade association that tracks antibody-related research.

“It’s not clear how many companies are really committed to moving them forward,” Reichert said in an email. The virus’s frequent mutations and the length of the FDA authorization process have deterred companies from developing new antibodies, experts said, because by the time drugs are approved, new, more immune-evasive mutations have likely already begun circulating.

The FDA declined to comment on discussions with companies about the status of their antibody drugs and whether it was considering issuing any new emergency use authorizations. The Antibody Society’s COVID-19 biologics tracker does not show any products that have reached that stage in the development process.

Omicron’s first iteration wiped out GSK and Vir Biotechnology’s drug, sotrovimab, as well as one made by Regeneron Pharmaceuticals. Vir, alongside GSK, is still evaluating sotrovimab’s efficacy against emerging variants, like BQ.1 and BQ.1.1, the company said in an email. A spokesperson also said that Vir has “identified several highly potent next generation” antibodies that have shown activity against all COVID variants tested to date, including BQ.1.1. Regeneron has also said it was working on next generation antibodies against current and future variants.

Lilly said in a statement that it continues to assess its drug bebtelovimab against emerging variants. During an earnings call earlier this month, Chief Scientific Officer Daniel Skovronsky said the company also has potentially broadly neutralizing antibodies in its labs that it would consider bringing forward “if there is a need and an aligned path forward with health authorities.”

During the same call, however, executives said that antibodies will not be a major driver of long-term growth for the company.

Currently, most monoclonal antibodies target COVID’s receptor binding domain, the part of the spike protein that latches directly onto human cells. But that region has been under tremendous pressure from both treatments and vaccines, making it a likely site for new mutations. Two other regions of the spike protein that have been shown to play a role in immune responses of people who have recovered from COVID could be new targets for antibodies.

Closely held Generate Biomedicines Inc. is developing a treatment targeted at a different region of the spike protein to see if it can build a more potent antibody that could be combined with other therapies. But that’s not likely to come in time for a winter surge: The Boston-based company is planning to start testing its product in humans in 2023.

White House COVID Response Coordinator Ashish Jha said this week that without government support, next-generation vaccines and treatments could take 5 to 10 years to develop. While the administration is requesting additional funding to help with development, securing that money will likely continue to be an uphill battle in Congress.

Bloomberg’s Immanual John Milton contributed to this report.

Boxes of Pfizer Inc.’s Paxlovid antiviral medication.

Boxes of Pfizer Inc.’s Paxlovid antiviral medication. (Kobi Wolf/Bloomberg)

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