Drug companies could create new drugs to protect the Covid vulnerable. Why aren’t they?

Twice, Janet Handal thought she would get a reprieve from semi-lockdown life. The first was when she was vaccinated in January, 2021. But a negative antibody test quickly dashed those hopes; the same immunosuppressants she took to prevent her body from rejecting a kidney transplant also prevented it from responding adequately to vaccines.

So the 71-year-old New Yorker turned her attention to a drug, then in clinical trials, designed to protect immunocompromised people like her, enriching their blood with antibodies they struggled to make on their own. Evusheld was authorized last Dec. 8 — six days before lab data showed it would be significantly less effective against Omicron, the immune-evasive variant about to sweep the globe.

Since then, Handal and the roughly 200,000 other Americans to receive Evusheld have had to recalibrate their hopes. Although the Food and Drug Administration doubled the recommended dose to compensate, and the drug — when given along with the full complement of vaccines — still offers protection against severe disease, gone are hopes that the most vulnerable could ditch masks or return to their pre-Covid lives.

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As the BA.5 variant spreads, Handal said she is seeing people in a Facebook group she runs for the immunocompromised, most of whom received Evusheld, getting “Covid left and right.” These BA.5 infections are generally mild, but members worry about what’s next.

“People are resigned to the fact that there’s going to be another variant and trying to make their peace with that,” she said. “Everybody had hoped it would be over and we could resume having a normal life.”

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Although the problem is now eight months old, few other prophylactic drugs for people with compromised immune systems are on the horizon. Several companies have announced plans to bring forward new Covid-19 antibodies, but they virtually are all either still in animal studies or are being principally developed as therapeutics.

The absence is particularly notable given the potential size of the market: Although Evusheld has remained vastly underused, a fact some physicians attribute to its hazily defined efficacy, between 7 and 10 million Americans are immunocompromised — a huge market by drug industry standards.

The situation has frustrated some physicians who treat transplant and cancer patients.

“I wish there was a more robust pipeline,” said Sophia Koo, an infectious disease specialist at the Brigham and Women’s Hospital.

The paucity of Evusheld successors on the horizon in part reflects just how unexpected Omicron was. Prior to the variant’s Thanksgiving emergence, a startup called Adagio had raised around $750 million to develop a long-acting, next-generation antibody that was supposed to be able to snare any SARS-CoV-2 variant and most closely related coronaviruses.

That drug might well have proven effective: Unblinded clinical trial data later showed that during the Delta-variant wave, the drug reduced the risk of developing symptomatic Covid-19 by 71%. But Omicron’s subvariants rendered the drug effectively inert, forcing Adagio back to the drawing board.

Omicron also wiped out Regeneron’s antibody cocktail. Although the drug had been authorized as a treatment for over a year, the company was hoping at the time to snag prophylactic authorization from the FDA.

Vir and GSK’s antibody remained effective against Omicron, but BA.2 knocked it out, just as Koo launched a prevention study (it is ongoing, albeit at a far higher dose). The FDA authorized a new antibody, bebtelovimab, from Eli Lilly for treatment, but a spokesperson told STAT the company “has no plans” to test it in prevention.

Koo said she received a similar answer when she inquired about studying bebtelovimab as prophylaxis, chalking up their reasoning to limitations on production.

It’s not difficult to isolate new antibodies that powerfully neutralize Omicron and its various offshoots, said James Crowe, the Vanderbilt immunologist who in 2020 first isolated the antibodies in Evusheld.

The question is whether companies are willing to bring them forward, especially when the U.S. government has shown little interest in shouldering the costs, as they did with many of the first wave of antibody drugs. Although the White House has spent months talking about updating vaccines and building universal shots, talk of new antibodies has been scarce.

“It becomes more of a business question than a medical question,” said Crowe.

The business case is tough. Before Omicron, investors “lost interest” in Covid projects because the vaccines were working, said Hugo Fry, a biotech entrepreneur. His startup, RQ Biotechnology, needed to take out a loan from a charity to develop its antibodies — which proved pivotal when Omicron appeared and AstraZeneca licensed the drug as a potential replacement for Evusheld.

Even with Omicron, though, the costs and potential profits from such a program remain murky. The first generation of Covid drugs were developed through expensive placebo-controlled trials. But with so much of the population now having some level of prior immunity, you would probably need very large trials to demonstrate efficacy.

“You’re adding your drug on top of three to four shots of vaccine,” said Ellie Hershberger, Adagio’s chief medical officer. “How do you demonstrate the value of that?”

Instead, Adagio, Regeneron and others, including another new, well-backed startup called Aerium Therapeutics, hope to get FDA authorization through small trials that just show their drug lowers viral loads in infected patients or gives uninfected people high levels of neutralizing antibodies for an extended period. The agency relied on similar data to authorize bebtelovimab during the Omicron surge, but they have not indicated what their bar will be going forward.

Perhaps the biggest concern, though, is that any authorization may only be a temporary state, viable as long as the virus complies. “You spend all this money and time developing these efforts,” said Koo. “And the virus keeps evolving.”

Accordingly, companies are trying to develop antibody combinations the virus can’t evade. Aerium has a pair that have held up against almost every variant they’ve tested, although it’s impossible to know if they will hold up forever; no one can precisely predict the virus’s movement. Flagship Pioneering, the VC firm behind Moderna, this month launched a new startup, Apriori Bio, which claims to stay ahead of the virus with machine learning, but they have said little about their underlying technology or when they plan to actually bring drugs forward.

Adagio is employing an alternative strategy, said co-founder Laura Walker. They’re looking for antibodies that glom onto parts of the coronavirus that humans rarely build antibodies against. The idea is that if the virus evolves to evade the immune arsenal most people develop in response to vaccine or infection, their antibody will still work. If the rest of the world zags, they will have zigged.

Crowe said it’s a worthwhile strategy. And any company that makes it work could have lucrative expertise to apply beyond this pandemic.

Antibodies are “a very interesting approach to treating and prophylaxis against not just Covid but potentially other diseases…. HIV, flu,” said Bob Nelsen, managing partner of ARCH Venture and co-founder of Vir, which has a $4 billion valuation based largely on a pipeline of antiviral antibodies.

For now, though, there’s only one cocktail available. Experts recommend it, but it’s not because they think it’s the best we can do.

“We really have nothing else,” said Priya Nori, an infectious disease physician at Albert Einstein College of Medicine.

In the meantime, many patients will continue to inhabit a different world than family and friends. Next month, Handal plans to attend a relative’s wedding. Handal will mask for the ceremony and join for an al fresco cocktail hour, but when dinner comes, she and her husband will eat at a single table outdoors, while the rest of the party dances on inside.

Source: STAT