A Crucial Group of Covid Drugs Has Stopped Working

A key tool in the early pandemic response, monoclonal antibodies are now ineffective against new variants. Immunocompromised patients are especially at risk.

In March 2020, as a mysterious respiratory virus was sweeping the globe, researchers at Vanderbilt University Medical Center in Tennessee tracked down some of the first known Covid-19 patients in North America and asked them for blood samples.

Doctors shipped vials of the blood to Nashville, where the Vanderbilt team got to work analyzing it for proteins called antibodies, which the immune system generates when it’s exposed to a virus or other foreign substance. In particular, the Vanderbilt team was looking for neutralizing antibodies—those capable of binding to the SARS-CoV-2 virus and preventing it from entering cells and causing infection.

They isolated hundreds of antibodies and, by the end of April 2020, identified two particularly potent ones that became the basis of Evusheld, a preventive drug for people with weakened immune systems who don’t respond well to the Covid-19 vaccines. Made up of two lab-made antibodies, Evusheld mimics natural ones that fight infection. But the latest coronavirus variants can evade the drug. On January 26, the US Food and Drug Administration (FDA) pulled Evusheld from the market, saying that it’s unlikely to work against more than 90 percent of the Covid-19 variants currently circulating in the United States.

“We had been seeing the data,” says Robert Carnahan, associate director of the Vanderbilt Vaccine Center. “We had already mourned the loss of Evusheld and knew it was just a matter of time.” It was the last remaining antibody drug designed to fight Covid-19.

Antibody drugs—also known as monoclonal antibodies—have been an important weapon against the virus. Meant to boost the immune system, these drugs have shown they can keep high-risk patients out of the hospital. Over the past two years, the FDA authorized a handful of them for the treatment of mild to moderate Covid-19, while Evusheld was meant as a prophylaxis. (Evusheld is given as an injection; others are a one-time infusion.) But one by one, all of them faltered as the virus mutated.

The problem with these existing monoclonal antibodies is that they bind to a very small piece of the virus known as the receptor binding domain, part of the spike protein. Throughout the pandemic, this part has constantly mutated, giving way to new variants and subvariants that current monoclonal antibodies can no longer recognize and neutralize.  

In November 2022, the FDA revoked the authorization of bebtelovimab, the last of the Covid treatment antibodies, saying the drug was not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1, which made up more than 57 percent of cases at the time. Those subvariants have been quickly supplanted by another, XBB.1.5, which made up around two-thirds of cases as of the beginning of February, according to the Centers for Disease Control and Prevention.

Antiviral drugs, such as Paxlovid, are still effective against XBB.1.5 and other Omicron lineages because they use a different mechanism to target the virus. Designed to hijack SARS-CoV-2’s replication process, antivirals stop the virus from making copies of itself and multiplying in the body.

Paxlovid is for adults and children 12 and older who are at higher risk of severe Covid-19. A study published in December found that the drug reduced patients’ risk of hospitalization or death from Omicron variants by 44 percent, compared to those who weren’t prescribed the drug.

Yet uptake of Paxlovid has lagged. There’s been confusion over who is eligible, and it previously took a positive test result to get a prescription. The FDA did away with that requirement on February 1, which could help more people access the pill when it is most effective—within the first few days of symptoms.

“It’s a lot more convenient for patients to pick up a pill from the pharmacy than it is to go for an infusion of a monoclonal antibody, especially when health care is so short-staffed right now,” says Danielle Wales, a primary care physician at Albany Medical Center in New York.

But not everyone can take Paxlovid. The drug can interact with a long list of other medications, including commonly prescribed statins, heart medications, and blood thinners. Ann Woolley, an infectious disease doctor at Brigham and Women’s Hospital in Boston, says that up until a few months ago, patients not eligible for Paxlovid would have gotten monoclonal antibodies. Now, the hospital has switched to treating those patients with the antiviral remdesivir, sold under the brand name Veklury, the first treatment to be approved for Covid-19 in October 2020.

But there are drawbacks. “The problem and limitation with remdesivir is that it’s given as an IV over the course of three days, and so it’s more difficult for patients to have to go to an infusion site for three consecutive days,” she says. “It also limits the number of patients that can be treated because there are limited spots.”

Lagevrio, or molnupiravir, is another antiviral option for patients who can’t take Paxlovid. It’s also a pill, but it’s less effective than Paxlovid.

Carnahan says there’s still a need for monoclonal antibodies, because people who don’t mount a good immune response following vaccination are now virtually unprotected against the virus. “For them, it’s back to day one of the pandemic,” he says. “The consequences for getting an infection could be very dire for them.” A recent study that reviewed data from more than 150,000 adult patients in the UK from January 2020 to February 2022 found that immunocompromised patients had a 44 percent higher risk of death from Covid-19 than those with healthy immune systems.

The Vanderbilt team and others are continuing the search for powerful antibodies that could be turned into new drugs, including preventive ones like Evusheld. But it’s a constant game of viral whack-a-mole. “The virus has changed so rapidly that antibody discovery efforts get stopped mid-track,” Carnahan says. “Variants are changing now on a three-month time scale.” His group would find an antibody that was effective against a current variant, only for it to be rendered useless by a new variant a few months later.

The changing nature of the virus also makes it difficult to conduct human clinical trials and get a new antibody to patients in time for it to work against the current variants. At a meeting in December, drugmakers asked US and European regulators to consider adopting new standards for approving new antibody drugs, especially those meant for immunocompromised people. They suggested that new antibody drugs that are similar to previously authorized ones shouldn’t have to go through large clinical trials to test their effectiveness. Instead, extensive lab tests and small safety trials, like what’s done for the annual flu vaccine, may be sufficient.  

Researchers are now looking for the holy grail of antibodies, one that would be longer-lasting and effective across many variants of SARS-CoV-2, including those that might emerge in the future. Carnahan’s team has identified what he calls a “small panel of antibodies” that, at least in lab, work against all of the existing Covid-19 variants, including XBB.1.5. They’re now looking for a company to partner with that could further develop those antibodies and test them in clinical trials. The group previously partnered with AstraZeneca, which commercialized Evusheld.

Scientists at Regeneron Pharmaceuticals, the New York–based biotech company that made one of the monoclonal antibody treatments, have identified an antibody that binds to a region outside the receptor binding domain. “We have been able to identify one antibody against a site of the virus that is very conserved,” meaning this part of the virus hasn’t changed much, says Christos Kyratsous, who heads infectious disease research at Regeneron. “It’s been conserved from the beginning of the pandemic all the way to today. It’s a very rare antibody, because unlike other antibodies that are binding to these conserved sites, it is extremely potent.”

And that gives him hope that lab-made antibodies developed to recognize this site will keep working, even if the virus’s receptor binding domain continues to mutate in the future. Still, Kyratsous says there’s often a trade-off between breadth and potency. There may be many antibodies that bind to many variants but don’t neutralize them well. So far, this one seems to do both. In clinical trials this summer, Regeneron plans to test the antibody as both a prophylaxis against and a treatment for Covid-19.

In December, AstraZeneca began testing a potential replacement for Evusheld in trials of immunocompromised patients. In lab studies, the new long-acting antibody has been shown to neutralize all SARS-CoV-2 variants tested to date, including variants that have proved resistant to other monoclonal antibodies, according to a company statement from January. AstraZeneca says it’s aiming to make the new antibody available in the second half of 2023, pending regulatory approval. The company estimates that around 2 percent of the global population could benefit from monoclonal antibodies for Covid-19 protection.

For the rest of the population, Adarsh Bhimraj, an infectious disease physician at Houston Methodist Hospital in Texas, thinks our current vaccines and antivirals will be enough. “This is not 2020, where we have no drugs and the pandemic is causing lots of deaths and hospitalizations,” he says.

He says there should be a higher bar for getting antibodies approved for treating Covid-19 now that effective antivirals are available, and death and hospitalization rates are down. He thinks drugmakers should be able to show that new antibodies can alleviate symptoms and shorten the length of disease, rather than simply keep people out of the hospital. “What matters to patients should be studied in trials,” he says.

For now, the FDA recommends that clinics and hospitals keep existing monoclonal antibody drugs on hand in case variants that are susceptible to them pop up again in the US. “Although the monoclonal antibodies don’t work right now, there is always a possibility that the circulating Covid-19 variants change so the monoclonal antibodies may work again in the future,” Wales says. “We don’t know that yet.”

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