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Michael Dahl walked into a UCSF clinic in San Francisco the other day, as he has done many times since the brain-sapping symptoms of long COVID changed his life nearly two years ago.
But this time, he and his doctors hoped it would be Dahl who will change long COVID. On Aug. 22, Dahl became the first person to receive an infusion of monoclonal antibodies aimed at treating the confounding condition that has impaired millions of people around the world. The clinical trial is one of only a small number testing a treatment or cure for the post-COVID condition, which is bafflingly complex, often robbing people of the ability to think clearly, wake up refreshed from sleep, exercise, or even breathe deeply. Yet, the repair that Dahl is testing is surprisingly simple. It rests on evidence that pieces of the coronavirus that causes COVID can linger in the body for years after infection. UCSF scientists want to see if annihilating those bits can improve or even erase the debilitating symptoms. “This is just hypothetical, but that is why we’re doing the study,” said Dr. Michael Peluso, principal investigator of the trial dubbed outSMART-LC. “We’re going to take the virus out of commission — we think — and see if people feel better.”
The drug that he and co-investigator Dr. Steven Deeks are aiming at the unwanted viral visitors is a monoclonal antibody, a lab-made protein that attacks viruses more effectively than natural antibodies. Called AER002, it’s manufactured by Aerium Therapeutics, a Boston biotech company. Normally, when people get sick their bodies produce antibodies that broadly target the invader like a shotgun, with some defense responses more effective than others. But researchers who developed monoclonal antibodies decades ago were able to sift through them and “find the ones that were most effective at preventing the virus from doing harm,” said Dr. Rajeev Venkayya, Aerium’s chief executive officer. As a result, they became “like guided missiles,” focused precisely on a single target, he said. It can take a year or two to bring to market the right kind of monoclonal antibody tailored to a particular invader. During the pandemic, federal regulators sped up the approval process, and doctors used them to help prevent COVID in especially vulnerable people, as well as to treat acute illness. They were developed specifically to disable the spike-shaped protein used by the virus like a door key to enter and infect cells. Then the coronavirus mutated. By fall 2022, those monoclonal antibodies, such as Evusheld and bebtelovimab, were useless for preventing or treating COVID, and no one gets sick from the old COVID variants anymore. But millions of people who were infected by those early strains now have long COVID. To Peluso and Deeks, who run UCSF’s long COVID research program, the outdated monoclonal antibodies were not useless but vital.
Their clinical trial is enrolling 30 participants with long COVID — but only people who were infected before September 2022, so that whatever bits of the virus may remain in their body would be susceptible to the monoclonal antibodies. “They also have these other magical properties where, in addition to neutralizing pieces of the virus, they can also hone and recalibrate a person’s natural immune response to be more effective,” Peluso said. “It’s a combination of latching on to those proteins and training your immune cells to do it on their own.” In the study, 20 participants will get a single 1,200mg dose of AER002, and 10 will get a placebo. Neither the doctors nor the participants will know who got which until the end of the study.
“If it turns out to be a cure, fantastic!” Dahl said. “Maybe I’ll help people out there. Save lives. Save long COVID suffering.”
Dahl knows a lot about that. At 65, he was fully vaccinated in January 2022 when he donned a mask and got on a bus to visit his aunt, a retired nun in San Rafael. Within days, Dahl felt ill. He tested positive for COVID for about a month but said he weathered the experience well. “I felt I had dodged a bullet.” But after a month, Dahl awoke exhausted and dizzy, with a throbbing in his right temple. Those and other symptoms never entirely went away. The World Health Organization defines long COVID as symptoms that impact everyday functioning and may begin months after infection, endure at least two months and “cannot be explained by an alternative diagnosis.” Dahl, who worked in quality assurance for a tech company, still feels ill many mornings and says he has episodes of short-term memory loss and “post-exertional malaise” — a common symptom where physical and mental activity prompts feelings of exhaustion — about twice a week. Dahl also lost his sense of smell, although he said he was delighted recently to get a whiff of popcorn and look up to see a woman carrying a bucket of it. Dahl doesn’t know whether the monoclonal antibodies will restore his health — or whether he even got the drug at all. But he hopes so. “I feel lucky,” he said. Peluso said he doesn’t know when participants who got the real drug might start feeling better. “If it has an effect, it will build up and persist in your body over three, four, five, six months,” he told Shelley Hayden, 55, as she lay with a needle in her arm at UCSF’s Clinical Research Center on Sept. 11. She was the third person to be infused. A marketing executive whose post-COVID symptoms forced her to stop working, Hayden has long felt frustrated by the scientific establishment’s emphasis on studying long COVID’s characteristics more than its treatment. Her impatience is shared by many sufferers who support each other online and trade ideas about alternative remedies for easing symptoms when their doctors shrug their shoulders.
As the clear liquid seeped into her arm in a small infusion room with a view of the orange tips of the Golden Gate Bridge, Hayden talked about the long-COVID community that has emerged in recent years. Beyond physical symptoms, she said, many people have newfound money woes because they can no longer work. “Or you just feel like you’re all alone and this is never gonna get any better,” Hayden said, recalling a woman who recently told the online community that she was considering suicide. To Peluso and the nurses in the room, she said, “I’m not here by myself. I am energetically representing millions of people around the world right now.” Some scientists are also looking at whether Paxlovid, the antiviral drug that eases acute COVID symptoms, might be a way to wrestle long COVID to the ground, with studies at Stanford, Yale and through the federal government’s $1.15 billion RECOVER program. Paxlovid blocks the virus from replicating and spreading “but might not get rid of it,” said Deeks, co-investigator of the monoclonal antibody study, who in August convened the first scientific conference devoted to long COVID. “We’re taking a different approach using therapies that have the ability to get rid of the virus,” Deeks said of the UCSF trial. Dr. Harlan Krumholz, a co-leader of the Yale Paxlovid study, called the UCSF effort “an important step from a different direction to test the viral persistence theory,” an idea he said was gaining credence. “We need to be doing more trials that address the suffering experienced by people with long COVID,” Krumholz said. The UCSF trial is small but “has the potential to suggest another line of treatment.” Aerium is supplying the drug for the UCSF trial. The nonprofit Patient-Led Research Collaborative and its research fund are supporting the trial with a $500,000 grant from Balvi, a fund that backs COVID projects overlooked by traditional funders “for being too early or ‘outside the box,’ or because there’s no financial incentive.” The PolyBio Research Foundation is providing additional support, including for viral persistence measurements. “We have no approved treatments for long COVID, and we have a profound shortage of clinical trials,” said Lisa McCorkell of Oakland, who co-founded the collaborative of patients pushing research after she developed the condition. “This trial is exciting as it will get us closer to understanding the pathophysiology of long COVID.”
Reach Nanette Asimov: nasimov@sfchronicle.com; Twitter: @NanetteAsimov
