NIH plots path forward for clinical trials of long COVID treatments

The National Institutes of Health has spent most of its nearly $1.7 billion in funding for long COVID on research designed to learn more about the condition rather than on trials for new treatments—a sore point for many advocates who feel frustrated by the lack of medical options. But if the 3-day meeting the agency just held to discuss the future of its RECOVER initiative is any indication, things are about to shift.

The NIH called the first phase of the initiative Researching COVID to Enhance Recovery (RECOVER). Its newest project will be called RECOVER-TLC, tacking on an acronym that stands for “treating long COVID.” Unlike the first iteration of RECOVER, the TLC phase will focus on clinical trials; it will be led by the National Institute of Allergy and Infectious Diseases (NIAID), an NIH subagency. Jeanne Marrazzo, director of that institute, will have a team dedicated to long COVID clinical trials reporting directly to her.

RECOVER plans to launch RECOVER-TLC Intervention Information Request Form by the end of the month, a portal that drugmakers and other researchers can use to submit potential treatments for the team to consider. Marrazzo emphasized the importance of her group’s timely responses to those submissions in her remarks during the meeting, which was held over 3 days in Washington, DC, and virtually.

“This should not be a yearlong process,” Marrazzo said. “We need to do this quickly.”

The urgency is a welcome change for critics of RECOVER. The initiative launched in 2021 and did not begin funding clinical trials until mid-2023. Even then, not all those studies were designed to test pharmaceutical interventions: half of them test a therapeutic video game and exercise therapy.

Critics say that at best that’s a misuse of funds. Anyone can try a nonpharmaceutical intervention like exercise, but it takes access to a physician—or a clinical trial—to try something like a medication. At worst, they’re dangerous. Exercise in particular has the potential to harm patients with postexertional malaise (PEM), a hallmark symptom that leaves people unable to exert themselves physically or cognitively. RECOVER’s lack of focus on pharmaceutical interventions has also excluded the few industry players working to develop drug candidates that could address long COVID symptoms.

Some executives of smaller biotechnology firms spoke during the RECOVER-TLC kickoff meeting. Tonix Pharmaceuticals CEO Seth Lederman, whose firm was until recently developing a drug for fibromyalgia-type long COVID, said that streamlined, widely accepted protocols for long COVID clinical trials could bring in private investors who otherwise don’t see a path to approval. Christopher McAleer, chief scientific officer at Aim ImmunoTech, raised a similar point.

“From the biotech perspective, I recommend at least part of RECOVER-TLC focus on generating data that can be used for [US Food and Drug Administration] approval,” Lederman said. The dearth of agreed-upon endpoints has presented “major obstacles to enticing industry biotech and investors to commit to the clinical development of long COVID drugs,” he added.

The next major challenge will be figuring out what those trial endpoints should be.

Long COVID can present very differently from person to person. It impacts the gut, brain, cardiovascular system, and endocrine functions to different degrees. Its symptoms share Venn diagrams with multiple other diseases: myalgic encephalomyelitis, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and fibromyalgia, among others.

“This is a disease that has many different heads, like a hydra,” said Paul Lee, deputy director of the FDA’s Office of Neuroscience, during a discussion Tuesday.

Some researchers want well-defined biomarkers, like microRNAs or microclots in the blood, to document the pathophysiology of the condition. Others point to nonbiological metrics, like clinically validated questionnaires for fatigue and cognitive function.

Access is a significant issue: people with a disease that robs their energy often cannot make their way to a medical center for blood tests or bone marrow biopsies, for instance. People with the most severe cases of long COVID cannot leave their homes or in some cases even their beds, which puts a spotlight on the need for decentralized trials that allow people to participate remotely.

There’s also the question of whether to measure potential treatments against placebo, as is standard for most novel medicines. While there are no approved drugs for long COVID, there are medications and other treatment protocols for the disorders that overlap with the condition—beta blockers for POTS, antihistamines for MCAS. Multiple speakers pointed out that those with long COVID may not feel motivated to participate in a clinical trial in which they might receive a placebo if they can access treatment outside the study.

“These studies are going to live or die, they’re going to succeed or fail, on study design,” said Josh Fessel, director of the Office of Translational Medicine at the National Center for Advancing Translational Sciences.

NIAID appears likely to green-light multiple types of trials. Lisa McCorkell, a cofounder of the Patient-Led Research Collaborative who coauthored a paper on clinical trial design for long COVID earlier this year (Life Sci. 2024, DOI: 10.1016/j.lfs.2024.122970), endorsed that approach during a presentation Wednesday. She also suggested that NIAID appoint a “quarterback” to spearhead that greenlighting—specifically, Michael Peluso, a UCSF researcher who has been studying long COVID since early 2020 and is currently running a trial of a monoclonal antibody in people with the condition.

For long COVID patients—McCorkell among them—the success of RECOVER-TLC is critical. As COVID-19 spreads, the cumulative toll of long COVID will only grow, as it has for the past 4½ years.

“Our lives are at stake. I cannot emphasize this enough,” McCorkell said. “We need to turn this meeting into action.”