Long COVID studies stymied by pharma’s lack of cooperation

Avindra Nath believes he has a way to treat certain people with long COVID—or at least shed a light on their condition.

Nath, a neurologist with the US National Institutes of Health (NIH), wants to use pembrolizumab to try to help improve the conditions of people with long COVID whose T cells may be exhausted. T-cell exhaustion is still poorly understood in long COVID—par for the course with the multifaceted postviral disease that’s now affected more than 400 million people worldwide (Nat. Med. 2024, DOI: 10.1038/s41591-024-03173-6). But some studies have revealed changes in T-cell responses that indicate the immune cells are, at the very least, dysfunctional, which could allow reservoirs of SARS-CoV-2 to persist and cause chronic inflammation (Lancet Infect. Dis. 2025, DOI: 10.1016/S1473-3099(24)00769-2).

Nath had previously used pembrolizumab in a small study to treat people with a brain infection called progressive multifocal leukoencephalopathy (PML). In five of the eight patients who took it, the drug managed to stabilize their condition, increasing immune activity against the virus that causes PML and reducing viral load (N. Engl. J. Med. 2019, DOI: 10.1056/NEJMoa1815039). 

Pembrolizumab is a checkpoint inhibitor that binds to the protein PD-1 on T cells to help them recognize and attack invaders. It’s better known as Keytruda, the blockbuster drug that earned its manufacturer, Merck & Co., $29.5 billion last year.

Nath figured the drug might have a similar effect in people with long COVID, based in part on the PML results. Last June, Nath approached Merck to ask for supplies of Keytruda to test that hypothesis. But just over a week after his email, according to correspondence reviewed by C&EN, a clinical director of clinical pharmacology named Gillian Gillespie replied, telling Nath that his proposed study was "not within our current company priorities." Gillespie did not elaborate, and a Merck spokesperson separately tells C&EN that the company does not comment on individual proposed studies.

Nath moved on. In September, he approached Bristol Myers Squibb (BMS), which 2 years earlier had launched a combination immunotherapy consisting of relatlimab and nivolumab. The drug, Opdualag, blocks two checkpoints—LAG-3 and PD-1—both of which are proteins on immune cells. "It targets two targets, so I thought this would be good," Nath explains. 

But he again hit a wall. On Sept. 24, a clinical trial lead for medical evidence generation named Bridget Anne McKinney declined Nath's request, saying that "the concept would not qualify for off-cycle review."

A BMS spokesperson confirms the exchange. The spokesperson tells C&EN the "request did not meet one of our therapeutic areas of interest," which include oncology, hematology, immunology, cardiovascular disease, and neuroscience. But large swaths of people with long COVID do have persistent cardiovascular and neurological issues, like postural orthostatic tachycardia syndrome (POTS), and immunological disorders, like mast cell activation syndrome (MCAS) (Nat. Rev. Microbiol. 2023, DOI: 10.1038/s41579-022-00846-2).

With both the Merck and the BMS drugs, Nath's studies would have been considered investigator-sponsored research. The NIH would have funded the mechanics of the trial—the salaries of Nath and his clinicians and analysts, any laboratory equipment, and fees paid to study participants—so the cost to the pharmaceutical companies would come down to the cost of the drug. Keytruda's wholesale acquisition price is $11,564.16 for a dose every 3 weeks. Opdualag's is $15,120 per vial. The cost to the companies is much lower.

"All the rest we can do ourselves," Nath says. "We just need the drug."

Nath is among several academic researchers who have sought to repurpose drugs for long COVID only to be met with refusals from the pharmaceutical companies that make them. It's not clear why these manufacturers have balked at supplying drugs for these trials. In some cases, the drugmakers cite the lack of a concrete biomarker—a biological metric, like a blood test—that could help researchers more definitively measure whether their drugs were causing clinical improvements. In others, they provide no reason at all, leaving scientists frustrated.

"They make billions of dollars off this drug alone," Nath says. "In dollar amounts, for them, [drug donation] is a drop in the bucket."

Persistence with little payoff

This dynamic has been playing out for as long as researchers have attempted to learn more about long COVID.

Northwestern University neurologist Igor Koralnik approached Eli Lilly and Company in early 2022 about trialing a drug called galcanezumab to treat headache in long COVID patients. In the context of the postviral condition, "headache" can be an understatement—some people have migraines so severe that they cannot move or see well, forcing them to miss out on work and family life.

According to emails reviewed by C&EN, Lilly reviewers told Koralnik "this study has merit," but the company ultimately did not provide galcanezumab, and the trial did not move forward.

Koralnik says he went through a similar rigmarole with a handful of other drugmakers, including Amgen. Amgen spokesperson Madison Howard was not able to procure information about whether the company had fielded inquiries from Koralnik.

"It was a big expenditure of energy and time on my end for no results," Koralnik says of his conversations with pharmaceutical companies. "It would be interesting if you could go to Eli Lilly and can talk to the people who are making the decision about headache and say, 'Have you ever even heard of Dr. Koralnik?' I would bet my saddle and my horse that they would say no." Lilly spokesperson Allison Howell declines to comment. 

Meanwhile, Koralnik and his colleagues have published prolifically on the neurological manifestations of long COVID, which include cognitive dysfunction, dysautonomia, and neuropathy in addition to headache. They’ve proposed pharmaceutical interventions ranging from inhaled steroids to the nerve pain medication nortriptyline (Neurotherapeutics 2022, DOI: 10.1007/s13311-022-01267-y). But few of those have moved into clinical trials.

Nancy Klimas, director of the Institute for Neuro-lmmune Medicine at Nova Southeastern University, says she approached GSK, Lilly, and Regeneron about testing monoclonal antibodies as treatments for long COVID patients and was repeatedly declined. GSK and Lilly representatives decline to comment. In emails to Klimas and C&EN, Regeneron staff cite the need for "robust," "objective criteria" before the company’s COVID-19 antibody REGEN-COV should be tested in long COVID, but a spokesperson declines to elaborate on what such criteria might be.

It took months of persistence—and assists from both the Schmidt Initiative for Long COVID and the Florida Department of Health—before Klimas finally scored a pharmaceutical collaborator. Late last year, AstraZeneca agreed to supply sipavibart, a long-acting antibody for COVID-19 that's designed to be a successor to Evusheld, for a study.

"I had a happy ending to this story instead of a terminally frustrating one," Klimas says. "Pharma companies expect academia to come up with good ideas and get the projects going, and then they snip off the best of those and move them forward.”

Her "simple request" of pharma companies "is simply to provide products."

Trials and tribulations

Only a handful of pharmaceutical compounds have been trialed as long COVID treatments. The NIH, through its Researching COVID to Enhance Recovery (RECOVER) initiative, has funded studies testing the antiviral Paxlovid, intravenous immunoglobulin, the heart rate-slowing medication ivabradine, the wakefulness-promoting drugs modafinil and solriamfetol, and the sleep hormone melatonin in subgroups of people with long COVID.

Pfizer spokesperson Kit Longley told C&EN in August that the company had supplied Paxlovid for studies run by the NIH, the Karolinska Institute, Yale School of Medicine, and Stanford Medicine.

"We believe COVID-19 will be with us for some time, if not indefinitely," Longley said by email. "As we’ve established, we intend to provide significant medical contributions across the COVID-19 disease spectrum, from prevention with vaccines to therapeutics that help patients avoid or address severe outcomes of disease."

Similarly, the Japanese firm Shionogi has provided its antiviral ensitrelvir for a trial run by University of California, San Francisco (UCSF) infectious disease clinician and researcher Michael Peluso. So has Aerium Therapeutics, with its monoclonal antibody AER002.

But these are exceptions, not the norm—and a trial is only the first step. Results are far from guaranteed in clinical science. Paxlovid didn't help the long COVID patients who took it for 15 days in the Stanford study, and while the UCSF ensitrelvir trial is ongoing, Shionogi posted mixed results from its own long COVID study last spring. Aerium shut down after providing AER002 for the UCSF trial.

Outside of investigator-sponsored research, biotech companies developing long COVID treatments on their own have struggled to find financial support for their development, leaving potential drugs abandoned on shelves.

The lackluster trial results and commercial struggles of long COVID–focused companies may scare off other pharmaceutical firms. Then there’s the fact that long COVID is closely tied in the psyche to COVID-19, a disease that most people would like to move past. Financially speaking, infectious diseases have long been "feast or famine"; a feast of funding is available when there’s an immediate threat, like COVID-19 was in 2020, but otherwise, comparatively little investment flows into the space.

"Pharma groups have come to us and said, 'We're not interested in COVID. We're not interested in any anti-infective,' " says Arnab Chatterjee, vice president of medicinal chemistry at the Calibr-Skaggs Institute for Innovative Medicines, a drug development division of Scripps Research that houses a massive database of compounds with the potential to be repurposed. He also points out that pharmaceutical companies with COVID-19 treatments may be wary of testing them as long COVID therapeutics. If a long COVID trial were to fail, that could leave a negative perception of their drug’s usefulness in acute COVID-19.

"In long COVID, it's still COVID," Chatterjee says. "It's a branding problem."

There's clearly an appetite for more drug trials among patient advocates. During a webinar in January, RECOVER representatives shared that 267 out of 404 responses to its latest request for proposals were for studies involving drugs rather than nonpharmaceutical therapies like exercise or nutrition changes. Of those, 40% of the suggested interventions were immunomodulatory agents. Another 25% were neurological agents, and 23% were antivirals.

UCSF’s Peluso says that when pharmaceutical companies do “seem interested and engaged” about donating drugs and placebo for trials, there’s often another constraint: funding. Drug manufacturers want to ensure that researchers have funding before committing to the donation. Funders want to ensure that researchers have the drug before committing to funding.

"You end up in this situation where nobody's making the commitment, aside from the people who actually want to do the research, and it just becomes this constant circular discussion," Peluso says.

There’s another chicken-and-egg problem. Some pharmaceutical firms want to await a concrete biomarker that could serve as a clinical trial end point before putting any resources toward long COVID studies, but it’s not possible to find such a metric without more studies.

Peluso points out that in some cases, drugs themselves can be used to find out how long COVID works. If an antiviral or monoclonal antibody that targets SARS-CoV-2 manages to alleviate symptoms in people with long COVID, that lends credit to the theory that viral reservoirs are a cornerstone of the disease, for instance. If a checkpoint inhibitor designed to boost T-cell activity gives a person with long COVID more energy or makes them more alert, that indicates that their immune cells are indeed exhausted and need pharmaceutical help.

Peluso says his group at UCSF has taken this approach with Shionogi and Aerium, and more trials are on the way. But in the meantime, the specter of long COVID is only growing as more people around the world are infected with COVID-19.

"I don't want to paint this picture that is horrible," Peluso says. "But we just really need to get moving."