Three clinical trials for Long COVID are testing JAK inhibitors to treat immune dysregulation

In December 2023, Jen began a two-month trial of the immunomodulating drug upadacitinib, commonly known by its brand name, Rinvoq. Jen, who requested to use only her first name for this story, had severe myalgic encephalomyelitis (ME) for nearly two decades after developing an illness while traveling in Central America in 2006. 

As a patient-researcher working with a dermatologist who runs a rheumatology clinic, she had tracked her immune system with various blood tests. She identified JAK inhibitors — a new class of drug that treats various autoimmune disorders — as a possible treatment after trialing more than a hundred other medications. She was most interested in Rinvoq because it was “a bigger gun,” targeting many pathways that were elevated in her tests. 

Her doctor prescribed her the drug, which can retail for over $8,000 a month. After a difficult process of appeals, her insurance authorized it, and she was able to access the drug through a savings program.

During her two months on Rinvoq, she said she experienced side effects of “profound weakness and paralyzing fatigue.” She stopped taking the drug after 66 days because she felt sicker than ever and hadn’t seen any results. “My white blood cells got too low and I considered the treatment a failure,” she said.

But when she did a follow-up cytokine panel, her markers were in normal ranges. Then, five weeks after stopping the treatment, she went into full remission. 

“Suddenly, one day, I was Lazarus from the dead,” she said. Jen first wrote about her experience on Health Rising last fall.

Over a year after her initial trial, she said she is still in remission and is working on publishing a case study. She also shared her data and experience in a closed virtual meeting with prominent Long COVID and ME researchers last summer, sparking more interest in JAK inhibitors for the diseases. JAK inhibitors have also been hypothesized as a potential treatment for ME by researchers well before the pandemic, and are included in the National Institutes of Health ME/CFS Research Roadmap.

Now, three separate clinical trials are investigating the drugs for Long COVID. Beth Israel Deaconess Medical Center’s CLEAR-LC is studying abrocitinib (Cibinqo), while multiple universities taking part in REVERSE-LC are studying baricitinib (Olumiant). A third, international multitiered study called LC-REVITALIZE is trialing Rinvoq as well as the anti-inflammatory drug pirfenidone. 

Another trial funded by the Department of Defense is trialing another immunomodulating drug (though not a JAK inhibitor) called bezisterim.

While most of these trials won’t have immediate results, their findings will be important puzzle pieces in understanding the pathobiology of Long COVID as well as identifying possible subsets of the disease. The Sick Times spoke with investigators of all three trials, patient-researchers, and people with Long COVID and ME who have tried these drugs on their own. Some people reported improvements, but others reported no significant change in their baselines. Many experienced side effects.

“It’s intriguing to me that three groups have come up with the same drugs using different ideas, methodologies, approaches, and thoughts,” said Douglas Fraser, the lead researcher of LC-REVITALIZE.

What are JAK inhibitors?

JAK inhibitors are drugs that target the JAK/STAT pathway, which is a cellular signaling route vital to the immune system. It helps regulate cytokines, or molecules that are involved with immune responses and inflammation. When dysregulated, the pathway can be a major contributor to cancers and autoimmune diseases.

The pathway is made up of over 50 cytokines and growth factors, including hormones, interleukins, and interferons, some of which can be tested in cytokine panels from common lab companies.

The pathway fits into a prominent Long COVID hypothesis: that the disease is at least partly driven by immune dysregulation. “If we can calm down this immune dysregulation,” said Wes Ely, lead investigator of the REVERSE-LC study, “then we may be able to calm down the disease process itself.”

By blocking the Janus kinase (JAK) enzyme, JAK inhibitors can help reduce inflammation and better regulate haywire immune systems. 

“I believe the JAK inhibitors are able to get the immune system unstuck from this persistent dysfunction [in ME],” Jen said. She hypothesizes that they can “unblock the cog” that’s holding up proper communication and allow the immune system to regain a stable internal environment, or homeostasis.

The JAK pathway was originally discovered in the late 1980s, but it wasn’t until 2011 that the Food and Drug Administration (FDA) approved the first drug targeting the pathway. Now, there are 11 FDA-approved JAK inhibitors for various diseases and conditions.

Researcher Vincent Lombardi of the University of Nevada, Reno, and his collaborators suspected the drugs might be useful in treating ME well before the pandemic and began a mechanistic study for which they received a grant from Solve M.E. in 2018. 

In an interview, Lombardi explained that there are actually four JAK pathways, JAK1, JAK2, JAK3, and TYK2. His ongoing research aims to identify which JAK activation profiles are most common in ME subgroups.

The drugs in the Long COVID trials are:

• Baricitinib (Olumiant), which inhibits the JAK1 and JAK2 pathways and treats rheumatoid arthritis, severe hair loss, and COVID-19 
• Upadacitinib (Rinvoq), which inhibits the JAK1 pathway and treats numerous autoimmune conditions, including Crohn’s disease, ulcerative colitis, and rheumatoid arthritis
• Abrocitinib (Cibinqo), which also inhibits JAK1 and treats eczema

Fraser, a physician-researcher and the lead of the LC-REVITALIZE trial, described the JAK/STAT pathway like a seesaw. After a viral illness like COVID-19, you can have viral processes occurring that weigh down one side, causing a rise in inflammation, he said. 

“In some people [with] Long COVID, this inflammation stays elevated. Data shows they’re very slow to come down,” he said. The inflammation can also cause other autoimmune issues as well as coagulation and platelet activation, which may explain microclots in people with Long COVID and ME.

“But by using one of these inhibitors, you can knock down some of these upstream pathways,” Fraser said. Theoretically, using JAK inhibitors should bring down viral and inflammatory responses, which may “allow for more healing processes to take place,” he said.

Theoretically, using JAK inhibitors should bring down viral and inflammatory responses, which may “allow for more healing processes to take place,” Fraser said.

As JAK inhibitors are drugs that suppress the immune system, many come with box warnings, which is the most serious warning the FDA puts on prescription drugs. These warnings inform patients that the drugs can cause severe side effects, injury, and even death. 

Through proper screening and large trials, researchers have found that over time, the benefits of taking these drugs outweigh the risks for other diseases and conditions. The new Long COVID trials will help assess their safety profile for this condition along with their potential effectiveness.

As a result, all three trials have a long list of exclusion criteria for participants, including cardiovascular events, clotting history, liver dysfunction, and active infections. Other immune-suppressing drugs, like rapamycin, are being trialed for Long COVID, but at low doses. JAK inhibitors present greater risks.

Researchers from CLEAR-LC and REVERSE-LC said study personnel wear masks at their sites to help protect participants from new infections during the trials, though the larger hospital systems they operate in may not. The Sick Times reached out to LC-REVITALIZE to verify if study personnel wear masks.

One additional concern with JAK inhibitors is that they could “reduce the immune system’s ability to clear viruses,” Collier said.

LC-REVITALIZE: A platform trial on four continents

Led by Fraser and his team at Western University in Ontario, Canada, LC-REVITALIZE will recruit 348 participants with Long COVID in six countries: Brazil, Canada, Italy, Uganda, the U.S., and Zambia. The study will begin by simultaneously trialing Rinvoq (at 15 milligrams) and the anti-inflammatory drug pirfenidone (at 267 milligrams) daily for 90 days. Pirfenidone is approved to treat pulmonary fibrosis, a chronic lung disease. 

“The reason why we went around the globe [for study sites] is because low-income and medium-income countries have a disproportionate burden of disease,” Fraser said. 

Of the three trials, Fraser and his team’s is the only platform trial, a type of clinical trial that is more open-ended and adaptable, allowing researchers to find possible treatments for a disease at a faster pace. 

The trial will begin with four arms testing each drug compared to respective placebos. Participants will take the drugs or placebos for three months and then do follow-up testing for three months to assess their safety. Then, the researchers will analyze the first round of data. If one of the drugs is promising, they can drop the other and trial the promising drug further. If both are promising, they could stop the trial there. 

“We also have the option of dropping both drugs if they’re not working well or if their safety profile is not adequate, and moving on to a new medication,” Fraser said.

Other potential candidates for drugs in the trial include platelet-inhibitor drugs for microclots, pre- or post-biotic therapy for the gut microbiome, or oral vaccines for viral persistence, Fraser said.

Fraser and his team began data collection for the trial in early 2024 with funding from the Schmidt Initiative for Long COVID (SILC), a nonprofit that supports global Long COVID research and clinical care. 

As a part of a prior study called LC-Optimize, Fraser’s team gathered blood samples from over 1,000 participants from around the world and analyzed thousands of proteins in each sample using proteomics. 

Despite the heterogeneity of the disease, “we were able to determine that there were 13 pathways that were common no matter what geographical area and no matter what symptom cluster people were suffering from,” Fraser said. 

The researchers will use these tests, performed before and after phases of the clinical trial, as one of the outcome measures that will help determine whether the drugs are effective.

Because of these consistent pathways, Fraser and his team decided that they didn’t need to search for subgroups of the disease — as some researchers are doing for other trials — but instead that they needed to knock down common signaling pathways to see if they helped participants improve.

Based on those 13 pathways, Fraser and his team used artificial intelligence (AI) to help locate existing FDA-approved drugs that already targeted these pathways, which led them to Rinvoq and preferidone. Both drugs target numerous upstream pathways that may be responsible for driving the disease.

“Repurposing existing drugs to treat [Long COVID] could help scientists uncover effective treatments far faster than creating a new medicine from scratch,” Colin Shepard, SILC’s chief medical officer, wrote to The Sick Times.

“While symptoms and presentations may differ with geography, ethnicity, and other factors, the needs of people with Long COVID are the same everywhere,” he wrote. “A diverse group of trial participants will help us ensure that any treatment scientists develop will actually help as many people as possible, wherever they may live.”

Repurposing existing drugs to treat [Long COVID] could help scientists uncover effective treatments far faster than creating a new medicine from scratch.

Colin Shepard, Schmidt Initiative for Long COVID

REVERSE-LC: From COVID-19 to Long COVID

Another study, REVERSE-LC, also came to their JAK inhibitor with the use of AI. 

Early in the pandemic, researchers assisted by computers identified baricitinib as a potential treatment for COVID-19. Then, working with Eli Lilly, the drug company that makes it, physician-scientist Wes Ely and his team constructed a double-blind, placebo-controlled phase 3 trial to test the drug for people hospitalized with acute COVID-19.  

The study, which was later published in The Lancet Respiratory Medicine, found that baricitinib reduced mortality from COVID-19 when combined with standard care.

“That study showed the largest survival advantage of any drug for acute COVID, more than steroids, more than any other drug,” Ely said. In 2022, the FDA approved the drug for acute COVID-19.

With its success in treating COVID-19, Ely and his colleagues were curious if the JAK inhibitor might also work for Long COVID. They received funding from the National Institutes of Health (NIH) at the end of 2023.

The largest of the three JAK trials, REVERSE-LC plans to enroll 550 participants in the U.S. across four different university study sites in Minneapolis, Nashville, Atlanta, and San Francisco. Participants — who must have had Long COVID for at least six months — will take a daily 4-milligram dose of the drug baricitinib (Olumiant) or a placebo for six months to see if it can help reduce brain and cardiovascular issues. 

Michael Sieverts, a policy advisor of the Patient-Led Research Collaborative* (PLRC), is one of those participants. He was initially drawn to the trial because of the emerging research on baricitinib and other JAK inhibitors. 

He’s been in the trial since March and is taking baricitinib or a placebo until September. During his first visit while enrolling for the trial, he said he underwent numerous neuropsychological and cognition tests that the researchers will use as endpoints to see if the drug is helping as well as a post-exertional malaise questionnaire and a one-day cardiopulmonary exercise test. 

PLRC and other researchers from #MEAction and the National Academy of Medicine also helped early on with the trial. Based on PLRC’s scorecards to rate patient involvement, the study has a high degree of collaboration.

The staff at the site Sieverts visits, at Vanderbilt University in Nashville, “know how to make patients feel included, welcomed, and recognized,” he said.

The trial will release its data in 2027, which Ely acknowledged will be difficult for many people with Long COVID to hear. “We want answers yesterday,” Ely said, “but that’s how long it takes to get good science done.”

We want answers yesterday, but that’s how long it takes to get good science done.

Wes Ely, REVERSE-LC trial

CLEAR-LC: A three-armed study

CLEAR-LC is the smallest of the three JAK trials, planning to enroll 90 participants for a randomized, double-blind, placebo-controlled study. It’s a phase 2 study, while the other two are phase 3.

Unlike the other two JAK trials, the team didn’t get to its candidate, abrocitinib, through AI. Instead, researchers noticed a trend of elevated inflammatory markers in JAK/STAT pathways from blood samples of people with Long COVID, among other findings, which they shared in a 2024 preprint. 

“We were able to see that, compared to people who had recovered from COVID, our patient population with Long COVID had persistently elevated JAK/STAT signaling in both blood samples using a transcriptomic assay and then a protein in their blood,” said physician-researcher Ai-ris Collier, an author of the study and the codirector of the clinical trials unit in the Center for Virology and Vaccine Research.

“It was serendipitous that we were identifying this one pathway and that we saw that there’s a medication available that specifically targets it,” Collier said. “I think it’s reassuring that [all three trials] independently arrived at JAK inhibitors.”

Collier’s team brought that data and their clinical trial idea to Pfizer, since the biotech company made a drug, abrocitinib (Cibinqo), that targeted this pathway and was already FDA-approved. The company was eager to collaborate.

In an email to The Sick Times, a representative of Pfizer said that as a collaborator of CLEAR-LC, Pfizer is providing the funding, study drug, and placebo and contributing to the study design. 

Participants of CLEAR-LC, a three-armed study, will take abrocitinib at 50 or 100 milligrams or a placebo for three months. The researchers plan on measuring outcomes through standardized quality-of-life scales, patient-reported outcomes, and a blood test to measure C-reactive protein, which they found was elevated in their cohort. 

The in-person study has broad inclusion criteria and is based in Boston, Massachusetts. Researchers plan to complete the trial in June 2026. 

“We are also taking exploratory blood samples so that we can follow the same transcriptomic and proteomic profiles before participants start the drug, as they’re on the medication, and after they stop,” Collier said. 

By doing so, Collier and her colleagues can better understand and narrow down what may be triggering or contributing to the disease and how effective the drug is at targeting those biological pathways.

Patient reports have been mixed

Drawn by Jen’s success on Rinvoq, a small group of people with long-term ME began their own patient-coordinated case study on the drug. A trio tried the drug together following Jen’s protocol, taking 15 milligrams of Rinvoq daily for one to two months.

In a document of their experiences shared with The Sick Times, one person “saw significant improvements,” but the other two in the case study did not see improvements on the drug.

They noted that all of them felt “significantly worse” on Rinvoq, even after they stopped taking the drug, and that it decreased their baselines “for at least six weeks post-treatment.”

The group of patient-researchers is now working on a small case study with their data. The study includes Jen as a fourth participant, though she is publishing her results separately as well.

Kennedy, a person with Long COVID who is based in the U.S. and wished to use a pseudonym, also took Rinvoq. He was prescribed the drug to treat Crohn’s disease and juvenile idiopathic arthritis — which he had prior to developing Long COVID. While Rinvoq helped many of his symptoms for Crohn’s and arthritis, he said it did not improve any of his Long COVID symptoms.

“I know a lot of people are really hopeful about what [Rinvoq] would do for ME and Long COVID,” he said, explaining the drug “worked miracles” on treating Crohn’s disease. “But I’m still trapped in bed [because of Long COVID], so it didn’t move the needle for me in any other way.”

Kennedy also stressed the serious side effects of JAK inhibitors, warning about the risks of the drugs. “A lot of people in the community talk about these drugs as if they are no big deal,” he said. “I worry they don’t understand the potential side effects.”

A lot of people in the community talk about these drugs as if they are no big deal. I worry they don’t understand the potential side effects.

Kennedy, person with Long COVID

Earlier this year, patient-researchers Arvi Jansen and Jasper (who wished to use his first name only) compiled a retrospective survey of people with ME who had tried various JAK inhibitors,most of them for four months or less, including Rinvoq, baricitinib, filgotinib, and tofacitinib. Their small survey of 35 people, which included Jen, found that 49% had significant improvement, while 20% had no benefit at all. 

They noted the survey may have a “positive bias” since negative responders may be less likely to respond. Other participants, they wrote, also had concurring autoimmune diseases for which the drugs may have helped relieve symptoms.

They also noted that some participants stopped taking the drugs due to side effects, including infections, low white blood cell counts, liver issues, and more. Some participants, they wrote in an email to The Sick Times, “declared stopping was unfortunate because they had to halt improvements.” Going forward in clinical trials, Jansen would like to see subgroups that differentiate people who have post-exertional malaise from those who don’t, he wrote in sharing the survey results. 

Elisa Kava, who tracks clinical trials for CrunchME and has Long COVID, says these mixed anecdotal reports are to be expected and that it is important to wait for the trials to finish and their data to be published before drawing conclusions.

“We’re at an exciting time in Long COVID clinical trials,” she said, with significant maturity and development in the research on this disease compared to a few years ago. 

“The fact that there are [these trials studying] the same class of drug is extremely significant for the field. I think that’s why I’m so enthused. Not just for the trials themselves, but what it means about the growing level of confidence in tackling Long COVID and other IACCs.” 

The fact that there are [these trials studying] the same class of drug is extremely significant for the field. I think that’s why I’m so enthused. Not just for the trials themselves, but what it means about the growing level of confidence in tackling Long COVID and other IACCs.

Elisa Kava, CrunchME

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Miles W. Griffis is a co-founder and the executive editor of  The Sick Times.

*Editor’s note: PLRC, like The Sick Times, has received support from the Balvi and Kanro funds. Our newsroom operates independently of financial supporters.

*This story has been updated to correct information about REVERSE-LC’s trial sites.

This story is part of a series about promising Long COVID treatment trials and how they are designed. To share tips or feedback for the series, reach out to us at editors@thesicktimes.org.

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