Novel anti-inflammatory drug shows early promise in treating Long COVID cognitive symptoms, fatigue, PEM. The study looked at multiple endpoints and consulted with people living with the disease.
Key points you should know:
- Pharmaceutical company BioVie recently concluded its phase 2 trial of bezisterim, a novel drug that may improve Long COVID symptoms.
- The trial’s research team examined 22 different outcome measures rather than focusing on one primary endpoint, in a design that it calls “signal-seeking” and “exploratory.”
- While bezisterim did not produce statistically significant results and some metrics have yet to be reported, some subgroups in the trial reported improvements in fatigue, PEM, and neurological symptoms.
- The $13 million trial, known as ADDRESS-LC, was funded by a 2023 Department of Defense (DOD) grant, through the Congressionally Directed Medical Research Programs (CDMRP).
- In what it calls “high-risk, high-reward” research, the CDMRP allocated funding for treatments for conditions including Long COVID and myalgic encephalomyelitis (ME) due to the work of advocates.
In September, BioVie reported phase 2 trial results for the novel drug bezisterim, which may improve Long COVID symptoms such as fatigue and post-exertional malaise (PEM) as well as neurological symptoms. This phase 2 trial, also known as ADDRESS-LC, will inform the phase 3 trial BioVie plans to pursue.
Bezisterim can cross the blood-brain barrier, directly impacting neurological symptoms. BioVie asserts that the drug can reduce inflammation and insulin sensitivity. In the ADDRESS-LC phase 2 trial, the drug and placebo were administered as single-dose capsules taken orally.
Years of advocacy, led by people with Long COVID and myalgic encephalomyelitis (ME), made ADDRESS-LC possible. Beginning a decade ago, advocates fought to include infection-associated chronic conditions (IACCs) in the so-called high-risk, high-reward funding priorities set by the U.S. Department of Defense’s Congressionally Directed Medical Research Programs (CDMRP), which allocated $13.1 million for BioVie’s promising phase 2 trial. While the phase 2 outcomes were not statistically significant across all participants, and specific metrics have yet to be made public, several patient subgroups reported symptom improvements.
BioVie CEO Penelope Markham spoke with The Sick Times about ADDRESS-LC as well as her personal interest in ME, due a family member living with the condition for 30 years. In addition to Long COVID, bezisterim is being trialed for Alzheimer’s and Parkinson’s diseases.
“I was really struck by how well [bezisterim] seems to be tolerated across different groups,” Markham said of the drug’s impact on people living with different conditions.
The ADDRESS-LC trial met many standards for a well-designed trial. The study included 203 individuals and was conducted across clinical sites in 17 states. Experts who spoke with The Sick Times noted that BioVie enlisted input from people with Long COVID on both its scientific advisory board as well as its patient advisory board, an important but atypical choice for a pharmaceutical company. Scientific advisory boards are often composed of professional experts, such as physicians and researchers, and help determine trial parameters, whereas patient advisory boards are composed of patients and caregivers and frequently influence trial design, communication, and informed consent.
Lisa McCorkell was a member of both the scientific and patient advisory boards. McCorkell is one of the co-founders of the Patient-Led Research Collaborative (PLRC) and said that during the ADDRESS-LC trial, clinicians and executives who don’t live with Long COVID deferred to people with the knowledge and expertise of their own lived experience.
“I felt like my opinion was really respected, which is not always the case in these spaces,” she said.
Nita Jain, a biotech founder who has participated in Long COVID clinical trials, said that the bezisterim results are the most promising she’s seen of any Long COVID drug trial so far, but that the bar has been low. Like other experts, she noted that no single endpoint reached statistical significance. But certain subgroups of people experiencing high levels of cognitive impairment, fatigue, and PEM showed improvements in those symptoms, or what’s known as a “signal.”
What remains to be better understood is whether bezisterim will stand up in subsequent trials and peer review, and what benefit, if any, it may offer people living with the one of these conditions.
I felt like my opinion was really respected, which is not always the case in these spaces.
Lisa McCorkell, PLRC Co-Founder, on her experience advising thE ADDRESS-LC trial
A “signal-seeking, exploratory” trial
The heterogenous nature of Long COVID symptoms and their severity makes it difficult to test potential treatments. Currently, there aren’t any known biomarkers for Long COVID. Clinical trials that lead to new drug development require numerous phases, and they must show statistical and clinical significance. So far, few Long COVID trials have shown promise.
Another complication is that a small percentage of trial participants may at any time make a spontaneous recovery. Plus, even if a new treatment is tested and approved, it’s not likely to work for all people with the disease.
Jain said she was glad to see subjective and objective measures in the bezisterim trial, with researchers evaluating cognition, fatigue, PEM, sleep, “burdensome symptoms,” and quality of life through surveys as well as cognitive testing. Rather than focusing on one primary outcome to determine the trial’s success, the study examined 22 outcomes.
In a scientific paper describing the trial’s design, the authors explained, “As a signal-seeking, exploratory phase 2 trial, the primary outcome is intended for estimation and hypothesis generation rather than formal hypothesis testing.”
The trial’s registration on Clinicaltrials.gov initially listed one primary endpoint, a set of neurological tests called the Cogstate cognition battery, then was edited to include eight. Markham explained that Clinicaltrials.gov requires at least one primary outcome measure and that clarifying language was later added.
BioVie is a publicly traded company, and its share price fell after the phase 2 trial failed to show statistical significance. BioVie’s stock price also fell by half in August, following a phase 2 trial to treat muscle loss in people with Parkinson’s disease, which used a composite rather than primary endpoint to evaluate results. (BioVie is also the subject of a lawsuit alleging clinical trial fraud and manipulation, related to a wider complaint by Alzheimer’’s drug developers that clinical trial sites faked data.)
Among the full group of 203 Long COVID trial participants, none of those 22 outcome measures showed a significant difference between bezisterim and the placebo. However, the researchers also analyzed those participants in three subgroups: one with high levels of fatigue when the trial started, one with high PEM, and one with high cognitive impairment. Within those groups, several measurements for those specific symptoms significantly improved with bezisterim compared to the placebo. In the subgroup impacted by neurological symptoms, for example, cognitive testing scores improved significantly.
The researchers also measured immune, inflammatory, epigenetic, proteomic, and metabolic markers, but have not yet shared those results. “Although we have effect sizes, we don’t yet know about the clinical magnitude of these effects and how much quality of life improved in absolute terms,” Jain wrote in an email.
Jain noted that further trials are needed to back up early optimism. “If the signal within these subgroups that benefited the most is demonstrated within an appropriately powered phase 3, I think we’ll have a win on our hands,” she added.
Trial staff supported participants
Alex Steiner, a patient advocate in Washington, D.C., who meets the clinical criteria for moderate ME, participated in the ADDRESS-LC trial. Minimal physical or cognitive activity can cause extreme PEM for Steiner, and she was in a monthslong crash and mostly bedbound when she received a call about trial participation.
She and the other participants were not unblinded during or after the study, which means that so far, patients don’t know whether they received bezisterim or a placebo.
In text messages, Steiner expressed enthusiasm for her experience in the trial, sharing with The Sick Times that study site staff seemed familiar with Long COVID and wore N95 masks when requested, and that exam rooms contained air purifiers to help reduce the risk of reinfection.
Additionally, she noted how her access needs were supported, which included flexible scheduling, breaks, and other mobility needs. “I was able to successfully complete the trial because of the flexibility staff afforded me,” she said.
Study visits caused moderate symptom exacerbation for Steiner, including headaches, sudden-onset fatigue, and nausea, which would subside within a few hours. “I feel that the testing certainly captured my cognitive deficits and issues with memory,” she explained. “At the first visit, I remember being frustrated with myself because I knew that I was ‘failing’ the tests but couldn’t do anything about it.”
In other trials focused on older people with Parkinson’s disease, bezisterim was well tolerated. The phase 2 trial targeting individuals living with Long COVID didn’t present any new “safety signals,” meaning no new adverse effects.
Speaking with The Sick Times in late September after the phase 2 trial results were announced, BioVie’s Markham was excited to proceed with further phases and noted, “We still have a lot of work ahead.”
I was able to successfully complete the trial because of the flexibility staff afforded me.
Alex Steiner, ADDRESS-LC Trial participant
Patient advocacy creating pathways for funding
Created in 1992, the CDMRP funds biomedical research into areas of high interest to U.S. Congress, the military, and the public. The topic areas can change every fiscal year, and the CDMRP prioritizes what are known as “high-risk, high-reward conditions,” which can be difficult to fund through other grant programs.
Organizations led by people with IACCs, including Solve ME, PLRC, and the Long COVID Campaign, were instrumental in the yearslong push to make IACCs eligible for CDMRP funding based on the risk-reward criteria. The two Long COVID–related trials funded through the CDMRP are considered higher risk, higher reward than previous clinical trials in the National Institute of Health’s RECOVER program.
Solve ME president Emily Taylor said her organization laid groundwork in 2016 to launch a public campaign the following year that included meeting with congressional representatives, drafting appropriations requests, and mobilizing their network to make calls and send emails. She noted that meeting with key congressional and committee members was particularly impactful, as those staffers then helped translate community demands into actionable funding requests.
That work culminated in 2019 when ME was included as an eligible research topic. “It took years of organized advocacy to open that door, and it takes continued advocacy to keep it open,” Taylor wrote in an email.
Taylor noted that in 2024, during the second Trump administration, Solve ME began protecting the existence of the CDMRP. In fiscal year 2025, CDMRP funding dropped significantly, to $650 million, before bouncing back above $1.2 billion in 2026. “Patients need both the opportunity for their disease to be studied and the resources to make that research possible,” she said.
Patients need both the opportunity for their disease to be studied and the resources to make that research possible.
Emily Taylor, Solve ME president
Federal funding for Long COVID treatments
In the U.S. there is a long history of military funding for medical research, particularly from the Department of Defense (DOD).
Members of the military, first responders, and their loved ones often live with chronic health conditions, many of which are linked to particular exposures. Gulf War illness (GWI), a cluster of symptoms known by several related terms including Gulf War Veterans’ Medically Unexplained Illness, is a condition sometimes compared to ME and Long COVID due to its chronic, multisymptomatic nature. In recent decades, researchers studying GWI have included conditions such as ME and Long COVID in their expanding range of inquiry.
Increasingly, the DOD is funding research related to Long COVID. In August, University of California, San Francisco, infectious disease researcher Michael Peluso announced $8 million in DOD grant funding for PROBE-PASC, a new network of trials that will start with a study comparing monoclonal antibody Pemgarda in conjunction with immune-modulator hydroxychloroquine. (Peluso also served on BioVie’s ADDRESS-LC scientific advisory board.)
There are a number of other initiatives underway adjacent or directly connected to the pandemic’s impact on military and veteran health, such as the National Academies of Sciences, Engineering, and Medicine forming a committee to examine the impact of SARS-CoV-2 infections on military force readiness and health system planning.
Phase 3 ahead for bezisterim
Following the phase 2 results, BioVie advisors urged the company to pursue phase 3 funding. In an ideal world, Markham explained, phase 3 trials might include a cohort of people living with ME diagnoses that precede the arrival of SARS-CoV-2 in order to assess the safety and efficacy of the drug for them as well. She aspires to include people living with severe symptoms, which would require the trial design to be as low-burden as possible, with decentralized sites and home visits.
She also hopes the U.S. Food and Drug Administration might approve a six-month open-label (or unblinded) extension study, which would mean every participant would find out if they are receiving the drug after an initial blinded period, and those on the placebo would have the option to try the drug. Such a design might increase participant retention, as individuals receiving the placebo might otherwise drop out. Capturing a year of data from those participants would also be highly valuable to the company.
Taylor of Solve ME noted that she’s cautiously optimistic about the drug, especially as it could be relevant to the neuroinflammation, metabolic dysfunction, and impaired energy regulation experienced by people living with ME and Long COVID. While she is encouraged by the trial’s scientific rationale, randomized and replicated results are needed, she said.
“Patients urgently need reasons for hope,” she said, “but they have also seen too many prospective treatments promoted before the evidence was ready.”
Steiner, who participated in the phase 2 trial, said that the positive results “demand immediate further action.”
Steiner, who participated in the phase 2 trial, said that the positive results “demand immediate further action.”
Britta Shoot is a San Francisco–based journalist and editor. She is writing a book about early HIV/AIDS pandemic activism.
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