Investigating Bezisterim for Neurological Symptoms of Long COVID: The Phase 2 ADDRESS-LC Study

Welcome to NeurologyLive^®'s Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 2 ADDRESS-LC study (NCT06847191), a unique study assessing the therapeutic potential of bezisterim (BioVie), a blood brain barrier-permeable, insulin-sensitizer, as a treatment for patients with neurological symptoms associated with Long COVID.¹

“The ADDRESS-LC clinical trial is highly significant for patients with Long COVID because it is studying a potential disease-modifying treatment that targets two of the most disabling symptoms: fatigue and cognitive dysfunction,” Lindsay McAlpine, MD, a neuroimmunologist in the Division of Neurological Infections and Global Neurology at the Yale University School of Medicine, told NeurologyLive^®. “Bezisterim is a highly promising treatment for Long COVID, a condition with no approved treatments. It is well tolerated and the mechanism of action aligns with our current understanding of how Long COVID affects the body and the brain.”

Bezisterim, also known as NE3107, is an investigational anti-inflammatory agent in development for Long COVID and other neurodegenerative disorders, including Alzheimer disease (AD) and Parkinson disease (PD), where toll-like receptor–mediated inflammation is associated with cognitive decline. In previous studies, the agent has been shown to inhibit TLR4-induced signaling and nuclear factor κB–mediated inflammatory pathways and is orally administered, crosses the blood-brain barrier, and is not considered immunosuppressive. In clinical studies of AD and PD, prior findings showed that bezisterim demonstrated a favorable safety and tolerability profile.

“It is critical for patients to have access to targeted disease-modifying treatments like bezisterim, in addition to symptomatic treatments. Bezisterim cross the blood-brain barrier and targets highly relevant pathways linked to Long COVID’s most disabling symptoms,” McAlpine added. “Converging evidence suggests that endothelial dysfunction and inflammatory immune dysregulation at the blood-brain barrier as well as metabolic and mitochondrial dysfunction contribute to Long COVID.”

She continued, “By selectively inhibiting NF-κB signaling pathway–mediated inflammatory cascades (including TNFα), bezisterim has the potential to reduce pathologic inflammation, improve insulin sensitivity, and modulate epigenetic regulation. Across clinical trials, this multi-targeted mechanism aimed directly at the biological drivers of disability in Long COVID distinguishes bezisterim as a promising treatment.”

ADDRESS-LC Study Design

The ADDRESS-LC trial is a randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, and tolerability of bezisterim in adults with Long COVID who experience cognitive impairment and fatigue. The primary end point is change from baseline in cognitive performance on the Cogstate Cognition battery at 12 weeks. Other secondary end points include assessing changes in patient-reported outcomes, including PROMIS Cognitive Function, Fatigue, and Sleep Disturbance short forms, SF-12 physical and mental component scores, and the DePaul Symptom Questionnaire post-exertional malaise domain.

The study is comparing bezisterim, administered as a 20 mg oral capsule twice daily, with a matching placebo to assess its effects on neurocognitive and fatigue-related symptoms. Participants will receive the treatment for 84 days, complete 5 clinic visits for evaluations, and participate in a follow-up phone assessment. Currently, there are no approved treatments for this condition, as many individuals across the country still face issues with fatigue and brain fog stemming from COVID-19 infection.

Inclusion Criteria

Eligible participants are adults aged 18 to 69 years who present with long COVID characterized by neurological symptoms, including fatigue and neurocognitive impairment, that begin or worsen following a confirmed or clinically diagnosed SARS-CoV-2 infection occurring at least 3 months prior to screening. Symptoms must persist for a minimum of 3 months and, in the opinion of the investigator, cannot be explained by another condition.

Participants are required to maintain stable doses of concomitant medications, use appropriate contraception, provide informed consent, and be willing to undergo blood collection and all screening procedures. Key exclusion criteria include receipt of a COVID-19 vaccination in 14 days prior to screening, prior admission to an intensive care unit for COVID-19, or a history of significant mental or physical illness preceding SARS-CoV-2 infection.

"The ADDRESS-LC trial was designed with input from Long COVID patients with the goal of helping to address the tremendous unmet needs of this community," Penelope Markham, PhD, Senior Vice President of BioVie’s Liver Disease and Long COVID Programs, said in a statement.² "Ongoing neuroinflammation has been observed in many patients with Long COVID, and BioVie leveraged its experience in studying other neurodegenerative diseases characterized by inflammation to create a unique trial that will both rigorously evaluate bezisterim in patients and add to our understanding of Long COVID pathology as a whole.”

Prior Phase 2 Parkinson Study

In PD, findings from a prior phase 2 study (NCT05083260) indicated that patients receiving bezisterim in combination with levodopa experienced significant improvements in morning ON symptoms and clinically meaningful gains in motor function compared with levodopa alone. The company noted that no drug-related adverse events were reported in the study.

Bezisterim is also being evaluated in the ongoing randomized, double-blind, placebo-controlled phase 2 SUNRISE-PD trial (NCT06757010), which assesses its potential to improve motor and nonmotor symptoms in patients with early-stage PD who have not received carbidopa/levodopa. The study, presented at the 4th Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 27-30, 2025, is examining bezisterim as monotherapy, with topline results expected in mid-2026.³

Phase 3 Alzheimer Study

In AD, previously reported topline results from a phase 3 study (NCT04669028) evaluating bezisterim suggested potential treatment effects that were comparable or greater than those observed with previously approved antiamyloid therapies. In the study, participants receiving the orally bioavailable, blood-brain barrier–penetrant anti-inflammatory insulin sensitizer demonstrated a mean reduction in biological aging of more than 5 years based on DNA methylation measures, compared with placebo.⁴

"Bezisterim has demonstrated the ability to modulate key inflammatory pathways implicated in the chronic inflammation seen in long COVID, that also play a key role in neurodegenerative diseases of aging, like Parkinson disease and Alzheimer disease. By reducing neuroinflammation and addressing potential metabolic dysfunction, our hope is that bezisterim may have the potential to help patients with long COVID,” Cuong Do, MBA, president and chief executive officer at BioVie, said in a statement.¹ "This trial will explore whether targeting these mechanisms can help restore normal function and improve quality of life for individuals affected by the neurological symptoms of long COVID, and we look forward to sharing our findings in the first half of 2026."

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REFERENCES
1. BioVie Enrolls First Patient in ADDRESS-LC Clinical Trial Assessing Novel Anti-Inflammatory Candidate Bezisterim for the Treatment of Neurological Symptoms Associated with Long COVID. News release. BioVie. May 15, 2025. Accessed April 29, 2026. https://investors.bioviepharma.com/news/news-details/2025/BioVie-Enrolls-First-Patient-in-ADDRESS-LC-Clinical-Trial-Assessing-Novel-Anti-Inflammatory-Candidate-Bezisterim-for-the-Treatment-of-Neurological-Symptoms-Associated-with-Long-COVID/default.aspx
2. BioVie Highlighted ADDRESS-LC Phase 2 Trial Design Exploring Bezisterim for the Treatment of Neurological Symptoms of Long COVID at Keystone Symposia on Long COVID and Other Post-Acute Infection Syndromes News release. BioVie. August 13, 2025. Accessed April 29, 2026. https://investors.bioviepharma.com/news/news-details/2025/BioVie-Highlighted-ADDRESS-LC-Phase-2-Trial-Design-Exploring-Bezisterim-for-the-Treatment-of-Neurological-Symptoms-of-Long-COVID-at-Keystone-Symposia-on-Long-COVID-and-Other-Post-Acute-Infection-Syndromes/default.aspx
3. BioVie Highlights Patient-Centric Design of SUNRISE-PD Trial at Advanced Therapeutics in Movement & Related Disorders® Congress (ATMRD). News Release. BioVie. Published June 26, 2025. Accessed April 29, 2026. https://investors.bioviepharma.com/news/news-details/2025/BioVie-Highlights-Patient-Centric-Design-of-SUNRISE-PD-Trial-at-Advanced-Therapeutics-in-Movement--Related-Disorders-Congress-ATMRD/default.aspx
4. BioVie announces efficacy data from phase 3 trial of NE3107 in patients with mild to moderate Alzheimer’s disease. News release. BioVie. November 29, 2023. Accessed April 29, 2026. https://www.globenewswire.com/news-release/2023/11/29/2787674/0/en/BioVie-Announces-Efficacy-Data-from-Phase-3-Trial-of-NE3107-in-Patients-with-Mild-to-Moderate-Alzheimer-s-Disease.html