BioVie’s Phase 2 ADDRESS-LC trial found significant improvements with bezisterim in prespecified Long COVID subgroups with high fatigue, PEM and cognitive impairment
Written By: Aasritha Thippavajjala, PharmD
Reviewed By: Pharmacally Editorial Team
BioVie has announced topline results from its Phase 2 ADDRESS-LC trial (NCT06847191), evaluating investigational bezisterim in adults with neurological symptoms associated with Long COVID. The 203-patient study did not achieve statistical significance on any individual endpoint in the overall intent-to-treat population. However, 21 of 22 endpoints numerically favored bezisterim over placebo, while prespecified subgroup analyses identified statistically significant improvements among patients with higher baseline symptom burden.
How the ADDRESS-LC Trial Was Designed
ADDRESS-LC was a Phase 2, multicenter, randomized, placebo-controlled proof-of-concept study. The program was described by BioVie as a 16-week study, while the published protocol specifies a 12-week treatment period followed by a 4-week follow-up. Participants received bezisterim 20 mg twice daily or matching placebo.
The trial evaluated 22 clinical outcome measures covering overall clinical benefit, subjective and objective cognitive function, fatigue, sleep disturbance, quality of life and post-exertional malaise (PEM). The study was designed primarily for treatment-effect estimation and hypothesis generation, rather than as a conventional pivotal study testing a single primary endpoint.
Stronger Signals in Prespecified Subgroups
In the overall ITT population, none of the 22 endpoints reached statistical significance, although 21 showed numerical trends favoring bezisterim. BioVie said the heterogeneous population and the presence of participants with low baseline symptom burden may have diluted the overall treatment signal because these patients had less room for improvement.
A stronger signal emerged in prespecified subgroup analyses focused on patients with higher baseline symptom burden. BioVie said these analyses were defined in the Statistical Analysis Plan submitted to the FDA before unblinding, helping distinguish them from post-hoc analyses.
Patients with high baseline fatigue showed statistically significant improvements on five endpoints, including three fatigue-specific measures. Patients with high PEM demonstrated statistically significant improvements across PEM, fatigue and objective cognitive measures. Those with substantial objective cognitive impairment showed statistically significant improvements on four clinically coherent objective cognitive endpoints. Treatment effect sizes in the higher-burden subgroups were more than twice those observed in the overall ITT population.
BioVie emphasized that these subgroup findings are exploratory and require confirmation in an adequately powered prospective study.
Safety and Tolerability
Bezisterim’s safety and tolerability profile was similar to placebo. Key findings included:
- Treatment-emergent adverse events: 41.6% with bezisterim vs 55.9% with placebo
- Headache: 4.0% vs 4.9%
- Serious adverse events: 0 vs 1
Mechanism of Action
Bezisterim, also known as NE3107, is an investigational oral small molecule that crosses the blood-brain barrier and is being developed as an anti-inflammatory and insulin-sensitizing agent. BioVie describes the drug as modulating key neuroinflammatory pathways, including ERK, NFκB and TNF-α, without suppressing the immune system. Earlier BioVie materials have also described bezisterim as inhibiting TLR4-induced and inflammatory NFκB signaling.
In Long COVID, BioVie is investigating the hypothesis that persistent circulation of spike protein fragments may contribute to inflammation through NFκB activation. The company believes bezisterim’s ability to modulate this pathway could help reduce inflammation associated with persistent neurological symptoms such as fatigue, cognitive impairment and post-exertional malaise.
Path Forward
BioVie said the ADDRESS-LC findings support continued development of bezisterim and a potential future Phase 3 trial. However, the statistically significant findings were observed in prespecified high-symptom-burden subgroups rather than in the overall ITT population. The company emphasized that these subgroup findings are exploratory and hypothesis-generating and will need to be confirmed in an adequately powered prospective study.
Reference
BioVie Announces Topline Results from Phase 2 ADDRESS LC Trial Evaluating Bezisterim for the Treatment of Neurological Symptoms Associated with Long COVID, Biovie, 15 September 2026
NE3107 in Adults With Neurological Symptoms of Long COVID (ADDRESS-LC), ClinicalTrials.gov ID NCT06847191
About the Writer
Aasritha Thippavajjala (Linkedin) is a pharm D student and aspiring medical writer with medical writing, clinical training experience and a strong interest in clinical research and patient safety She has hands-on exposure to clinical pharmacy activities including medication profile assessment, clinical case review, identification of potential drug-related problems, ADR awareness, patient counselling, and clinical documentation. She has also gained experience in medical literature review, evidence synthesis, and scientific communication through her published review article on digital twin-based patient simulation and her poster presentation at the 74th Indian Pharmaceutical Congress. Certified in ICH Good Clinical Practice (E6(R3)) and Scientific Writing in Health Research, she is passionate about applying her clinical knowledge and research skills to medical writing ,clinical research and contributing to accurate, evidence-based healthcare.