BioVie's bezisterim hits subgroup endpoints in Phase 2 Long COVID trial
BioVie Inc. has reported topline results from its Phase 2 ADDRESS-LC trial evaluating bezisterim in 203 patients with neurological symptoms associated with Long COVID, saying the oral candidate demonstrated statistically significant benefits in pre-specified subgroups representing approximately 78–80% of trial participants.
The NASDAQ-listed clinical-stage company was careful to note that the overall intent-to-treat (ITT) population of 203 patients did not reach statistical significance on any individual endpoint. In that broader cohort, 21 of 22 measures showed numerical trends favouring bezisterim over placebo, but the signal was likely diluted by patients who entered the trial with low baseline symptom burden and therefore had limited room to improve.
Subgroup findings and the path to Phase 3
The more compelling data emerged in pre-specified subgroup analyses, which were locked in a statistical analysis plan submitted to the FDA prior to unblinding. Patients in the most symptomatic half for fatigue showed statistically significant improvements on five endpoints, three of which were fatigue-specific. Those with high post-exertional malaise (PEM) at baseline saw significant improvements across malaise, fatigue and objective cognitive measures. Patients entering the trial with substantial objective cognitive impairment showed significant gains on four coherent cognitive endpoints. The company said effect sizes more than doubled compared to the ITT analysis in these subgroups, reflected in higher Cohen's d values.
Bezisterim's safety profile compared favourably with placebo: 41.6% of treated patients experienced at least one treatment-emergent adverse event versus 55.9% in the placebo arm. Headache was the most frequently reported drug-related event, at 4% versus 4.9% for placebo. No serious adverse events were reported in the bezisterim arm.
Cuong Do, BioVie's president and chief executive, said the findings were particularly encouraging because fatigue, PEM and cognitive dysfunction are defining features of the more severe and persistent Long COVID phenotypes identified in large cohort studies such as RECOVER. "To our knowledge, this is the first time a drug candidate has shown the ability to help patients improve across these persistent Long COVID symptoms," Do said.
The ADDRESS-LC trial was fully funded by a $13.13 million grant from the US Department of War's Peer-Reviewed Medical Research Program.
Market context and regulatory read-across
Long COVID remains one of the largest unmet needs in post-infectious disease, with an estimated 17–20 million US adults affected and no FDA-approved treatment options currently available. The condition's heterogeneity has frustrated previous development efforts: the NIH-funded RECOVER initiative has evaluated more than a dozen interventions across eight Phase 2 trials without demonstrating clear benefit for any agent.
Bezisterim is a small-molecule anti-inflammatory that modulates the ERK, NFκB and TNFα pathways and is believed to improve insulin sensitivity without systemic immune suppression. BioVie is also studying it in Parkinson's disease and Alzheimer's disease, giving the company a broad neuroinflammation thesis across three indications. Investors will note that the failure of the ITT analysis to reach significance is a meaningful caveat: regulators will expect a prospective, adequately powered Phase 3 trial designed around the high-burden subpopulation before any approval pathway becomes viable. FDA has not validated the endpoints used in ADDRESS-LC as surrogate endpoints for Long COVID, and subgroup findings are hypothesis-generating by nature. BioVie has signalled it intends to advance bezisterim to a confirmatory Phase 3 study, with the subgroup data informing enrolment criteria and endpoint selection.