Phase 2: Bezisterim Eases Fatigue and Cognitive Symptoms in Severely Affected Long COVID Patients, BioVie Reports

BioVie Inc. (NASDAQ: BIVI, BIVIW) on Monday released topline results from its Phase 2 ADDRESS-LC trial showing that bezisterim, an oral small molecule that crosses the blood–brain barrier, produced statistically significant improvements in fatigue, cognitive symptoms and post-exertional malaise (PEM) for participants with a high baseline symptom burden.

Trial Design and Overall Results

The randomized 203-patient trial evaluated whether bezisterim—believed to reduce inflammation and improve insulin sensitivity—could relieve common Long COVID complaints such as fatigue, brain fog and cognitive impairment. Investigators used 22 clinical outcome measures alongside several biomarkers to assess efficacy.

Pre-Specified Subgroup Findings

In subgroup analyses that were pre-specified with the FDA before unblinding, roughly 78% of participants who entered the study with greater baseline symptom burden showed statistically significant benefit on multiple related endpoints. Effect sizes in these subgroups were more than double those seen in the full cohort, and a greater number of endpoints reached statistical significance.

Notable subgroup outcomes included:

• Patients with the most severe fatigue improved on five fatigue-related endpoints.
• High-PEM patients improved on measures of malaise, fatigue and cognition.
• Participants with pronounced cognitive impairment improved on four cognitive endpoints.

Full Intent-To-Treat Population

When the full intent-to-treat (ITT) population of 203 patients was analyzed without subgrouping, bezisterim produced favorable numerical trends across nearly all measures—21 of 22 endpoints trended in the drug's favor—but those results did not reach statistical significance. BioVie noted that patients with low baseline symptom burden had limited room for measurable improvement, which may have diluted the overall signal.

Safety and Tolerability

Bezisterim’s safety profile was comparable to placebo. Treatment-emergent adverse events (TEAEs) occurred in 41.6% of bezisterim-treated patients versus 55.9% on placebo. Headache was the most common drug-related adverse event (4.0% for bezisterim vs. 4.9% for placebo). No serious adverse events were reported in the bezisterim arm; one serious adverse event occurred in the placebo arm.

Expert Reaction and Next Steps

Michael Peluso, UCSF: "These results are among the most promising seen in the field and warrant a confirmatory Phase 3 trial. If bezisterim can truly help patients with high symptomatic burden, that would be a significant benefit for the patient community."

BioVie CEO Cuong Do said the company believes this is the first drug candidate to demonstrate improvement across persistent neurological Long COVID symptoms, and emphasized that Phase 3 confirmation is required before any therapeutic claims can be made.

Conclusion

The ADDRESS-LC topline data suggest bezisterim may provide meaningful benefit for Long COVID patients who present with a high symptom burden, particularly for fatigue, PEM and cognitive deficits. However, the company and investigators stress that the subgroup findings are exploratory and must be confirmed in an adequately powered, prospective Phase 3 trial.