Treatment Database

An orally bioavailable, blood-brain-barrier-permeable small molecule with dual anti-inflammatory and insulin-sensitizing properties. Bezisterim selectively inhibits inflammation-driven ERK signaling and modulates NF-κB activation, reducing downstream expression of inflammatory cytokines. The Long COVID rationale: persistent SARS-CoV-2 spike protein and RNA are hypothesized to drive chronic TLR4-mediated NF-κB activation, producing the neuroinflammation, metabolic dysfunction, and blood-brain barrier disruption underlying cognitive impairment and fatigue. The Phase 2 ADDRESS-LC trial (NCT06847191; n=203; 20 mg twice daily vs. placebo for about 3 months; funded by a $13.1M Department of Defense award) reported topline results in September 2026. These are sponsor-reported and not yet peer-reviewed. Across 22 outcome measures, none reached statistical significance in the full study population, although 21 of 22 numerically favored bezisterim. In exploratory subgroups with higher baseline severity (about 78% of participants), the sponsor reported significant improvements: in fatigue measures among those with the most severe fatigue, in malaise, fatigue and objective cognition among those with high post-exertional malaise, and in four objective cognitive endpoints among those with measurable cognitive impairment. At the American Neurological Association meeting in October 2026, BioVie presented the fatigue result: in the most-fatigued subgroup, PROMIS Fatigue scores fell by 8.93 points on bezisterim vs 5.30 on placebo (p=0.02). The company describes these subgroup analyses as exploratory and hypothesis-generating, and they need confirmation in a new trial. BioVie plans a Phase 3 trial. Earlier evidence is indirect: a 28-day Phase 2 trial in Parkinson's disease (n=45), an open-label Alzheimer's study (n=23), and a Phase 3 Alzheimer's trial in which protocol violations left data from only 81 of 439 participants evaluable.