BioVie's Bezisterim Misses Significance in Full Long COVID Population but Shows Phase 2 Subgroup Signal
核心洞察
BioVie's Phase 2 ADDRESS-LC trial of oral bezisterim missed statistical significance on all 22 endpoints in the full 203-patient intent-to-treat Long COVID (搜索) population.
Pre-specified subgroups with high baseline fatigue, cognitive impairment or post-exertional malaise showed statistically significant improvements, representing about 78% of participants.
Bezisterim's safety profile was similar to placebo, with 41.6% of treated patients reporting treatment-emergent adverse events versus 55.9% on placebo.
BioVie Inc. (NASDAQ: BIVI) reported topline results on September 15, 2026, from its Phase 2 ADDRESS-LC trial (NCT06847191) evaluating the investigational oral drug bezisterim in adults with neurological symptoms of Long COVID (搜索). The trial did not achieve statistical significance on any of its 22 clinical outcome measures in the full intent-to-treat (ITT) population of 203 patients, a result that sent the company's shares down nearly 9.7% in premarket trading.
The mixed readout centered on pre-specified subgroup analyses, submitted to the FDA prior to data unblinding, in which patients with greater baseline burden on one or more symptoms — approximately 78% of trial participants — demonstrated statistically significant improvements on multiple clinically coherent endpoints. Bezisterim's safety and tolerability profile was similar to placebo.
Trial Design and Endpoints
ADDRESS-LC was a Phase 2, multicenter, randomized (1:1), double-blinded, placebo-controlled, signal-finding proof-of-concept study. It enrolled 203 patients with Long COVID (搜索) who had cognitive impairment sequelae and fatigue, comparing bezisterim 20 mg oral capsules twice daily with matching placebo to assess effects on neurocognitive and fatigue-related symptoms.
The trial explored 22 clinical outcome measures, with no single endpoint pre-specified as the primary determinant of study success. Endpoints included changes in overall clinical benefit, subjective and objective cognitive function, fatigue, sleep disturbance, quality of life and post-exertional malaise (PEM). As a signal-finding study, it was designed to identify efficacy signals, measure treatment effect magnitude and identify patient subgroups most likely to benefit, to inform future Phase 3 design. The study was fully funded by a $13.13 million grant from the U.S. Department of War through the Peer-Reviewed Medical Research Program (Award No. HT9425-24-1-0113).
Full Population Misses Significance
In the heterogeneous ITT population, no individual endpoint reached statistical significance (p<0.05), which BioVie attributed to patients with low baseline symptom burden having little room to improve, potentially diluting the overall signal. Twenty-one of the 22 endpoints showed numerical trends favoring bezisterim, as reflected in Cohen's d effect sizes, where a positive value indicates a greater treatment effect in the bezisterim arm than placebo.
"The results suggest that bezisterim may help improve symptoms of fatigue, post-exertional malaise, and cognitive impairments in patients with high symptom burden, which represents approximately 80% of patients who entered the trial," said Cuong Do, BioVie's President and CEO. "Patients who were not experiencing a meaningful symptom at the outset have little room to show improvement on that measure."
Subgroup Analyses Show Differential Effects
In the pre-specified subgroup analyses, treatment effect sizes more than doubled compared with the ITT population, as seen with higher Cohen's d values, and the number of endpoints reaching statistical significance increased. The most severe half of patients with fatigue symptoms showed statistically significant improvements on five endpoints, three of which were fatigue-specific, along with trends in PEM and sleep. Patients with high PEM experienced statistically significant improvements across malaise, fatigue and objective cognitive measures, while those entering with substantial objective cognitive impairment demonstrated statistically significant improvements on four clinically coherent objective cognitive endpoints.
BioVie noted that these subgroup findings are exploratory and require confirmation in an adequately powered prospective study. The company also cautioned that subgroup analyses are hypothesis-generating and may not be replicated in future trials, and that the FDA has not validated these endpoints as surrogate endpoints for Long COVID (搜索).
"I am excited by the findings in the ADDRESS-LC study. These results are among the most promising we have seen in this field so far and clearly warrant progressing to a confirmatory Phase III trial," said Michael Peluso, MD, MHS, Associate Professor of Medicine at the University of California, San Francisco. "If bezisterim can truly help the patients with high symptomatic burden, that would be a significant benefit for the patient community."
"We have not seen anything like this from any other trial," commented Ezra Spier, Long COVID (搜索) patient advocate and ADDRESS-LC Patient Advisor. "We have not seen results that are this clear or compelling before, and this could have a significant impact for Long COVID patients."
Grace McComsey, Professor of Medicine and infectious diseases researcher, said: "I am super excited for the Long COVID (搜索) community because of this data. At Case Western Reserve University, we have been a part of almost every negative study so far. It's great to see a trial showing such potential effectiveness while using a well-tolerated oral drug."
Safety Profile Comparable to Placebo
Overall, 41.6% of bezisterim-treated patients experienced at least one treatment-emergent adverse event compared with 55.9% for placebo. The most frequently reported drug-related adverse event was headache, reported by 4% of bezisterim patients versus 4.9% for placebo. No serious adverse events were reported in the bezisterim arm, versus one in the placebo arm. BioVie noted the safety findings are particularly important given the extensive concomitant medication use observed in the trial population.
Precision Medicine Strategy and Next Steps
Joseph Palumbo, MD, BioVie's EVP of Research & Development and Chief Medical Officer, framed the subgroup approach as a precision medicine strategy. "Research has demonstrated that Long COVID (搜索) is not a single disease, but a complex and heterogeneous syndrome with multiple clinical and biological subtypes," he said. "A key challenge in clinical development is not only establishing efficacy but also identifying the patients most likely to benefit and understanding the drivers of that response."
BioVie said it plans to advance bezisterim into a Phase 3 trial to confirm efficacy and safety in a larger patient population, though no Phase 3 program has been confirmed. A potential future development strategy could involve further evaluation of patients with higher baseline symptom burden. The company hosted a conference call at 8:30 a.m. EDT on September 15, 2026, to discuss the results.
Mechanism and Disease Context
Bezisterim (NE3107) is an investigational oral drug that crosses the blood-brain barrier and is designed to reduce inflammation and improve insulin sensitivity without suppressing the immune system and with a low risk of drug-drug interactions. It modulates key pathways involved in neuroinflammation — ERK (搜索), NFκB and TNFα — and may have therapeutic potential across several indications, including Parkinson's disease (搜索), Long COVID (搜索) and Alzheimer's disease (搜索).
The hypothesis under study in Long COVID (搜索) is that neurological symptoms may be triggered by persistent circulation of spike protein fragments that drive inflammation via NFκB activation, which bezisterim has been shown to modulate. Chronic innate inflammation accompanied by ongoing immune dysregulation is among the leading hypotheses proposed to explain Long COVID symptoms.
An estimated 17–20 million U.S. adults are reported to be living with Long COVID (搜索), with 3.8 million experiencing significant limitation to their daily lives, and almost 50% developing persistent or intermittent symptoms. Neurological and neuropsychiatric symptoms — including fatigue, PEM, sleep disturbance and persistent difficulty with thinking and memory — are among the most common and disabling manifestations. Currently, there are no FDA-approved treatment options for Long COVID. BioVie noted that eight Phase 2 clinical trials have been conducted by various organizations to assess 13 interventions in Long COVID, and none have demonstrated benefit thus far.
In Parkinson's disease (搜索), BioVie completed the SUNRISE-PD trial, which enrolled 57 patients to establish proof of mechanism and proof of concept in early-stage disease in individuals not previously treated with carbidopa/levodopa; topline results showed improvements in blood-based markers of inflammation and biomarkers associated with cellular health and neuronal integrity, with greater clinical improvements than placebo across measures of daily functioning, motor and non-motor symptoms. In Alzheimer's disease (搜索), BioVie has conducted Phase 2 and Phase 3 trials, with preliminary data suggesting improvements in cognition and biomarkers.