Buntanetap in Mild-to-Moderate Alzheimer’s: Phase 2/3 Study Findings
Key Takeaways
- In the intent-to-treat population, primary endpoints changed similarly in pooled buntanetap and placebo groups; however, post-hoc analyses showed 38% of participants lacked amyloid burden.
- Buntanetap was well tolerated, with no serious treatment-related adverse events reported, although treatment-emergent adverse events related to study drug were numerically more common with active treatment than placebo and were not statistically different from placebo.
- In post hoc biomarker-positive mild Alzheimer's disease analyses, buntanetap showed dose-dependent ADAS-Cog11 improvement versus baseline that was nominally significant, while ADCS-CGIC did not show treatment-related improvement.
The dose-ranging study used quadruple blinding at 54 U.S. sites, masking participants, care providers, investigators, and outcome assessors during the 12-week treatment period. Eligible adults were 55 to 85 years old, had MMSE scores of 14 to 24, needed a study partner, and were excluded for current suicidal ideation or a recent attempt. Mean age was 73.6 years, 50.6% to 65.5% of groups were female, racial and ethnic minority representation exceeded 41%, and more than 99% used concomitant medications. Co-primary endpoints were Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) change from baseline to week 12 and Alzheimer's Disease Study-Clinical Global Impression of Change (ADCS-CGIC) at week 12, with Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) serving as the key secondary measure.
For the main efficacy analyses, investigators pooled all active doses rather than testing each dose separately against placebo. In the intent-to-treat population, pooled buntanetap and placebo groups showed similar improvement on ADAS-Cog11, ADCS-CGIC, and ADCS-ADL through week 12.
Safety analyses included 346 participants who received at least one dose, with monitoring based on adverse events, medications, ECGs, laboratory tests, vital signs, examinations, and Columbia-Suicide Severity Rating Scale (C-SSRS). Treatment-emergent adverse events occurred in 33.3% of buntanetap recipients and 26.1% of placebo recipients, while study-drug-related events occurred in 8.9% and 3.4%, respectively; the higher percentage with buntanetap was not statistically different from placebo and showed no dose-dependent pattern. No serious treatment-emergent events were attributed to study drug, although serious events occurred in three participants receiving 30 mg and three receiving placebo. Reported adverse events were otherwise mild to moderate in severity, and no severe adverse events were reported. Discontinuations for adverse events affected 1.9% of active treatment recipients, and dizziness, headache, and nausea recurred most often.
Post hoc biomarker work showed that about 38% of enrolled participants lacked amyloid burden, while 62.1% or 216 participants were classified as having Alzheimer's pathology. Among biomarker-positive participants, MMSE stratification defined mild disease as 21 to 24 and moderate disease as 14 to 20. In the biomarker-positive mild subgroup of 95 participants, buntanetap showed dose-dependent ADAS-Cog11 improvement versus baseline that was nominally significant, but ADCS-CGIC showed no treatment-related improvement. In the 30 mg group, plasma t-Tau, TDP43, IL5, IL6, S100A12, IFN-γ, IGF1R, and NFL decreased, whereas GFAP showed no treatment effect. Because these analyses were post hoc, not multiplicity-adjusted, and affected by misclassification, short duration, and limited power, the subgroup and biomarker signals remain exploratory while phase 3 confirmation is underway.