Improvements in Cognition, Alzheimer Disease Biomarkers Linked to Novel Small Molecule Drug

Treatment with buntanetap (Annovis Bio, Malvern, PA), an oral molecule with potential therapeutic applications in neurodegenerative conditions such as Parkinson disease (PD) and Alzheimer disease (AD), was associated with significant improvements in cognition and biomarker measures in people with AD. Buntanetap, formerly known as Posiphen or ANVS401, binds to an iron-responsive element in amyloid precursor protein (APP) mRNA and other neurotoxic proteins to inhibit their translation, thereby reducing amyloid beta (Aβ), tau, alpha-synuclein (aSYN), and TDP43 production.

The findings come from a phase 2/3 randomized, double-blind, placebo-controlled study (NCT05686044) assessing the efficacy, safety, and tolerability of buntanetap for people with mild to moderate AD. A total of 353 participants from 54 sites in the United States completed the trial, receiving buntanetap at 7.5 mg, 15 mg, or 30 mg or placebo daily in addition to their standard of care for 12 weeks. The primary outcomes were Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog 11) and Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scores measured at baseline and at the end of 12 weeks.

• People who received buntanetap at all 3 dose levels showed significantly improved ADASCog 11 scores compared to those assigned to receive placebo and to baseline scores.
• Among participants with biomarkerconfirmed mild AD (n=90), the difference between ADAS-Cog 11 scores at baseline and week 12 increased with increasing dose level.
• Treatment response was found to be highly correlated to  Mini Mental State Examination (MMSE) score at baseline, with response to buntanetap treatment being more pronounced in those with early AD compared with those with more advanced AD.
• There was a reduction in plasma total tau levels seen with all 3 dose levels of buntanetap which were consistent with findings from a previous phase 2 trial.
• There were no statistically significant changes in ADCS-CGIC across all groups.

Additionally, buntanetap was found to be safe and well-tolerated. Annovis Bio plans to conduct a pivotal phase 3 trial in people with biomarker-positive early AD.