Annovis Bio publishes Phase 2/3 buntanetap Alzheimer's data in Nature

Annovis Bio has published Phase 2/3 results for its oral candidate buntanetap in the peer-reviewed journal Nature NPJ Dementia, reporting statistically significant, dose-dependent improvements in cognition in biomarker-confirmed early Alzheimer's disease patients. The Pennsylvania-based company said the publication marks a key step in the scientific validation of a candidate it is now taking into a pivotal Phase 3 trial.

The randomised, double-blinded, placebo-controlled study enrolled 351 patients with mild to moderate AD across three buntanetap doses — 7.5 mg, 15 mg, and 30 mg — over a 12-week treatment period. Cognitive improvements, measured by the ADAS-Cog11 scale, were statistically significant in pTau217 biomarker-positive patients with mild disease (MMSE scores 21–24). At the highest 30 mg dose, Annovis reported a consistent treatment effect across subgroups stratified by age, sex, ethnicity, body mass index, ApoE4 carrier status, and concomitant medication use.

Biomarker signals and safety profile

Beyond cognition, biomarker analyses pointed to potential disease-modifying activity. The study reported reductions in neurotoxic proteins TDP-43 and tau, as well as in neuroinflammation markers including IL-5, IL-6, S100A12, IFN-γ, and IGF1R. Neurofilament light chain (NfL), a marker of neurodegeneration, also declined. Annovis noted that comparable trends were seen in plasma samples from patients with moderate AD, extending the mechanistic rationale.

Buntanetap was well-tolerated across all dose levels and disease stages. Notably, no increase in adverse events was observed in ApoE4 carriers — the population at greatest genetic risk of AD — compared with non-carriers or placebo. The drug was also tolerated alongside approved symptomatic therapies, meaning patients did not need to discontinue existing medication regimens during the trial.

Cheng Fang, Senior Vice President of Research and Development at Annovis, said the data "reinforce what we have seen across multiple studies: buntanetap addresses the underlying pathology of AD with a safety profile that supports its use in a broad, genetically diverse patient population."

Pivotal Phase 3 and competitive landscape

The Phase 2/3 findings are intended to support the ongoing pivotal Phase 3 trial (NCT06709014), which is enrolling pTau217 biomarker-positive patients with early AD (MMSE 20–28). Annovis said 80% of that trial's target enrolment has been reached. The Phase 3 design evaluates buntanetap at six and 18 months, with the latter timepoint specifically aimed at measuring potential disease-modifying benefit.

Buntanetap's mechanism — inhibiting translation of multiple neurotoxic proteins via an RNA-targeting pathway — positions it differently from the approved anti-amyloid monoclonal antibodies lecanemab and donanemab, which require infusion administration and carry well-documented risks of amyloid-related imaging abnormalities (ARIA). An oral, broadly tolerated candidate that also appears to reduce tau and neuroinflammation markers could address an unmet need for patients ineligible for, or intolerant of, antibody-based therapies — though this advantage will require Phase 3 confirmation at scale.

Peer publication in a Nature Portfolio journal lends external scientific credibility beyond a company press release, though the 12-week duration of the Phase 2/3 study is short for a disease with a protracted course. Investors and clinicians will look to the Phase 3 readout at the 18-month timepoint as the definitive test of whether the biomarker reductions seen here translate into meaningful clinical benefit.