According to a new announcement, the FDA has accepted an updated protocol for Annovis Bio’s pivotal phase 3 AD study testing the therapeutic potential of its investigational agent buntanetap, an orally available small molecule.1
In October 2024, the company received FDA approval to launch its phase 3 trials for AD after phase 2/3 (NCT05686044) results highlighted cognitive benefits in patients with early-stage AD. In the original launch, the phase 3 study was intended to be 2 separate trials. Slated to begin this month, the newly revised phase 3 study is now comprised of a 6-month symptomatic analysis along with a 12-month assessment to study disease-modifying impacts of the agent.
"This consolidated protocol will accelerate the development timeline while maintaining the scientific rigor necessary to advance buntanetap as a treatment for AD," Maria Maccecchini, PhD, founder, president, and chief executive officer at Annovis, said in a statement.1 "With this design, we can leverage the 6-month symptomatic data to potentially support a New Drug Application (NDA) filing, all while continuing the same study seamlessly to assess long-term disease-modifying outcomes. We are excited to move forward with this approach, which brings us closer to delivering a novel treatment to patients in need."
Buntanetap, which has shown promising effects in other neurodegenerative disorders like Parkinson disease (PD), targets neurodegeneration by inhibiting the formation of multiple neurotoxic proteins, including amyloid-ß, alpha-synuclein, and TDP-43. By suppressing amyloid precursor protein, tau, and alpha-synuclein synthesis, the belief is that buntanetap can normal the levels of these toxic proteins and re-establish proteostasis, rescue axonal transport and endosomal function, and stave off nerve cell death and neurodegeneration.
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In early 2024, data from the aforementioned dose-ranging phase 2/3 study provided insight on buntanetap’s potential in AD. In the study, treatment with the agent resulted in statistically significant improvements in the primary end point of Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog11) over 3 different dose groups (7.5 mg: improved 2.19 [SE, 0.87]; P = .013; 15 mg: 2.79 [SE, 0.81]; P = .001; 30 mg: 3.32 [SE, 0.82]; P <.001). Of note, investigators recorded a 3-fold difference in the proportion of patients who improved in the 30 mg group relative to placebo.2
Top Takeaways
- Phase 2/3 data revealed buntanetap improved cognitive scores in patients with Alzheimer disease, with the highest dose (30 mg) showing a 3-fold improvement over placebo.
- Buntanetap reduced key neurotoxic proteins, including amyloid-β and tau, in cerebrospinal fluid, supporting its potential to address Alzheimer underlying pathology.
- In patients with Parkinson disease, 20 mg buntanetap significantly improved motor function and slowed cognitive decline compared to placebo over a 3-year study.
Buntanetap’s safety was originally evaluated in a single-ascending dose, a multiple ascending dose, and in a proof-of-concept (POC) trial. In the POC study, 5 patients with mild cognitive impairment were given 4 x 60 mg buntanetap treatment for 10 days. Overall, the therapy effectively reduced APP and its downstream products, total tau, phosphorylated tau, and alpha-synuclein in patients cerebrospinal fluid, supporting its inhibitory effects on these neurotoxic aggregating proteins.3
Buntanetap was also evaluated in a Phase 3 study (NCT05357989) involving 450 patients with Parkinson disease aged 40-85 with Mini-Mental State Exam (MMSE) scores of 20-30. Participants received either low-dose (10 mg) or high-dose (20 mg) buntanetap, or a placebo, over 3 years. Among patients diagnosed within the last 3 years, those taking 20 mg of buntanetap improved by nearly 4 points on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part II+III, while the 10 mg group showed little change, and the placebo group worsened.4
In patients with mild dementia (MMSE scores of 20-26), cognitive decline was faster in the placebo group compared with those taking 10 mg buntanetap. The 20 mg group showed notable cognitive improvement compared with placebo. Across the entire study population, those on placebo experienced cognitive decline throughout the trial, while both buntanetap groups maintained their baseline cognitive levels, demonstrating a statistically significant effect in preventing cognitive decline.
REFERENCES
1. FDA Accepts Final Protocol for Pivotal Phase 3 Alzheimer’s Disease Study, Streamlining Development Pathway. News release. Annovis Bio. January 7, 2025. Accessed January 8, 2025. https://www.biospace.com/press-releases/fda-accepts-final-protocol-for-pivotal-phase-3-alzheimers-disease-study-streamlining-development-pathway
2. Annovis Bio announces statistically significant phase 2/3 data in patients with early Alzheimer’s disease. April 29, 2024. Accessed January 6, 2025. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=7f4c17db-2a47-4e91-8059-8d07dae9de11
3. Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry. 2012;83(9)894-902. doi:10.1136/jnnp-2012-302589
4. Annovis Bio Announces New Data from Phase III Parkinson’s Study Highlighting Improvements in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Cognition after Treatment with Buntanetap. News release. Annovis Bio. July 2, 2024. Accessed January 8, 2025. https://finance.yahoo.com/news/annovis-bio-announces-data-phase-120000626.html?
