Buntanetap Transitioning to Crystal Form Following FDA Go-Ahead

Author(s):

The investigational therapy, which targets neurodegeneration, has shown promise in phase 2 and 3 studies of Alzheimer disease and Parkinson disease, with additional studies on the way.

Michael Christie, PhD

Credit: Annovis Bio

Following a review of submitted comprehensive data, the FDA has granted approval for Annovis’ investigational agent buntanetap to transition to a new solid crystal form for future clinical trials. This will ultimately allow for the company to conduct a comparative study between the old and new forms of the therapy in a small, single-dose, bioavailability study in humans as part of the transition process.¹

Buntanetap, a medication in development for neurodegenerative disorders like Parkinson disease (PD) and Alzheimer disease (AD), targets neurodegeneration by inhibiting the formation of multiple neurotoxic proteins, including amyloid-ß, alpha-synuclein, and TDP-43. Different from monoclonal antibody therapies, buntanetap is an orally available small molecule, and its unique mechanism of action allows it to inhibit multiple neurotoxic proteins at once.

Less than a month ago, Annovis announced the filing of a provisional patent covering the manufacturing process of the newly approved solid forms of buntanetap. The patent, which encompasses methods for manufacturing the new crystalline form of the therapy, covers the entire synthesis process, from basic starting materials to finished GMP product, suitable for manufacturing scale at ton quantities. According to the company, the new process offers significant benefits, including excellent yields, the avoidance of potentially genotoxic reagents, and a purer product.²

At the time, Michael Christie, PhD, vice president of Process Chemsitry at Annovis, said in a statement, "As we continue to advance our pipeline, securing our manufacturing rights for new forms of buntanetap is vital. This ensures we maintain control over the production process, protect our intellectual property, and continue our mission to deliver novel therapeutics for patients suffering from neurodegenerative disorders."

Earlier this year, the company released data from a phase 2/3, dose-ranging study (NCT05686044) assessing the therapy in patients with mild to moderate AD. Following 3 months of treatment, all 3 buntanetap groups demonstrated statistically significant improvements in the primary end point of Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog11; 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.³

Buntanetap was also assessed in a phase 3 study (NCT05357989) of patients with PD, aged 40-85 years, with Mini-Mental State Exam scores between 20-30. In the study, patients were assigned to either low- or high-dose buntanetap or placebo for a 3-year period. Using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part II+III, those with less than 3 years since diagnosis who were assigned to buntanetap 20 mg demonstrated changes of nearly –4 points of improvement whereas those in the 10 mg group showed minimal change and those on placebo worsened.⁴

In a subgroup of patients with mild dementia, defined by MMSE scores between 20-26, cognition deteriorated at a faster pace in the placebo group compared with those on 10 mg buntanetap. Moreover, the 20 mg buntanetap group showed significant improvement in cognition compared with placebo. In the entire enrolled population, those on placebo showed cognitive worsening throughout the trial in comparison with the buntanetap dosed groups, which maintained baseline levels, indicating a statistically significant effect in stopping cognitive decline.

REFERENCES
1. Annovis Bio receives FDA approval to transition to new crystal form of buntanetap. News release. July 16, 2024. Accessed July 17, 2024. https://finance.yahoo.com/news/annovis-bio-receives-fda-approval-120000146.html
2. Annovis Bio files provisional patent for new manufacturing process of crystalline form of buntanetap. News release. June 27, 2024. Accessed July 17, 2024. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html
3. Annovis Bio announces statistically significant phase 2/3 data in patients with early Alzheimer’s disease. April 29, 2024. Accessed July 17, 2024. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=7f4c17db-2a47-4e91-8059-8d07dae9de11
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 July 17, 2024. https://finance.yahoo.com/news/annovis-bio-announces-data-phase-120000626.html?