Buntanetap helps subgroup of mild Alzheimer’s patients, data show
Cognitive function improved in those positive for certain biomarkers
Treatment with buntanetap, a small molecule being developed by Annovis Bio for neurodegenerative diseases, improved cognitive function in people with mild Alzheimer’s positive for certain disease biomarkers, especially in earlier stages of the disease.
These are findings from a Phase 2/3 clinical study (NCT05686044) in which 353 patients, ages 55 to 85, were randomly assigned to receive buntanetap at one of three doses, or a placebo, on top of their standard of care for 12 weeks (roughly three months).
Buntanetap was safe and well tolerated at all three doses, and resulted in a reduction in the levels of tau, a protein that builds up as toxic tangles in Alzheimer’s, causing damage to brain cells and the resulting loss of cognitive function.
“These findings are a significant milestone for Alzheimer’s patients,” Kore Liow, MD, one of the study’s principal investigators and a clinical professor at the University of Hawaii, said in a press release from Annovis. “Buntanetap has the potential to be the first safe and convenient oral therapy that provides symptomatic efficacy while slowing disease progression.”
Annovis said it will share the findings with the U.S. Food and Drug Administration (FDA) and ask for an end-of-Phase 2 meeting to discuss next steps for the clinical program. A longer, Phase 3 study with enough patients with early Alzheimer’s is planned to study buntanetap’s potential to modify the course of disease.
Blocking translation to reduce toxic protein clumps
The company also plans to deliver a presentation at the 2024 Alzheimer’s Association International Conference (AAIC2024), which will take place July 28 to Aug. 1 in Philadelphia and online, and publish the data in a peer-reviewed scientific journal.
Buntanetap, formerly known as ANVS401 or Posiphen, is in clinical testing for Alzheimer’s and Parkinson’s disease as capsules to be taken by mouth. It works by reducing the levels of proteins that form toxic clumps in nerve cells, such as beta-amyloid and tau in Alzheimer’s and alpha-synuclein in Parkinson’s.
The small molecule does that by blocking translation, which is the process by which cells make proteins based on the genetic blueprints of DNA. “Based on buntanetap’s unique mechanism of action, we believe it can give patients both symptomatic and disease-modifying benefits,” said Melissa Gaines, senior vice president of clinical operations at Annovis, and Cheng Fang, PhD, senior vice president of research and development.
In an earlier Phase 2a study (NCT04524351) involving 15 people with early Alzheimer’s, daily treatment with 80 mg buntanetap for about 25 days improved cognitive function and reduced the levels of both beta-amyloid and tau proteins compared with a placebo.
Of the 353 patients with mild to moderate Alzheimer’s enrolled in the recently completed Phase 2/3 dose-ranging study, 325 completed the study across 54 sites in the U.S. The goal was to test the efficacy, safety, and tolerability of buntanetap at 7.5, 15, or 30 mg against a placebo.
While this criterion was not pre-specified in the study protocol, the researchers focused their analysis on a group of 202 patients who had confirmed Alzheimer’s based on a ratio of pTau217/tTau equal to or greater than 4.2%. This ratio measures the levels of pTau217, a version of tau typically found in Alzheimer’s, divided by total tau levels.
The team further subdivided this patient population into those who had mild Alzheimer’s, based on Mini Mental State Examination (MMSE) scores of 21–24 points, or moderate Alzheimer’s, based on MMSE scores of 14-20 points.
In the subgroup of patients who had mild Alzheimer’s, all three doses of buntanetap resulted in a significant improvement of cognitive function over time from baseline (the study’s start).
Cognitive function was evaluated using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11). Here, total ADAS-Cog11 scores range from 0 to 70, with higher scores indicating greater cognitive impairment.
Compared with a placebo, where ADAS-Cog11 scores dropped by 0.3 points from baseline, cognitive function was significantly improved in patients treated with 15 mg buntanetap, by 2.79 points, and in those treated with the higher dose, by 3.32 points from baseline.
In patients treated with 30 mg buntanetap, response to treatment was significantly correlated with MMSE scores at baseline. In other words, the higher the MMSE scores at baseline, indicating less cognitive impairment, the greater the improvement in cognitive function.
Company says results indicate disease-modifying benefits
All three doses of buntanetap resulted in a reduction in the levels of total tau protein, supporting buntanetap’s mechanism of action and suggesting disease-modifying benefits, according to the company.
“It’s really exciting to see that this study confirmed what we have observed in the previous Phase [2] studies in both the improvement of patients’ cognition and the improvement of biomarkers,” Gaines and Fang said.
However, the study did not find significant changes in daily living activities measured by the Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change (ADCS-CGIC), which relies on perceptions of caregivers. This was perhaps due to the small number of patients and short study duration, the company said.
As in earlier clinical studies, including those involving Parkinson’s patients, buntanetap was safe and well tolerated. Most side effects were mild to moderate in severity, and none was serious.
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