A Quantitative‐EEG Assessment of Alpha‐1062, a Novel Pro‐Drug of Galantamine for the Treatment of Mild to Moderate Dementia Associated with Alzheimer’s Disease.
Bibliographic record
Abstract
Abstract Background Acetylcholinesterase inhibitors (AChEIs) enhance cognitive functioning in Alzheimer’s disease (AD). The use of AChEIs at therapeutic doses is limited by gastrointestinal (GI) side effects, such as nausea, vomiting and diarrhea. Alpha‐1062 is a pharmacologically inactive prodrug of the AChEI galantamine specifically designed to reduce or eliminate GI side effects and provide increased safety. In addition to its activity as an AChEI, galantamine exhibits a second important mechanism of action, binding allosterically to nicotinic cholinergic receptors enhancing their responsiveness to acetylcholine. In Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) trials in young and elderly healthy subjects, Alpha‐1062 demonstrated both evidence of an improved GI side effect profile and enhanced cognition. Here we extend the findings of the SAD and MAD studies with an additional analysis of the effects of Alpha‐1062 on quantitative‐EEG (qEEG) data collected as part of the MAD study. Methods Subjects (n = 12/dose) were administered two doses per day of Alpha‐1062 for 7 consecutive days. Pharmaco‐EEG measurements were performed for 4 min eyes closed / 4 min eyes open, on day 1 and day 7 at various timepoints both pre‐dose and post‐dose using a standard 10‐20 electrode montage with 21 channels. qEEG data analysis was conducted using qEEG indices developed using a machine learning algorithm based on the analysis of 39 AD patients administered galantamine (Sci Rep 7, 5775 [2017]). These were an AD index and a galantamine index, which were expected to be sensitive to the effects of Alpha 1062 administration. Results In healthy elderly subjects, Alpha‐1062 administration improved response on the AD index (p <0.05) compared to placebo, at the pre‐dose timepoint on day 7. The AD index was also reduced at all post‐dose timepoints on day 7 relative to placebo. Changes in several other relevant measures of qEEG function suggested Alpha‐1062 improved brain function. Conclusion These data demonstrate the potential benefit Alpha‐1062 in the treatment of AD. Alpha‐1062 was safe in the dose range investigated, and influenced pharmaco‐EEG outcomes in healthy elderly subjects that were consistent with the previously documented positive effects in tests related to sustained attention and working memory.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".