IC‐P‐108: VOLUMETRIC MRI RESULTS OF BMS AVAGACESTAT IN A PRODROMAL AD POPULATION
Bibliographic record
Abstract
Avagacestat (BMS-708163), an oral γ-secretase inhibitor designed for selective inhibition of Aβ synthesis, was studied in Prodromal AD in a Phase 2 clinical trial (CN156-018). We assessed volumetric MRI changes of avagacestat versus placebo treated subjects in whole brain, lateral ventricles and hippocampus over the course of this multi-year study. 263 Prodromal AD subjects were selected, with the following inclusion criteria: MMSE 24 to 30, objective memory impairment, and CDR-global score of 0.5 with a memory box score ≥ 0.5, CSF Aβ42 levels < 200pg/mL or total tau/Aβ42 ratio ≥ 0.39. Subjects were excluded if they met DSM-IV-TR criteria for dementia. 3DT1 MRI scans were collected at Baseline, Weeks 24, 56 and 104 to assess whole brain, lateral ventricle and hippocampal volumes. Subjects were also scanned more frequently for safety monitoring. 20 additional subjects that met all clinical inclusion criteria but were amyloid-negative based on CSF biomarker levels entered an observational cohort and were scanned at Baseline and Week 60. Whole brain atrophy and lateral ventricle enlargement were assessed using Tensor Based Morphometry. Hippocampal atrophy was assessed using Boundary Shift Integral.Mean brain volume loss was measured at each volumetric timepoint after adjusting for time between scans. T-tests were also performed in order to compare atrophy results between treated and non-treated subjects. Mean volume loss for each structure of interest is reported in Tables 1-3. The results of the t-tests are shown on Table 4. As expected, biomarker-negative observational cohort subjects showed less loss of brain volume compared to Prodromal AD subjects after 1 year for brain (p<0.01), ventricles (p<0.05) and hippocampus (p<0.001).Volume loss was greater for avagacestat than placebo-treated subjects at Weeks 24 and 56 for brain (p<0.01), ventricles (p<0.05) and hippocampus (p<0.01). At Week 104, the difference was not significant. Biomarker-positive Prodromal AD subjects demonstrated greater brain atrophy at 1 year compared with biomarker-negative observational cohort subjects. Avagacestat-treated subjects exhibited greater volume loss than did placebo subjects, a seemingly paradoxical result similar to findings previously reported with other amyloid-lowering treatments such as AN1792 (Fox et al, Neurology 2005) or bapineuzumab (pooled analysis, Fox et al, CTAD 2012).
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".