Use of plasma P‐tau217 for enrichment in the Phase 2 PROSPECT‐ALZ study of LY3372689 in early symptomatic Alzheimer’s disease: Cohort selection and baseline characteristics
Bibliographic record
Abstract
Abstract Background Inhibition of O‐linked N‐acetyl glucosaminidase (OGA) is hypothesized to impede the formation of hyperphosphorylated, insoluble tau aggregates and neurofibrillary tangles. LY3372689 is an orally available, potent inhibitor of OGA being tested in the ongoing PROSPECT‐ALZ study. This is the first study assessing the safety and efficacy of an OGA inhibitor in individuals with early symptomatic Alzheimer’s Disease (AD). To improve efficiencies in identifying individuals with desired levels of tau pathology, PROSPECT‐ALZ implemented a gated screening approach using plasma P‐tau217 as an enrichment step prior to tau PET. We present the study design, findings from the screening process, and baseline characteristics of the PROSPECT‐ALZ study cohort. Method With 68 sites across Australia, Canada, Japan, Poland, and the US, PROSPECT‐ALZ is an ongoing multicenter, double‐blind, placebo‐controlled Phase 2 study with 1:1:1 randomization of daily LY3372689 low dose, LY3372689 high dose, or placebo. The primary objective is to evaluate the effect of LY3372689 on AD clinical progression, as assessed by the change from baseline to endpoint (76‐124 weeks with common close design) on the integrated AD Ratings Scale (iADRS). Pre‐screening procedures include the Mini‐Mental State Examination (MMSE, scores of 22‐30) and a plasma P‐tau217 test to determine eligibility for further screening. Subsequent key inclusion requirements to meet were age 60‐85 years, a CDR global score of 0.5 or 1 with a memory box score of ≥ 0.5, and a PET (18F‐flortaucipir) scan demonstrating an intermediate or high level of aggregated brain tau by combined visual and quantitative assessment. Result After consent, 2180 participants entered screening. The top reason for screen failure was a P‐tau217 result below the eligibility threshold. Performance of the P‐tau217 test for pre‐screening patient selection as well as characteristics and demographics of the screening and randomized cohorts will be presented. Conclusion As blood‐based biomarkers become more accessible, their use in selecting participants for clinical research is desirable. The PROSPECT‐ALZ study successfully implemented plasma P‐tau217 in sequence with tau PET to improve efficiency in identifying trial participants. This study of LY3372689, the first orally administered OGA inhibitor to be investigated in AD, has topline trial results anticipated in 2024.
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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 | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".