P4‐359: Effects of oral ELND005 (Scyllo‐inositol) on brain scyllo‐inositol and myo‐inositol levels: Spectroscopy results from a phase 2 study in MILD‐TO‐MODERATE Alzheimer's disease
Bibliographic record
Abstract
ELND005 (Scyllo-inositol), a Myo-inositol stereoisomer, is being developed as a potential disease modifying agent based on its amyloid anti-aggregation effects in preclinical models (McLaurin et al., 2000). Endogenous Myo and Scyllo-inositol concentrations in brain are ∼ 4–5mM and < 1mM, respectively. Myo-inositol, through its phosphorylated derivatives, is involved in the Phospho-inositol (PI) cycle, an important signaling pathway of G protein-coupled receptors (GPCRs). Unlike Myo-inositol, Scyllo-inositol is not thought to be phosphorylated or involved in PI signaling (Fenili et al. 2007). Study AD201, a 78-week study, included 351 AD patients who received placebo or ELND005 (250, 1000, or 2000 mg, all BID). Brain Scyllo and Myo-inositol levels were assessed in 104 patients by proton-magnetic resonance spectroscopy (MRS), at baseline, 24, 48, and 78 weeks. MRS measurements (1.5 or 3 Tesla) were obtained from an 18 cm 3 voxel in posterior medial cingulate cortex. Analyses of inositol levels were performed by a central imaging laboratory (NeuroRx Research, Montreal). Brain levels of Scyllo-inositol showed a dose-dependent increase with ELND005 treatment at 250mg and 1000mg doses, and reached apparent saturation above 1000 mg. Brain levels of Myo-inositol showed a reciprocal decrease at same time points: Percent change from baseline (PCBLs) at the 250mg and 1000mg doses were -36% to -45% and -61% to -64%, respectively, and also reached apparent saturation at doses above 1000 mg. These effects on Scyllo and Myo-inositol were observed from 24 through 78 wks, and were similar in Mild and Moderate patients. Total brain inositol levels were generally constant at any given visit, and Scyllo and Myo-inositol were highly inversely correlated (at 24, 48 wks: r= 0.86, 0.9, both p < 0.0001). ELND005 dose-dependently decreased brain Myo-inositol levels, likely due to competition for active uptake by the Sodium/Myo-inositol transporter, which has similar affinity for Myo and Scyllo-inositol (Fenili et al., 2011). ELND005, through reduction of Myo-inositol levels, may play a regulatory role in the PI pathway and in signal transduction of neurotransmitter and growth factor stimuli.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".