3591 Tolebrutinib versus placebo in non-relapsing secondary progressive multiple sclerosis: efficacy and safety results from the phase 3 HERCULES trial
Bibliographic record
Abstract
Background Tolebrutinib, a brain-penetrant, bioactive, Bruton’s tyrosine kinase inhibitor modulates persistent immune activation, including disease-associated microglia and B-cells, potentially affecting smoldering neuroinflammation, a major driver of disability accumulation. We report results of a phase-3 trial evaluating efficacy and safety of tolebrutinib versus placebo in non-relapsing secondary progressive MS (nrSPMS).Methods HERCULES ( NCT04411641) was a phase-3, double-blind, placebo-controlled, event-driven trial. Participants were 18–60 years old with secondary progressive MS, Expanded Disability Status Scale (EDSS) score 3.0–6.5, documented evidence of disability progression during prior 12-months, no clinical relapses during 24-months before screening. Participants were randomized 2:1 to receive oral tolebrutinib (60mg once daily) or matching placebo. Primary endpoint was time to onset of 6-month confirmed disability progression (CDP). Secondary endpoints included additional measures of disability, MRI, and safety.Results 1131 participants were randomized 2:1 to tolebrutinib (N=754) or placebo (N=377) with well-balanced baseline characteristics (mean age:48.9 years, EDSS score:5.5 [median, 6.0], time since relapsing remitting MS symptom onset:17.3 years, and time since most recent relapse:7.5 years). Tolebrutinib treatment was associated with 31% risk reduction in 6-month CDP versus placebo ( P=0.0026). More participants experienced 6-month confirmed disability improvement with tolebrutinib versus placebo (secondary endpoint). There was a slight increase in adverse events with tolebrutinib, including respiratory infections, compared to placebo. Rare events of high liver enzyme increases were observed with tolebrutinib and occurred within 90-days of treatment start. Additional efficacy and safety data will be presented.Conclusion HERCULES is the first trial to demonstrate a slowing of disability accumulation in people with nrSPMS.
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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) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 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".