Tolebrutinib liver safety: A detailed overview
- Journal
- Multiple sclerosis and related disorders (Q1)
- Published
- 23 July 2026
- Study design
- Non-randomized / quasi-experimental trial
- Evidence level
- Level 2, Moderate (CEBM 2b)
- Authors
- Christina R Maxwell, Timothy J Turner, Erik Wallstroem, Suhad Patel, Stephen C Pappas, James H Lewis, et al.
- PMID
- 42546561
- DOI
- 10.1016/j.msard.2026.107404
Why clinicians should know about it
- Picked for Hepatology (top studies of the week, 9 August 2026).
Abstract
Tolebrutinib is an oral brain-penetrant Bruton's tyrosine kinase inhibitor thought to modulate persistent maladaptive immune activation within the CNS. It was evaluated in four Phase 3 trials and an open-label long-term safety extension across multiple sclerosis (MS) phenotypes: relapsing MS (RMS; GEMINI 1&2), non-relapsing secondary progressive MS (nrSPMS; HERCULES), and primary progressive MS (PPMS; PERSEUS), with 2958 participants exposed overall. Tolebrutinib reduced disability progression by 31% in nrSPMS and 29% in RMS but showed no meaningful benefit in PERSEUS. During clinical development, drug-induced liver injury (DILI) emerged as an important identified risk of tolebrutinib exposure. A total of 139 (4.7%) of the 2958 tolebrutinib-exposed participants experienced ALT elevations >3 × ULN, including 49 (1.66%) with elevations >8 × ULN and 17 (0.57%) >20 × ULN. Six (0.20%) cases met Hy's Law criteria predictive of serious liver injury. All cases occurred within the first 90 days of exposure and resolved without sequelae except one participant who required a liver transplant and died from postoperative complications. Only one of the Hy's Law cases occurred among the 920 participants (0.11%) exposed following implementation of enhanced liver test monitoring. Weekly liver test monitoring for 12 weeks enabled earlier detection of elevated ALT (40 vs 60 days) and earlier recovery (44 vs 57 days) compared to less frequent monitoring. Mechanistic studies using liver spheroids showed no evidence of direct hepatocellular toxicity, supporting an idiosyncratic mechanism. This overview summarizes tolebrutinib liver safety data, characterizes DILI cases, describes mechanistic and biomarker findings, and demonstrates the impact of enhanced monitoring on early detection and risk mitigation. CLINICALTRIALS.GOV IDENTIFIERS: NCT04410978, NCT04410991, NCT04411641, NCT04458051, NCT06372145.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.