Tolebrutinib liver safety: A detailed overview

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.