Targeting smouldering neuroinflammation in multiple sclerosis: insights from tolebrutinib clinical trials

The quest to mitigate disability progression in multiple sclerosis (MS) has long been hindered by our limited understanding of chronic or smouldering neuroinflammation and its drivers.Recent pathological and biomarker data indicate that chronic neuroinflammation, characterised by persistent microglial activation, oxidative injury, iron and glutamate toxicity, mitochondrial dysfunction, and axonal neurodegeneration, plays a crucial role throughout the course of MS. 1 Current disease-modifying therapies (DMTs) predominantly target acute inflammatory events but fail to adequately address these chronic mechanisms.The recent results from two pivotal trials place Bruton's tyrosine kinase (BTK) inhibition at the forefront of this unsolved clinical challenge 2,3 and bring hope that even progressive forms of MS might become readily treatable conditions.The GEMINI 1 and 2 trials 2 evaluated the efficacy of tolebrutinib, an oral, central nervous system (CNS)-penetrant BTK inhibitor, against teriflunomide in patients with relapsing MS over a median follow-up of nearly three years.The GEMINI 1 trial screened participants for eligibility at 162 sites in 24 countries.GEMINI 2 screened participants for eligibility at 155 sites in 25 countries.A total of 1873 eligible participants were randomly assigned in a 1:1 ratio to receive either oral tolebrutinib or oral teriflunomide.Demographic and disease characteristics of the participants were similar in the two treatment groups.Meanwhile, the HERCULES trial 3 focused on people with nonrelapsing secondary progressive MS, a population with no approved therapeutic options who continue to experience disability accumulation despite the absence of clinical relapses.A total of 1131 participants were randomly assigned in a 2:1 ratio to receive a daily dose of oral tolebrutinib or matching placebo for about 48 months.The results from these trials reveal both the promise and the limitations of BTK inhibitors.In the GEMINI trials, 2 tolebrutinib did not significantly reduce the primary endpoint of annualised relapse rate (ARR) compared to teriflunomide, and it even correlated with an increase in gadolinium-enhancing lesions on MRI.Notably, a pooled