# The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
## 4 Discussion
In particular, first-generation inhibitors like brtininib are hampered by broad kinase inhibition and systemic toxicity, limiting their usability in chronic neurologic conditions [94]. Second-generation CNS-penetrant BTKis, such as tolebrutinib, evobrutinib, fenebrutinib, and orelabrutinib, offer the potential for direct modulation of compartmentalized neuroinflammation. Tolebrutinib, in the 2025 HERCULES phase III trial involving non-relapsing secondary progressive MS, reduced the risk of disability progression [74]. However, serious liver-related adverse events occurred among treated patients versus placebo, one of which led to liver transplantation and death before intensified monitoring was implemented. Indeed, this has prompted updated recommendations for weekly liver enzyme monitoring during the first 12 weeks of therapy. Fenebrutinib shows favorable in vitro microglial modulation and is undergoing evaluation in FENhance and FENtrepid, with preliminary data suggesting improved tolerability and lower off-target toxicity [13; 73]. Evobrutinib showed consistent efficacy in reducing gadolinium-enhancing lesions in RMS patients and a favorable safety profile in the phase III EVOLUTION trials, with no significant liver toxicity or serious infections reported in over 700 patient-years of exposure [72]. Orelabrutinib, currently in phase II trials for MS, has shown promising CNS penetrance and BTK occupancy in cerebrospinal fluid, along with a clean hepatic safety profile in preliminary reports [95]. Nevertheless, the long-term comparative safety profiles, CNS pharmacokinetics, and off-target risks of these agents remain to be defined. Indeed, while several BTKis have shown promising preclinical and early clinical results, some clinical trials have failed to meet primary endpoints, underscoring the need for a deeper understanding of the underlying causes. One critical factor is the differential ability of BTKis to cross the BBB. Even among newer-generation agents, significant variability exists in their cerebrospinal fluid concentrations and BTK occupancy, which may explain the divergent clinical outcomes despite similar peripheral pharmacodynamics [96; 42; 97]. Moreover, the timing of administration relative to the disease course appears crucial; administration during late-stage neurodegeneration, when irreversible neuronal loss predominates, may not yield significant functional recovery despite the modulation of inflammation. Thus, future clinical trials should incorporate stratified patient selection based on both the disease stage and markers of active inflammation. Pharmacogenomic profiling, including BTK expression patterns and immune signatures, may also help identify the subgroups most likely to benefit from BTK inhibition. In addition, head-to-head trials and rigorous biomarker-driven monitoring must guide optimal BTKi selection standardizing CNS exposure assessments and considering adaptive designs that account for interindividual variability in drug penetration and target engagement [98]. These measures may enhance the translational success of BTKis and clarify their true therapeutic potential across distinct neurodegenerative phenotypes. Future research, therefore, should aim to delineate disease- and context-specific roles of BTK within the neuroimmune axis. Integration of single-cell transcriptomic profiling, spatial transcriptomics, and advanced imaging modalities may offer insight into BTK's cell-specific functions in vivo. In summary, BTK inhibition represents a promising avenue in the modulation of neuroinflammation across diverse neurodegenerative diseases. The expanding body of mechanistic and translational data strongly supports the continued exploration of BTKis as part of next-generation, targeted neurotherapeutic interventions.