Multiple Sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system, including the brain and spinal cord. In MS, the body’s immune system mistakenly attacks myelin, the protective sheath around nerve fibers, disrupting communication between the brain and the body. This can lead to symptoms such as muscle weakness, balance issues, numbness, and blurred vision. Bruton’s Tyrosine Kinase (BTK) inhibitors are a new class of drugs being investigated as a potential treatment for MS.
Understanding BTK Inhibitors
Bruton’s Tyrosine Kinase (BTK) is a protein crucial for B-cell development and function within the immune system. As a component of the B-cell receptor signaling pathway, BTK activity is necessary for B-cell maturation, survival, proliferation, and antibody production. Its activation upon B-cell stimulation leads to increased kinase activity and downstream signaling.
BTK inhibitors block the BTK protein, disrupting its signaling pathways and affecting cell function. Developed for various diseases, including blood cancers, these inhibitors are now explored for autoimmune conditions like MS.
BTK is found in B-cells, monocytes, macrophages, and microglia. This broad expression allows BTK inhibitors to influence multiple immune responses, important for treating complex autoimmune diseases.
How BTK Inhibitors Target Multiple Sclerosis
BTK inhibitors exert therapeutic effects in MS by impacting B-cell activity and other immune cells within the central nervous system (CNS). They inhibit the BTK enzyme, expressed in B-cells and myeloid cells like microglia and macrophages. Blocking BTK disrupts the B-cell receptor signaling pathway, reducing B-cell activation, proliferation, and differentiation into antibody-producing plasma cells. This decreases autoantibody and pro-inflammatory cytokine production, contributing to MS pathogenesis.
Many BTK inhibitors cross the blood-brain barrier (BBB), acting directly within the CNS. This enables them to target immune cells like B-lymphocytes and disease-associated microglia in the brain and spinal cord. This direct CNS action addresses “smoldering neuroinflammation,” which contributes to neurodegeneration and disability accumulation in progressive MS.
Microglia, resident CNS immune cells, express BTK and contribute to CNS inflammation and neurodegeneration in MS. BTK inhibitors inhibit BTK-mediated signaling in microglia, reducing their activation and the release of pro-inflammatory cytokines and chemokines. This modulates microglial activity, attenuating CNS inflammation and potentially promoting remyelination, benefiting both relapsing-remitting and progressive MS.
Current Research and Clinical Trials
BTK inhibitors for MS are in advanced clinical trials, evaluating safety and efficacy. Many are in Phase 2 and Phase 3 studies.
Various BTK inhibitors, including tolebrutinib, fenebrutinib, evobrutinib, orelabrutinib, and remibrutinib, are under study. These drugs are evaluated for effectiveness in different MS forms: relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive (PPMS). Tolebrutinib, for example, is in Phase 3 trials for both relapsing and progressive MS, with some studies comparing it to placebo and others to an active comparator.
While some Phase 2 studies show promising results, like reduced new gadolinium-enhancing lesions and decreased relapse rates, not all Phase 3 trials have met primary endpoints. For instance, two Phase 3 trials for evobrutinib in relapsing MS showed no significant difference in annualized relapse rates compared to teriflunomide. However, other BTK inhibitors, like fenebrutinib, have shown encouraging Phase 2 results, demonstrating near-complete suppression of disease activity and disability progression in relapsing MS patients over 48 weeks.
Therapeutic Potential and Safety Profile
BTK inhibitors offer therapeutic potential for MS, addressing inflammatory and neurodegenerative aspects. By inhibiting B-cell activation and modulating microglia, these drugs reduce relapse rates and slow disease progression.
Many BTK inhibitors cross the blood-brain barrier, an advantage allowing direct targeting of CNS inflammation, which contributes to long-term disability. Benefits include reduced relapse frequency, decreased new brain lesions, and potentially slowed disability accumulation.
For example, a Phase 3 trial showed tolebrutinib delayed confirmed disability progression by 31% in non-relapsing secondary progressive MS patients compared to placebo. More patients on tolebrutinib also experienced confirmed disability improvement.
BTK inhibitors have a manageable safety profile, though side effects exist. Common side effects include cold/flu-like symptoms. Liver enzyme elevations have been observed with some compounds (e.g., tolebrutinib, fenebrutinib), leading to partial clinical holds and increased liver function monitoring. Differences in selectivity and binding mechanisms among BTK inhibitors may influence individual safety profiles.