Targeting Bruton Tyrosine Kinase for Multiple Sclerosis Treatment

June 30, 2020

An in-depth look into the expanding landscape of multiple sclerosis treatments that target bruton tyrosine kinase.

Bruton Tyrosine Kinase (BTK), a Tec family nonreceptor tyrosine kinase1 critical for the development of B cells and several other hematopoietic lineages2 (except for T cells, plasma cells, and natural killer cells3), is a recent focus of therapeutics.4 BTK informs immune responses by acting as an early downstream amplification enzyme of the B-cell antigen receptor (BCR)5-8 and cytokine receptor pathways.8,9 BTK signaling influences antigen presentation on B cells10 and is essential to the production of antibodies, proinflammatory cytokines and chemokines, and cell adhesion molecules.11,12 Through these mechanisms, BTK helps transmit the signals that allow immune cells to respond to foreign antigens by targeting the cells presenting them for destruction.13-15

Harmful consequences arise when the immune system mistakes self-proteins as foreign antigens, with BTK promoting autoantibody secretion by autoreactive B cells.8,14,15 Autoimmune diseases such as multiple sclerosis (MS)16 result from this dysregulated production of autoantibodies, which leads to destruction of normal tissue.17 Malfunctioning BTK mutants have been linked to increased disease susceptibility, correlating with diminished numbers of mature B cells and immunoglobulin isotypes.18,19 BTK therefore serves as an important target for therapeutic agents that modulate innate immunity.

Interactions between T cells, B cells, and myeloid cells promote MS pathology,16 and BTK is a component of signaling events with a critical role in regulating hematopoietic cell circulation.20 MS is a chronic, inflammatory, demyelinating disease of the central nervous system21 and is the most common, nontraumatic, disabling neurological autoimmune disease, with approximately 2.3 million cases diagnosed worldwide.22 B cells contribute to MS pathogenesis as a result of being skewed toward a proinflammatory profile involving antibody production, antigen presentation, T-cell stimulation, production of proinflammatory cytokines, formation of ectopic meningeal germinal centers, and deposition of oligoclonal bands of immunoglobulin in areas of active demyelination.23-25 Briefly, the body’s immune system begins to attack myelin, a protective sheath covering nerve fibers. The nervous system is consequently “short-circuited,” potentially permanently.26

Treatments for MS aim to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability.27 The most well-studied type of therapy targeting B cells consists of monoclonal antibodies (mAbs) that deplete B cells through mechanisms of antibody-dependent cellular cytotoxicity and apoptosis.23 Rituximab, for example, a mAb targeting the B-cell antigen CD20, depletes B cells and reduces T cells in the cerebrospinal fluid. However, rituximab is incapable of penetrating the blood-brain barrier (BBB) or lymphoid organs and is unsuccessful in slowing disease progression.23,28 To overcome the limitations of mAbs,28 MS treatment efforts have turned to BTK inhibitors (FIGURE).29

The ideal BTK inhibitor would be a rapidly reversible, BBB-penetrant, highly selective, modulatory approach to target B-cell activation without widespread depletion of B cells.8,9,23,30,31 Rather, the B-cell response to BCR stimuli is lowered, tolerogenic B cells are maintained, and antigen-mediated proinflammatory activation is neutralized.8,12,15,31 BTK is already a target in treatment of lymphoma, leukemia, and rheumatoid arthritis via the prominent BTK inhibitor ibrutinib. However, ibrutinib exhibits off-target kinase-inhibitory effects and is associated with immunosuppression and bleeding complications.32-34 BTK inhibitors in development for chronic administration thus have more refined pharmacologic profiles, including high BTK selectivity and moderate clearance.29,35

Three BTK inhibitors are in clinical development for treatment of MS: Merck KGaA’s M2951 (evobrutinib), Principia Biopharma and Sanofi’s PRN2246 (SAR442168), and Biogen’s BIIB091. Evobrutinib is a potent, obligate-type covalent, selective, BBB-penetrant BTK inhibitor for the treatment of autoimmune diseases, including MS.29 Evobrutinib’s constrained acrylamide warhead confers BTK selectivity, biochemical and cellular potency, and plasma stability.29 Evobrutinib is the subject of an ongoing phase 2 trial which reached its primary completion date in January 2018 (NCT02975349).36 An analysis of that data published in the New England Journal of Medicine in 2019 compared 3 doses of evobrutinib (25 mg once daily, 75 mg once daily, 75 mg twice daily) with placebo or dimethyl fumarate (Tecfidera; Biogen) in patients with relapsing MS.37 The primary end point was total number of T1 gadolinium-enhancing lesions at 12, 16, 20, and 24 weeks. Secondary end points included annualized relapse rate and change from baseline on the Expanded Disability Status Scale.37 Among the 267 patients randomized, those who received 75 mg evobrutinib once daily had significantly fewer gadolinium-enhancing lesions at weeks 12 through 24 compared with placebo; however, covalent binding combined with a high daily dose was found to induce liver injury.29,37 Additional statistical analysis revealed no dose response nor any effect of evobrutinib on annualized relapse rate or disability progression.37

SAR442168 is also a potent, covalent, selective, BBB-penetrant BTK inhibitor that has demonstrated a dose-dependent protection from MS induction alongside no serious medication-related adverse events in participants (with 7.5- to 120.0-mg daily doses) in a phase 1 trial (NCT04171310).38 Encouraging results from the phase 2B trial39 reported in April 2020 revealed an 85% relative reduction in new gadolinium-enhancing lesions in the 60-mg group with a mean number of new lesions of 0.13 (P = .03) compared with 0.76 in the 30-mg group, 0.77 in the 15-mg group, 1.39 in the 5-mg group, and 1.03 with placebo.40 In addition, patients in the 60-mg group demonstrated an 89% relative reduction in new or enlarging T2 hyperintense lesions (P <.0001) at 12 weeks, with a mean number of lesions of 0.23 compared with 1.30 in the 30-mg group, 1.32 in the 15-mg group, 1.90 in the 5-mg group, and 2.12 in the placebo group; however, the trial did not consider disease development readouts such as relapse rates and MS progression.40 Based on the results, manufacturer Sanofi plans to initiate 4 phase 3 pivotal trials.40

Biogen’s BIIB091 is still in early stages of development, with its ongoing phase 1 clinical trial (NCT03943056) expected to reach primary completion sometime in spring 2020.41

Although early data appear promising, comprehensive trials with stringent statistical analysis are required to confirm the efficacy and safety of BTK inhibitor use for treatment of MS.

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41. A safety, tolerability, pharmacokinetic, and pharmacodynamic study of BIIB091, a Bruton's tyrosine kinase (BTK) inhibitor, in healthy adult participants.

https://clinicaltrials.gov/ct2/show/NCT03943056