Targeting Bruton Tyrosine Kinase for Multiple Sclerosis Treatment

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.

REFERENCES

1. Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal. 2010;22(8):1175-1184. doi:10.1016/j.cellsig.2010.03.001

2. Mangla A, Khare A, Vineeth V, et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood. 2004;104(4):1191-1197. doi:10.1182/blood-2004-01-0207

3. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279-290. doi:10.1016/0092-8674(93)90667-F

4. Tai Y-T, Chang BY, Kong S-Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120(9):1877-1887. doi:10.1182/blood-2011-12-396853

5. Rawlings DJ, Scharenberg AM, Park H, et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996;271(5250):822-825. doi:10.1126/science.271.5250.822

6. Tsukada S, Simon MI, Witte ON, Katz A. Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proc Natl Acad Sci U S A. 1994;91(23):11256-11260.

7. Lowry WE, Huang X-Y. G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton’s agammaglobulinemia tyrosine kinase. J Biol Chem. 2002;277(2):1488-1492. doi:10.1074/jbc.M110390200

8. Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL. The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy. Expert Rev Clin Immunol. 2016;12(7):763-773. doi:10.1586/1744666X.2016.1152888

9. Whang JA, Chang BY. Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 2014;19(8):1200-1204. doi:10.1016/j.drudis.2014.03.028

10. Gabhann JN, Hams E, Smith S, et al. BTK regulates macrophage polarization in response to lipopolysaccharide. PLOS One. 2014;9(1):e85834. doi:10.1371/journal.pone.0085834

11. Schmidt U, Boucheron N, Unger B, Ellmeier W. The role of Tec family kinases in myeloid cells. Int Arch Allergy Immunol. 2004;134(1):65-78. doi:10.1159/000078339

12. Menzfeld C, John M, Rossum D van, et al. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia. 2015;63(6):1083-1099. doi:10.1002/glia.22803

13. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34-47. doi:10.1038/nri2206

14. Engel P, Gómez-Puerta JA, Ramos-Casals M, Lozano F, Bosch X. Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol Rev. 2011;63(1):127-156. doi:10.1124/pr.109.002006

15.Satterthwaite AB. Bruton’s tyrosine kinase, a component of B cell signaling pathways, has multiple roles in the pathogenesis of lupus. Front Immunol. 2018;8. doi:10.3389/fimmu.2017.01986

16. Mishra MK, Yong VW. Myeloid cells — targets of medication in multiple sclerosis. Nat Rev Neurol. 2016;12(9):539-551. doi:10.1038/nrneurol.2016.110

17. Rankin AL, Seth N, Keegan S, et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J Immunol. 2013;191(9):4540-4550. doi:10.4049/jimmunol.1301553

18. Anderson JS, Teutsch M, Dong Z, Wortis HH. An essential role for Bruton’s [corrected] tyrosine kinase in the regulation of B-cell apoptosis. Proc Natl Acad Sci U S A. 1996;93(20):10966-10971. doi:10.1073/pnas.93.20.10966

19. Solvason N, Wu WW, Kabra N, et al. Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells. J Exp Med. 1998;187(7):1081-1091. doi:10.1084/jem.187.7.1081

20. Sic H, Kraus H, Madl J, et al. Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis. J Allergy Clin Immunol. 2014;134(2):420-428. doi:10.1016/j.jaci.2014.01.037

21. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23(1):683-747. doi:10.1146/annurev.immunol.23.021704.115707

22. Filippi M, Bar-or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. doi:10.1038/s41572-018-0041-4

23. Milo R. Therapies for multiple sclerosis targeting B cells. Croat Med J. 2019;60(2):87-98.

24. Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol. 1998;43(4):465-471. doi:10.1002/ana.410430409

25. Miyazaki Y, Niino M. Molecular targeted therapy against B cells in multiple sclerosis. Clin Exp Neuroimmunol. 2014;5(s1):16-27. doi:10.1111/cen3.12160

26. Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CCA, Oksenberg JR. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol. 1999;163(9):5133-5144.

27. Oh J, O’Connor PW. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. CNS Drugs. 2013;27(8):591-609. doi:10.1007/s40263-013-0080-z

28. Voge NV, Alvarez E. Monoclonal antibodies in multiple sclerosis: present and future. Biomedicines. 2019;7(1). doi:10.3390/biomedicines7010020

29. Caldwell RD, Qiu H, Askew BC, et al. Discovery of evobrutinib: an oral, potent, and highly selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of immunological diseases. J Med Chem. 2019;62(17):7643-7655. doi:10.1021/acs.jmedchem.9b00794

30. Nyhoff LE, Clark ES, Barron BL, Bonami RH, Khan WN, Kendall PL. Bruton’s tyrosine kinase is not essential for B cell survival beyond early developmental stages. J Immunol Baltim Md 1950. 2018;200(7):2352-2361. doi:10.4049/jimmunol.1701489

31. Häusser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.00201

32. Bitar C, Sadeghian A, Sullivan L, Murina A. Ibrutinib-associated pityriasis rosea-like rash. JAAD Case Rep. 2018;4(1):55-57. doi:10.1016/j.jdcr.2017.06.035

33. de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102(10):1629-1639. doi:10.3324/haematol.2017.164103

34. McMullen JR, Boey EJH, Ooi JYY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829-3830. doi:10.1182/blood-2014-10-604272

35. Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80. doi:10.1186/s13045-016-0313-y

36. A study of efficacy and safety of M2951 in subjects with relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/NCT02975349

37. Montalban X, Arnold DL, Weber MS, et al; Evobrutinib phase 2 study group. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. 2019;380(25):2406-2417. doi:10.1056/NEJMoa1901981

38. Study of excretion balance and pharmacokinetics of [14C]-SAR442168 in healthy male subjects. https://clinicaltrials.gov/ct2/show/NCT04171310

39. Dose-finding study for SAR442168 in relapsing multiple sclerosis. https://clinicaltrials.gov/ct2/show/NCT03889639

40. Sanofi brain-penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis. News release. Sanofi. April 23, 2020. Accessed May 26, 2020. https://sanofi.com/en/media-room/press-releases/2020/2020-04-23-07-00-00

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