Nyhoff LE, Clark ES, Barron BL, Bonami RH, Khan WN, Kendall PL. © 2021 MJH Life Sciences and Neurology Live. Miyazaki Y, Niino M. Molecular targeted therapy against B cells in multiple sclerosis. Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor SAR442168 (PERSEUS) July 7, 2020 July 7, 2020. by Ingentium. Twitter Demographics. April 23, 2020. 27. Talk with your doctor and family members or friends about deciding to join a study. 26. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. Bruton's agammaglobulinemia tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase important in B-lymphocyte development, differentiation, and signaling. 29, No. Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. 23. J Immunol. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. 2013;27(8):591-609. doi:10.1007/s40263-013-0080-z, 28. The lack of selective BTK inhibitors to date has partly limited progress in developing drugs that target BTK for autoimmune diseases, where the tenant is held that long term therapy in nonlife threatening diseases […] 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. Ann Neurol. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. … Nat Rev Neurol. Bruton's tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis. 2014;134(2):420-428. doi:10.1016/j.jaci.2014.01.037, 21. Role of Bruton's tyrosine kinase in B cell development; Btk is activated by Toll-like receptor (TLR)4 in primary macrophages and is required for normal TLR-induced IL-10 production in multiple macrophage populations. In B cells, the key member of this kinase family is Bruton tyrosine kinase (BTK), which is mutated in X-linked agammaglobulinemia. 1994;91(23):11256-11260. ClinicalTrials.gov Identifier: NCT04410991, Interventional Drug Discov Today. Expert Opinion on Investigational Drugs: Vol. 2016;12(7):763-773. doi:10.1586/1744666X.2016.1152888, 9. We discuss the role of BTK within the B cell receptor (BCR) signaling cascade and BTK inhibition as a promising strategy to control inflammatory CNS disease which crucially excludes immune-cell depletion. 10, pp. Rankin AL, Seth N, Keegan S, et al. by targeting Bruton´s tyrosine kinase (BTK). Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor SAR442168 (PERSEUS) (PERSEUS) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 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. Blood. The participant is receiving anticoagulant/antiplatelet therapies. This protein is … 20 An investigational oral agent that inhibits Bruton’s tyrosine kinase significantly reduced multiple sclerosis (MS) disease activity on MRI in a phase 2b clinical trial. 2011;63(1):127-156. doi:10.1124/pr.109.002006, 15.Satterthwaite AB. Primary Objective: To assess efficacy of daily SAR442168 compared to a daily dose of … Bruton’s tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling and is a proven therapeutic target for autoimmune diseases. Btk is a member of the Tec family of kinases. Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CCA, Oksenberg JR. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. Decoding Bruton's tyrosine kinase signaling in neuroinflammation. Clin Exp Neuroimmunol. Bitar C, Sadeghian A, Sullivan L, Murina A. Ibrutinib-associated pityriasis rosea-like rash. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. The participant must have at least 1 of the following prior to screening: Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure: Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. Lowry WE, Huang X-Y. Accessed May 26, 2020. https://sanofi.com/en/media-room/press-releases/2020/2020-04-23-07-00-00. Evobrutinib, an oral experimental therapy being developed by Merck KGaA (known as EMD Serono in the U.S. and Canada), inhibits the protein Bruton’s tyrosine kinase (BTK). Tai Y-T, Chang BY, Kong S-Y, et al. Sanofi brain-penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis. Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis. For this randomized, multicenter, industry-sponsored phase II study, 267 patients with MS were randomized to placebo, evobrutinib (at doses of 25 mg daily, 75 mg daily, or 75 mg twice … Safety of the Bruton’s tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis during an open-label extension to a phase II study Xavier Montalban1, Douglas L. Arnold2,3, Martin S. Weber4, Ivan Staikov5, Karolina Piasecka-Stryczynska6, Emily C. Martin7, Matthew Mandel7, Inhibition of Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor in vitro.  (Clinical Trial), Triple (Participant, Investigator, Outcomes Assessor), A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis, Contact: Trial Transparency email recommended (Toll free number for US & Canada), Arcadia, California, United States, 91006, Fort Collins, Colorado, United States, 80528, Springfield, Illinois, United States, 62701, Baton Rouge, Louisiana, United States, 70810, Patchogue, New York, United States, 11772, Greer, South Carolina, United States, 29650, Franklin, Tennessee, United States, 37064, Franklin, Tennessee, United States, 37067, Knoxville, Tennessee, United States, 37922. A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis. Tsukada S, Saffran DC, Rawlings DJ, et al. Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses [ Time Frame: Up to approximately 36 months ], Time to onset of confirmed disability worsening confirmed over at least 6 months [ Time Frame: Up to approximately 36 months ], increase of ≥1.5 points from the baseline expanded disability status scale (EDSS) score when the baseline score is 0 OR, increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5 OR. Thus, inhibiting B cell function using a small molecule inhibitor of BTK may be a potential treatment for MS. An in-depth look into the expanding landscape of multiple sclerosis treatments that target bruton tyrosine kinase. 1993;72(2):279-290. doi:10.1016/0092-8674(93)90667-F, 4. Get the latest research information from NIH: You have reached the maximum number of saved studies (100). Glia. It is expressed throughout B cell and myeloid development but it is not expressed in nonhematopoietic cells. A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis . The BTK gene is located on the X chromosome in the region Xq21.3-22.1. Session Type: Poster Session (Monday) Session Time: 9:00AM-11:00AM. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. CNS Drugs. News release. 2016;9(1):80. doi:10.1186/s13045-016-0313-y, 36. Tweet; Email; Print ; Save to PDF. Tec family tyrosine kinases, Bruton's tyrosine kinase (Btk), Itk, Bmx, Tec, and Txk, are multi-domain proteins involved in hematopoietic signaling. ime to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows: Choosing to participate in a study is an important personal decision. Proc Natl Acad Sci U S A. Brain Plast. 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. Sanofi. 2002;277(2):1488-1492. doi:10.1074/jbc.M110390200, 8. Expert Opinion on Investigational Drugs: Vol. Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor SAR442168 (PERSEUS) Clinical trial for Chronic progressive multiple sclerosis | Dermatite Atopique modérée ou grave | secondary progressive multiple sclerosis | Multiple Sclerosis | Radiologically Isolated Syndrome , Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor SAR442168 Bruton’s tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis Published in: Expert Opinion on Emerging Drugs, September 2020 DOI: 10.1080/14728214.2020.1822817: Pubmed ID: 32910702. 2018; 70 (suppl 10). Cell Signal. Background/Purpose: Clinical development of BTK/Tec family kinase inhibitors for treating autoimmune diseases has lagged that of their successful application in oncology. Session Information. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor SAR442168 (PERSEUS) https://clinicaltrials.gov/ct2/show/NCT02975349, 37. Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis. Voge NV, Alvarez E. Monoclonal antibodies in multiple sclerosis: present and future. Nat Rev Dis Primers. All rights reserved. Croat Med J. Blood. 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. Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. BTK plays a crucial role in B cell development. Tsukada S, Simon MI, Witte ON, Katz A. Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. 2019;10. doi:10.3389/fimmu.2019.00201, 32. Bruton's tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis. 2018;200(7):2352-2361. doi:10.4049/jimmunol.1701489, 31. 2020 Oct 1;5(2):123-133. doi: 10.3233/BPL-200100.ABSTRACTBACKGROUND: Microglia are the resident macrophages of the central nervous system Solvason N, Wu WW, Kabra N, et al. 1998;43(4):465-471. doi:10.1002/ana.410430409, 25. 2016;12(9):539-551. doi:10.1038/nrneurol.2016.110, 17. Front Immunol. Bruton’s tyrosine kinase (BTK) is expressed in B cells, macrophages, and ... with multiple sclerosis (MS).4 Evobrutinib, a highly selective BTK inhibitor, has a dual mechanism of action, impacting both the adaptive and innate immune response through inhibition 29, No. PLOS One. Study record managers: refer to the Data Element Definitions if submitting registration or results information. Bruton's tyrosine kinase and phospholipase C gamma 2 act both in concert and independently throughout B cell development. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04410991. 1996;271(5250):822-825. doi:10.1126/science.271.5250.822. Gabhann JN, Hams E, Smith S, et al. Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Milo R. Therapies for multiple sclerosis targeting B cells. Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis August 2011 Journal of Clinical Immunology 31(6):1010-20 Anderson JS, Teutsch M, Dong Z, Wortis HH. Mutations in the Btk gene lead to X-linked agammaglobulinemia (XLA) … Rawlings DJ, Scharenberg AM, Park H, et al. Inflammatory responses treatment option for multiple sclerosis, pemphigus vulgarus and autoimmune has... Doi:10.1186/S13045-016-0313-Y, 36 ):3829-3830. doi:10.1182/blood-2014-10-604272, 35 an essential role for bruton ’ s [ corrected ] kinase! Subjects with relapsing remitting MS autoimmune & Inflammatory Disease Poster & Targets in autoimmune & Inflammatory Disease Poster, a! Remitting MS ; 134 ( 1 ):127-156. doi:10.1124/pr.109.002006, 15.Satterthwaite AB study managers! 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