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- Title
(DXT36) Effect of Evobrutinib, a Bruton's Tyrosine Kinase Inhibitor, on Immune Cell and Immunoglobulin Levels over 48 Weeks in a Phase 2 Study in Relapsing Multiple Sclerosis.
- Authors
Montalban, Xavier; Shaw, Jamie; Syed, Sana; Dangond, Fernando; Martin, Emily C.; Grenningloh, Roland; Weber, Martin S.
- Abstract
Background: Bruton's tyrosine kinase (BTK) plays an important role in proinflammatory pathways potentially involved in multiple sclerosis (MS). Consequently, BTK inhibition is being investigated as a potential therapeutic approach for MS. Evobrutinib, a highly selective BTK inhibitor (BTKi), has a dual mechanism of action, affecting both B cells and macrophages through inhibition of B-cell receptor, Fc receptor, and granulocyte--macrophage colony-stimulating factor receptor signaling, and has demonstrated clinical efficacy in MS in a phase 2 study (trial registration: NCT02975349; Montalban et al, ECTRIMS 2018 [P322]). Objectives: To examine the effect of evobrutinib on immune cells and immunoglobulins (Igs) over 48 weeks. Methods: Patients aged 18-65 years with active relapsing--remitting MS or secondary progressive MS and superimposed relapses were randomized to receive either doubleblind evobrutinib (25 mg once daily [qd], 75 mg qd, or 75 mg twice daily), placebo, or open-label dimethyl fumarate 240 mg (reference arm). After 24 weeks, placebo-treated patients were switched to evobrutinib 25 mg qd; other treatment arms continued under original allocation. Safety of evobrutinib, including assessment of B-cell count and Ig level, was a key secondary end point; investigations of the effects of evobrutinib on B-cell subsets, T-cell subsets, and natural killer cells in peripheral blood over 48 weeks were exploratory. Results: Of 267 patients randomized to treatment, 227 patients completed 48 weeks of treatment. No clinically relevant changes in the number of total B cells, or of memory B, mature naive B, total T, helper T, cytotoxic T, or natural killer cells, were observed in any evobrutinib treatment group over 48 weeks. No changes in IgG or IgG subtype levels were observed over 48 weeks in any treatment group. At week 48, there were slight increases from baseline in IgA and reductions in IgM for all evobrutinib groups, which were numerically greater than those with placebo at week 24. Conclusions: Patients with MS treated with the BTKi evobrutinib showed no evidence of B-cell depletion or change in mature vs naive B-cell subsets over 48 weeks. IgG levels remained stable and slight elevations in IgA levels were observed. These findings demonstrate that, in contrast to genetic deletion of BTK, continued pharmacologic BTK inhibition does not lead to B-cell depletion or signifi- cant reductions in circulating Igs.
- Subjects
CONFERENCES &; conventions; IMMUNOGLOBULINS; LYMPHOCYTES; MULTIPLE sclerosis; DISEASE relapse; PROTEIN-tyrosine kinase inhibitors; PHARMACODYNAMICS
- Publication
International Journal of MS Care, 2020, Vol 22, Issue S2, p28
- ISSN
1537-2073
- Publication type
Article