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
ECTRIMS Online Library. Shaw J. 09/13/19; 278560; P1358
Jamie Shaw
Jamie Shaw
Contributions
Abstract

Abstract: P1358

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

X. Montalban1, J. Shaw2, S. Syed2, F. Dangond2, E.C. Martin2, R. Grenningloh2, M.S. Weber3, Evobrutinib Phase 2 Study Group

1Vall d´Hebron University Hospital, Barcelona, Spain, 2EMD Serono Research & Development Institute, Inc., Billerica, MA, United States, 3University Medical Center Göttingen, Göttingen, Germany

Background: Bruton's tyrosine kinase (BTK) plays an important role in pro-inflammatory pathways potentially involved with multiple sclerosis (MS). Consequently, BTK inhibition is being investigated as a potential therapeutic approach for MS. Evobrutinib, a highly selective BTK inhibitor, has a dual mechanism of action, impacting both B cells and macrophages through inhibition of BCR, Fc receptor, and GM-CSF receptor signaling and is the first BTK inhibitor to demonstrate clinical efficacy in MS in a Phase 2 study (NCT02975349; Montalban et al. ECTRIMS 2018).
Objective: Here we examine the effect of evobrutinib on immune cells and immunoglobulins (Ig) over 48 weeks.
Methods: Patients (18-65 years) with active relapsing-remitting MS or secondary progressive MS with superimposed relapses were randomized to receive either double-blind evobrutinib 25 mg QD, 75 mg QD, 75 mg BID, 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 numbers and Ig levels, was a key secondary endpoint; investigations of the effects of evobrutinib on B cell subsets, T cell subsets, and natural killer (NK) 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 naïve B, total T, helper T, cytotoxic T, or NK 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 that were numerically greater than those with placebo at Week 24.
Conclusions: MS patients treated with the BTK inhibitor, evobrutinib, showed no evidence of B cell depletion or change in mature versus naïve B cell subsets over 48 weeks. IgG levels remained stable and slight elevations in IgA levels were observed with evobrutinib. These new findings demonstrate that, in contrast to genetic deletion of BTK, continued pharmacological BTK inhibition does not lead to B cell depletion or significant reductions in circulating immunoglobulins.
Disclosure: X Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past 3 years with Biogen, Merck Serono, Sanofi-Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, NMSS, MSIF and Excemed
MS Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, F. Hoffmann- La Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. MS Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme
J Shaw, S Syed, F Dangond, EC Martin, and R Grenningloh are employed by EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA

Abstract: P1358

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

X. Montalban1, J. Shaw2, S. Syed2, F. Dangond2, E.C. Martin2, R. Grenningloh2, M.S. Weber3, Evobrutinib Phase 2 Study Group

1Vall d´Hebron University Hospital, Barcelona, Spain, 2EMD Serono Research & Development Institute, Inc., Billerica, MA, United States, 3University Medical Center Göttingen, Göttingen, Germany

Background: Bruton's tyrosine kinase (BTK) plays an important role in pro-inflammatory pathways potentially involved with multiple sclerosis (MS). Consequently, BTK inhibition is being investigated as a potential therapeutic approach for MS. Evobrutinib, a highly selective BTK inhibitor, has a dual mechanism of action, impacting both B cells and macrophages through inhibition of BCR, Fc receptor, and GM-CSF receptor signaling and is the first BTK inhibitor to demonstrate clinical efficacy in MS in a Phase 2 study (NCT02975349; Montalban et al. ECTRIMS 2018).
Objective: Here we examine the effect of evobrutinib on immune cells and immunoglobulins (Ig) over 48 weeks.
Methods: Patients (18-65 years) with active relapsing-remitting MS or secondary progressive MS with superimposed relapses were randomized to receive either double-blind evobrutinib 25 mg QD, 75 mg QD, 75 mg BID, 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 numbers and Ig levels, was a key secondary endpoint; investigations of the effects of evobrutinib on B cell subsets, T cell subsets, and natural killer (NK) 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 naïve B, total T, helper T, cytotoxic T, or NK 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 that were numerically greater than those with placebo at Week 24.
Conclusions: MS patients treated with the BTK inhibitor, evobrutinib, showed no evidence of B cell depletion or change in mature versus naïve B cell subsets over 48 weeks. IgG levels remained stable and slight elevations in IgA levels were observed with evobrutinib. These new findings demonstrate that, in contrast to genetic deletion of BTK, continued pharmacological BTK inhibition does not lead to B cell depletion or significant reductions in circulating immunoglobulins.
Disclosure: X Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past 3 years with Biogen, Merck Serono, Sanofi-Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, NMSS, MSIF and Excemed
MS Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, F. Hoffmann- La Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. MS Weber is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme
J Shaw, S Syed, F Dangond, EC Martin, and R Grenningloh are employed by EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA

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