Abstract: P675
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Evobrutinib (M2951) is a potent, highly specific, irreversible, oral inhibitor of Bruton's Tyrosine kinase (BTK). Inhibition of BTK is expected to achieve B-cell silencing and interfere with innate immune cell activation. Evobrutinib has been shown to inhibit primary B-cell responses including proliferation, and antibody and cytokine release in a T cell-independent manner. The role of B-cells in the pathogenesis of multiple autoimmune diseases has been underlined by the efficacy of B-cell depleting approaches in rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (MS). Functional impairment of B-cells without depletion may show similar efficacy and perhaps a more favorable safety profile.
This study (NCT02975349) aims to evaluate the efficacy, safety, dose-response, and pharmacokinetic/pharmacodynamic relationships of evobrutinib in patients with relapsing MS (RMS) who are clinically and radiologically active. The presence of other autoimmune diseases, concomitant medications affecting the immune system, and laboratory evidence of immune system dysfunction are exclusionary. This Phase II design consists of five treatment arms with 50 patients in each arm: three oral (BID) doses of evobrutinib, placebo and an active control arm of dimethyl fumarate. Rescue treatment with corticosteroids is allowed for the treatment of relapses. After a 24-week treatment period, placebo patients will be switched to evobrutinib and all other groups will continue unchanged for a further 24 weeks. Open label extension treatment is planned for treatment beyond 48 weeks.
The primary endpoint is the sum of gadolinium-positive (Gd+) T1 magnetic resonance imaging lesions at Weeks 12, 16, 20, and 24 of treatment. The secondary endpoint is the total number of Gd+ T1 lesions at Week 48. Safety endpoints including immune function measures will be evaluated across the treatment period. The primary analysis will take place when all patients have reached 24 weeks of treatment or prematurely discontinued treatment, at which time the study team, but not the sites, will be unblinded. An interim analysis for futility may be carried out when 50% of patients have reached 24 weeks of treatment. A final analysis will be conducted when all patients complete 48 weeks of treatment. The first patient was randomized to treatment in April 2017 and the study is expected to be completed in early 2019. This will be the first clinical proof of concept study of a BTK inhibitor in RMS.
Disclosure:
JB, EM and JM are employees of EMD Serono; a business of Merck KGaA, Darmstadt, Germany.
XM has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall.
Abstract: P675
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Evobrutinib (M2951) is a potent, highly specific, irreversible, oral inhibitor of Bruton's Tyrosine kinase (BTK). Inhibition of BTK is expected to achieve B-cell silencing and interfere with innate immune cell activation. Evobrutinib has been shown to inhibit primary B-cell responses including proliferation, and antibody and cytokine release in a T cell-independent manner. The role of B-cells in the pathogenesis of multiple autoimmune diseases has been underlined by the efficacy of B-cell depleting approaches in rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (MS). Functional impairment of B-cells without depletion may show similar efficacy and perhaps a more favorable safety profile.
This study (NCT02975349) aims to evaluate the efficacy, safety, dose-response, and pharmacokinetic/pharmacodynamic relationships of evobrutinib in patients with relapsing MS (RMS) who are clinically and radiologically active. The presence of other autoimmune diseases, concomitant medications affecting the immune system, and laboratory evidence of immune system dysfunction are exclusionary. This Phase II design consists of five treatment arms with 50 patients in each arm: three oral (BID) doses of evobrutinib, placebo and an active control arm of dimethyl fumarate. Rescue treatment with corticosteroids is allowed for the treatment of relapses. After a 24-week treatment period, placebo patients will be switched to evobrutinib and all other groups will continue unchanged for a further 24 weeks. Open label extension treatment is planned for treatment beyond 48 weeks.
The primary endpoint is the sum of gadolinium-positive (Gd+) T1 magnetic resonance imaging lesions at Weeks 12, 16, 20, and 24 of treatment. The secondary endpoint is the total number of Gd+ T1 lesions at Week 48. Safety endpoints including immune function measures will be evaluated across the treatment period. The primary analysis will take place when all patients have reached 24 weeks of treatment or prematurely discontinued treatment, at which time the study team, but not the sites, will be unblinded. An interim analysis for futility may be carried out when 50% of patients have reached 24 weeks of treatment. A final analysis will be conducted when all patients complete 48 weeks of treatment. The first patient was randomized to treatment in April 2017 and the study is expected to be completed in early 2019. This will be the first clinical proof of concept study of a BTK inhibitor in RMS.
Disclosure:
JB, EM and JM are employees of EMD Serono; a business of Merck KGaA, Darmstadt, Germany.
XM has received speaker honoraria and travel expenses for scientific meetings, steering committee member, and advisory board member of clinical trials for Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall.