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Clinical Trial
. 2024 Apr;30(4-5):558-570.
doi: 10.1177/13524585241234783. Epub 2024 Mar 4.

Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study

Xavier Montalban  1 , Karolina Piasecka-Stryczynska  2 , Jens Kuhle  3 , Pascal Benkert  4 , Douglas L Arnold  5 , Martin S Weber  6 , Andrea Seitzinger  7 , Hans Guehring  7 , Jamie Shaw  8 , Davorka Tomic  9 , Yann Hyvert  7 , Danielle E Harlow  8 , Martin Dyroff  8 , Jerry S Wolinsky  10
Affiliations
Clinical Trial

Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study

Xavier Montalban et al. Mult Scler. 2024 Apr.

Abstract

Background: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS.

Objective: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study.

Methods: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily.

Results: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population (Z-scores); T1 gadolinium-enhancing lesion numbers remained low. No new safety signals were identified. In the OLE, evobrutinib was detected in the CSF of all sub-study patients.

Conclusion: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.

Keywords: Bruton’s tyrosine kinase; Evobrutinib; cerebrospinal fluid; multiple sclerosis; open-label extension.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: X.M. has received speaking honoraria and/or travel expenses for participation in scientific meetings and/or has been a steering committee member of clinical trials and/or participated in advisory boards of clinical trials in the past years with Actelion; Alexion; Bayer; Biogen; Bristol Myers Squibb/Celgene; EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; Genzyme; F. Hoffmann-La Roche; Immunic; Janssen Pharmaceuticals; MedDay; Merck Healthcare KGaA, Darmstadt, Germany; Mylan; Nervgen; Novartis; Sanofi Genzyme; Teva Pharmaceutical; TG Therapeutics; Excemed; MSIF and NMSS. K.P.-S. has received travel funding and/or speaker honoraria from EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; Sanofi-Aventis; Biogen Idec; Teva Pharmaceutical; F. Hoffmann-La Roche; Bayer and Novartis and has served on scientific advisory boards for Sanofi-Aventis; Biogen Idec and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. J.K. received speaker fees, research support, travel support, and/or served on advisory boards by Swiss MS Society; Swiss National Research Foundation (320030_189140/1); University of Basel; Progressive MS Alliance; Alnylam; Bayer; Biogen; Bristol Myers Squibb; Celgene; Immunic; Merck Healthcare KGaA, Darmstadt, Germany; Neurogenesis; Novartis; Octave Bioscience; Quanterix; Roche; Sanofi and Stata DX. P.B. has nothing to disclose. D.L.A. has received personal fees for consulting from Albert Charitable Trust; Alexion; Biogen; Celgene; F. Hoffmann-La Roche; Frequency Therapeutics; Genentech; Med-Ex Learning; Merck Healthcare KGaA, Darmstadt, Germany; Novartis; Receptos and Sanofi-Aventis; grants from Biogen and Novartis and has an equity interest in NeuroRx Research. M.S.W. has received travel funding and/or speaker honoraria from Biogen Idec; EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; Novartis; F. Hoffmann-La Roche; Teva Pharmaceutical; Bayer and Genzyme. Y.H., A.S. and H.G. are the employees of Merck Healthcare KGaA, Darmstadt, Germany. J.S., D.E.H. and M.D. are the employees of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. D.T. is an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, and received stock or an ownership interest from Novartis. J.S.W. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Cleveland Clinic Foundation; EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; Novartis; Roche/Genentech; Sanofi Genzyme; The University of Alabama and Zenas BioPharma. Royalties have been received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation.

Figures

Figure 1.
Figure 1.
(a) Annualised relapse rate. (b) Mean (SEM) number of new T1 Gd+ lesions at week 12. (c) Mean (SEM) number of T1 Gd+ lesions over time. (d) Median T2 lesion volume over time. ARR (95% CI) for the whole OLE period (week 48/OLE BL to week 192) was: placebo + evobrutinib 25 mg QD, 0.18 (0.10–0.28); evobrutinib 25 mg QD, 0.15 (0.08–0.26); evobrutinib 75 mg QD, 0.09 (0.04–0.16); evobrutinib 75 mg BID, 0.13 (0.07–0.22). Cut-off 30 September 2021. aPatients switched from placebo to evobrutinib 25 mg QD after 24 weeks in the DBP. bEvobrutinib-treated patients (n = 151), mean (±SD) duration of exposure to evobrutinib 75 mg QD dose before the switch to 75 mg BID: 50.6 (±6.0) weeks. cMean number of new T1 Gd+ lesions was estimated using negative binomial regression, with covariates for presence or absence of baseline T1 Gd+ lesions and treatment arm. dT1 Gd+ lesion counts reported here were measured at individual time points (and do not represent annualised or cumulative values). ARR: annualised relapse rate; BID: twice-daily; BL: baseline; CI: confidence interval; DBP: double-blind period; Gd+: gadolinium-enhancing; OLE: open-label extension; QD: once-daily; SD: standard deviation; SEM: standard error of mean; Tx: treatment; W: weeks.
Figure 2.
Figure 2.
(a) Evobrutinib CSF and free plasma concentrations. (b) Evobrutinib CSF and free plasma concentrations relative to the population PK model. CI: confidence interval; CSF: cerebrospinal fluid; PK: pharmacokinetic.
See this image and copyright information in PMC

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