Efficacy and Safety of the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib for Relapsing Multiple Sclerosis Over 3.5 Years of Treatment: An Ongoing Phase II Open-Label Extension
Xavier Montalban1, Jerry S. Wolinsky2, Douglas L. Arnold3, Martin S. Weber4, Karolina Piasecka-Stryczynska5, Davorka Tomic6, Andrea Seitzinger7, Hans Guehring7
1Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, 2Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 3NeuroRx Research, and Montreal Neurological Institute, 4Institute of Neuropathology and the Department of Neurology, University Medical Center, University of Göttingen, 5Department of Neurology and Cerebrovascular Diseases, Poznan University of Medical Sciences, 6Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, 7The healthcare business of Merck KGaA, Darmstadt, Germany
Objective:
To report the long-term effect of evobrutinib on efficacy and safety in patients with relapsing multiple sclerosis (PwRMS) over 3.5 years of the open-label extension (OLE) of a Phase II trial (NCT02975349).
Background:
Evobrutinib is a highly selective, central nervous system-penetrant, covalent Bruton’s tyrosine kinase inhibitor. In the Phase II trial, the efficacy (relapses and disability) and safety profile of evobrutinib observed in the double-blind period (DBP) were maintained over 2.5 years of the OLE.
Design/Methods:
During the 48-week (W) DBP, PwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily [QD] after W24), evobrutinib 25mg QD, 75mg QD, 75mg twice-daily (BID), or open-label dimethyl fumarate (120mg BID for the first week, 240mg BID thereafter). All doses were administered fasted. At W48, patients could enter the OLE and received evobrutinib 75mg QD (mean [±SD] duration 49.8W [±6.2]) and then switched to 75mg BID. Data are reported from W48/OLE baseline to either 228W of treatment (annualized relapse rate [ARR]) or ≥228W of treatment (treatment-emergent adverse events [TEAEs]).
Results:
Of 213 patients who entered the OLE, 155 (72.8%) completed ≥228W of treatment. During the OLE, the pooled ARR was reduced with the post-switch evobrutinib 75mg BID dose (0.10) compared with the pre-switch 75mg QD dose (0.18). Overall, the pooled ARR remained low during the OLE up to W228 (0.13). TEAEs were reported by 178/213 patients (83.6%); 60/213 (28.2%) reported treatment-related TEAEs, 7/213 (3.3%) reported serious treatment-related TEAEs. Severe/opportunistic infections (≥Grade 3) were reported by 11/213 patients (5.2%).
Conclusions:
The pre- and post-switch ARR data support that BID dosing (75mg fasted, comparable to 45mg BID fed in Phase III) provides maximal efficacy on clinical endpoints. Evobrutinib, over 3.5 years in the OLE, continues to show maintained treatment benefits and acceptable tolerability, with no new safety signals.