Safety and Efficacy of Evobrutinib, a Bruton’s Tyrosine Kinase Inhibitor in Relapsing Multiple Sclerosis Over 2.5 Years of The Open-Label Extension to a Phase II Trial
Xavier Montalban1, Jerry S. Wolinsky2, Douglas L. Arnold3,4, Martin S. Weber5, Ivan Staikov6, Karolina Piasecka-Stryczynska7, Davorka Tomic8, Emily C. Martin9, Kristina H. Holmberg9, Hans Guehring10
1Vall d'Hebron University Hospital, 2McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 3Montreal Neurological Institute, McGill University, 4NeuroRx Research, 5Institute of Neuropathology and the Department of Neurology, University Medical Center, University of Göttingen, 6Department of Neurology, Acibadem City Clinic Tokuda Hospital, 7Department of Neurology and Cerebrovascular Diseases, Poznan University of Medical Sciences, 8Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, 9EMD Serono, 10The healthcare business of Merck KGaA
Objective:
Report the safety and efficacy of evobrutinib over 2.5 years in an open-label extension (OLE).
Background:
Evobrutinib, a covalent, blood-brain barrier-penetrating Bruton’s tyrosine kinase inhibitor, was well tolerated and effective at reducing gadolinium-enhancing lesions in a double-blind, randomized phase II trial in patients with relapsing multiple sclerosis (pwRMS; NCT02975349).
Design/Methods:
In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily at W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF; 240mg twice-daily). At W48 patients could enter the OLE (DMF: 4–8W washout); evobrutinib 75mg once-daily (median ~48W) then 75mg twice-daily. The latest available OLE data are now reported.
Results:
Of 267 DBP patients, 213 (80%) entered the OLE; 164 (61%) completed ≥132W of OLE treatment. Treatment-emergent adverse events (TEAEs) were reported by 165/213 patients (77.5%); 59 (27.7%) had a treatment-related TEAE. Six serious TEAEs were deemed treatment-related. Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%); 3 were fatal (Covid-19 pneumonia [n=2] and E. coli sepsis [n=1]; not considered treatment-related). At OLE W120, most patients had IgG (91%), IgA (88%) and IgM (82%) within normal ranges. Overall mean CD19+ B cells levels were 0.218x106 cells/mL (OLE baseline) and 0.122x106 cells/mL (OLE W96). ALT/AST elevations were observed only in patients previously receiving DMF/evobrutinib 25mg and occurred within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, but without clinical signs and symptoms. Based on all available OLE data, ARR was 0.12 (95%CI 0.07–0.20) for patients receiving 75mg twice-daily in the DBP.
Conclusions:
Evobrutinib safety and efficacy data over 2.5 years in pwRMS continue to show acceptable tolerability, with no new safety signals, and maintained efficacy.