MRI and Clinical Outcomes of Evobrutinib, a Bruton's Tyrosine Kinase Inhibitor, in Relapsing Multiple Sclerosis Over 2.5 Years of the Open-Label Extension to a Phase 2 Trial

Evobrutinib (EVO), a highly selective Bruton's tyrosine kinase (BTK) inhibitor, was effective at reducing T1 gadolinium-enhancing (Gd+) lesions and new/enlarging T2 lesions in a double-blind, randomised, Phase 2 trial (NCT02975349) in patients (pts) with relapsing multiple sclerosis (pwRMS). The objective of current analyses was to describe the long-term treatment (Tx) effect of EVO on magnetic resonance imaging (MRI) outcomes (number of T1 Gd+ lesions and T2 lesion volume) and Expanded Disability Status Scale (EDSS) score in pwRMS up to Week (W) 144 of the open-label extension (OLE) of the Phase 2 trial. In the 48W double-blind period (DBP), pwRMS (n = 267) received placebo (PBO; switched to EVO 25mg once-daily [QD] at W24), EVO 25mg QD, 75mg QD, or 75mg twice-daily (BID), or open-label dimethyl fumarate (DMF; 120 mg BID for the first week and 240 mg BID thereafter) in fasted state. At W48, pts could enter the OLE (DMF: 4–8W washout) and received EVO 75mg QD for a mean time of 49.8W, before switching to 75mg BID. Of the 213 DBP pts that entered the OLE, 160 (75.1%) had reached OLE ≥144W at time of analysis. Mean no. of T1 Gd+ lesions per Tx group at DBP BL were: PBO, 1.19; EVO 25mg QD, 0.92; EVO 75mg QD, 1.65; EVO 75mg BID, 1.72; DMF, 2.20. At W48 (end of DBP; OLE BL), mean no. of T1 Gd+ lesions by DBP Tx group were: PBO/EVO 25mg QD, 0.92; EVO 25mg QD, 1.63; EVO 75mg QD, 0.71; EVO 75mg BID, 0.48; DMF, 0.25. Fluctuations occurred when switching from DBP doses to 75mg QD at W48 and then to EVO 75mg BID. Pooling all pts, during the 75mg QD stage of OLE, mean no. of T1 Gd+ lesions rose (W48: 0.76, W96: 1.42) before dropping after switching to 75mg BID (W144: 0.55, W192: 0.79). Overall change of median volume (cm3) of T2 lesions pooled across Tx groups from DBP BL was low (W96: 0.072, W144: 0.074, W192: 0.119). Mean EDSS score pooled across Tx groups was stable from DBP BL (3.27) to W192 (3.31) and the overall change in the mean EDSS score from DBP BL was low (W96: ‑0.04, W144: ‑0.01, W192: 0.00). After ≥144W of OLE, the number of T1 Gd+ lesions remained low compared with DBP BL and were reduced after switching from 75mg QD to 75mg BID, providing supporting evidence that EVO 75mg BID (fasted – equivalent to 45 mg BID fed dose in Phase 3) was the optimal dose in this trial. The change in T2 lesion volume from baseline was low across Tx groups. EDSS scores remained stable.