Evobrutinib, a Bruton's Tyrosine Kinase Inhibitor, Decreases Neurofilament Light Chain Levels Over 2.5 Years of Treatment in Patients with Relapsing Multiple Sclerosis

Introduction Evobrutinib (EVO) is a highly selective Bruton's tyrosine kinase (BTK) inhibitor. A prior post hoc analysis of a Phase 2 trial of EVO in patients with relapsing multiple sclerosis (pwRMS; NCT02975349) showed that EVO 75 mg twice-daily (BID) significantly lowered neurofilament light chain (NfL) levels from baseline (BL) at Weeks (W) 12 and 24. The objective was to assess the long-term treatment effect of EVO on blood NfL levels in patients with relapsing multiple sclerosis (pwRMS). Material(s) and Method(s) Levels of NfL were measured (Simoa NF-light™) in the double-blind (DB) arms of the intent-to-treat (ITT) population. During the 48W DB period (DBP), pwRMS received placebo (PBO; switched to EVO 25 mg once-daily [QD] at W24), EVO 25 mg QD, 75 mg QD or 75 mg BID. Patients participating in the open-label extension (OLE) after the end of the DBP (W48) received EVO 75 mg QD and then, after a mean of a further 49.8W, switched to EVO 75 mg BID. NfL levels were reported as age and BMI adjusted median (interquartile range [IQR]) percentiles based on healthy controls (Benkert et al., Lancet Neurol. 2022) to OLE W96 (144W of treatment). Treatment effects versus PBO/EVO 25 mg QD, up to W48 were reported as estimated mean differences, based on a mixed effects model using Z-scores as dependent variable, in the modified ITT and patients with BL and ≥1 post-BL NfL value. Result(s) The median BL NfL level was 11.4 pg/mL. BL, W48 and W144 median percentiles (IQR), respectively, were: PBO/EVO 25 mg QD/75 mg BID: 90.5 (51.0, 99.1), 81.0 (31.0, 92.0), 54.5 (29.0, 83.0); EVO 25 mg QD/75 mg BID: 87.0 (32.0, 98.4), 70.5 (38.0, 90.0), 51.0 (36.0, 75.0); EVO 75 mg QD/75 mg BID: 91.5 (55.0, 98.0), 59.0 (34.0, 91.0), 49.0 (19.0, 76.0); EVO 75 mg BID: 87.0 (56.0, 99.0), 55.5 (24.0, 78.0), 45.0 (30.0, 79.0). Estimated mean NfL Z-scores dose-responses were observed at W12, 24 and 48; with EVO 75 mg BID these NfL Z-scores were significantly reduced, versus PBO/EVO 25 mg QD, from W12 (W12: -0.46, p=0.01; W24: -0.41, p=0.03; W48: -0.53, p=0.01). Conclusion(s) At the group level, EVO reduced and normalised NfL levels up to 144W of treatment. EVO 75 mg BID (fasted dose – predicted to be comparable, with respect to exposure and BTK occupancy, to 45 mg BID fed dose in Phase 3) significantly reduced NfL levels from W12, compared with PBO/EVO 25 mg QD, showing an early dose-response. This reduction in NfL provides evidence that EVO markedly reduces neuroaxonal damage in pwRMS.