Evobrutinib Significantly Reduces Relapses and MRI Outcomes in Patients with Multiple Sclerosis: Association with Baseline Neurofilament Light Chain Levels

Background: Evobrutinib is a highly selective Bruton’s tyrosine kinase inhibitor (BTKi). In a post hoc analysis of a Phase II randomized trial (NCT02975349), evobrutinib 75 mg twice daily (BID) significantly lowered blood neurofilament light chain (NfL) levels at Weeks 12 and 24. NfL is a biomarker of neuro-axonal damage in MS.

Objectives: To evaluate the prognostic value of baseline blood NfL levels on clinical relapse and MRI lesion activities, and to further evaluate the treatment effect of evobrutinib in MS.

Methods: The analysis included patients in the modified intent-to-treat population with NfL values at baseline (excluding the dimethyl fumarate arm). Patients were grouped by high dose (evobrutinib 75 mg once daily [QD] or 75 mg BID) or placebo/low dose (placebo or evobrutinib 25 mg QD). Baseline NfL was measured blinded to treatment (Simoa NF-light™). Patients were stratified by geometric mean baseline NfL levels as either high NfL (≥11.36 pg/mL) or low NfL (<11.36 pg/mL), to evaluate the effect on qualified relapses over 24 weeks; patients were also stratified by gadolinium-enhancing (Gd+) T1 lesions and T2 lesions over Weeks 12, 16, 20, and 24. Treatment effect was also evaluated, stratified by baseline NfL group.

Results: The NfL analysis population included 162 patients. Patients with high NfL had higher disease burden at baseline as well as higher levels of clinical relapses and MRI lesion activity over 24 weeks. The odds of qualified relapse were significantly reduced for the high dose group versus placebo/low dose, when stratified by baseline NfL levels (odds ratio: 0.12; p=0.0028). A significant reduction in the cumulative number of Gd+ T1 lesions and new or enlarging T2 activity was observed for the high dose group versus placebo/low dose, regardless of baseline NfL: Gd+ T1 relative reduction (RR)=69.4% (p=0.0102) and RR=69.2% (p=0.0018), new or enlarging T2 lesions RR=73.4% (p=0.0012) and RR=54% (p=0.0458), for the NfL low and high groups, respectively.

Conclusions: This is the first study describing the interaction of blood NfL levels and the effects of a BTKi in patients with MS. The data indicate that higher doses of evobrutinib reduce MRI activity, regardless of baseline NfL levels, and significantly reduce the proportion of patients with relapses versus placebo/low doses in the high blood NfL level group. These data also support the value of blood NfL levels as a prognostic marker of future disease activity.

Role of the Study Sponsor: This study was sponsored by EMD Serono (CrossRef Funder ID: 10.13039/100004755). The study sponsor was involved in the study design, collection, analysis, and interpretation of data, and was involved in the decision to submit the abstract for publication.