BTK Inhibitor Evobrutinib Demonstrates Significant Impact on Neurofilament Light Over 2.5-Year Stretch in Relapsing MS

Jens Kuhle, MD, PhD

Findings from a phase 2 study (NCT02975349) and its open-label extension showed that treatment with evobrutinib (EMD Serono), an investigational Bruton tyrosine kinase (BTK) inhibitor, resulted in significantly reduced neurofilament light (NfL) levels, a marker of neuroaxonal damage, compared with placebo over a 2.5-year treatment period.¹

These data were presented at the 2022 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, October 26-28, in Amsterdam, Netherlands. All told, evobrutinib decreased NfL levels in a dose-dependent manner during the 12-week double-blind period, and these reduced levels were maintained up to week 144. Evobrutinib, a highly selective, central nervous system-penetrant agent, is also currently being evaluated in 2 phase 3 trials—EVOLUTIONRMS 1 (NCT04338022) and EVOLUTIONRMS 2 (NCT04338061).

Lead investigator Jens Kuhle, MD, PhD, head, MS Center, and senior physician, University Hospital Basel, originally reported these findings earlier this year at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, June 1-4.² At the time, Kuhle told NeurologyLive® that the 2 main messages from the data are that "neurofilament light is highly prognostic for disease activity, and that the treatment has an effect on this important fluid biomarker, leading towards normalization of increased levels."

In total, 166 of the 213 patients from the original double-blind portion of the trial entered the extension phase. The effect of evobrutinib 25 mg QD, 75 mg QD, or 75 mg BID on NfL levels over time was assessed vs the placebo/evobrutinib 25 mg QD treatment arm, otherwise referred to as the placebo. In the modified intent-to-treat population, the median NfL level at baseline was 11.4 pg/mL, and thus, z-scores were used to assess treatment effect using a mixed-model repeated measures model.

For those who switched from placebo to evobrutinib 75 mg BID in the open-label extension, NfL levels overall and within the original double-blind treatment groups were reduced to similar levels. In comparison with placebo treatment with evobrutinib 75 mg BID resulted in reduced NfL z-scores in a dose-dependent manner as early as week 12, and were significantly sustained for up to week 48. Notably, when stratified by z-scores, Kuhle et al identified an association between lower NfL z-score and number of gadolinium-enhancing T1 and T2 lesions.

"The good thing is the straightforward specificity of neurofilament light. It’s neuron-specific and completely unspecific to the mechanisms leading to their destruction. But this unspecified part can also be a benefit in some situations where you want to quantify neuronal degeneration," Kuhle added. "In the context with reliable data, I believe we can capture these small subtle increases in neurofilaments, as compared with focal inflammatory events. That’s an important step forward for clinical application."

No Evidence of Elevated MS Relapse Risk Following Fertility Treatments

Among 43 cycles that achieved pregnancy, investigators observed decreases of annualized relapse rates from 0.26 to 0.09.

Additional data from the 2022 CMSC Annual Meeting showed that evobrutinib demonstrated an acceptable tolerability profile and efficacy over the 2.5-year period. At the end of the open-label extension, the annualized relapse rate was 0.12 (95% CI, 0.07-0.20) for patients on evobrutinib 75 mg twice daily. In total, 77.5% (165 of 213) of the overall cohort reported at least 1 treatment-emergent adverse event (TEAE) and 27.7% (n = 59) had a treatment-related TEAE, 6 of which were considered serious.³

Evobrutinib continues to be evaluated in the phase 3 EVOLUTION studies, which are randomized, parallel-group, double-blind, double-dummy, active-controlled in design that compare the effects of evobrutinib and teriflunomide (Aubagio; Sanofi) in adults with relapsing MS. Both studies have approximately 930 patients each, with the primary end point of ARR up to 156 weeks of treatment.

Click here for more coverage of ECTRIMS 2022.

REFERENCES
1. Kuhle J, Kappos L, Montalban X, et al. Evobrutinib, a Bruton’s tyrosine kinase inhibitor, decreases neurofilament light chain levels over 2.5 years of treatment in patients with relapsing multiple sclerosis. Presented at: ECTRIMS Congress 2022; October 26-28; Amsterdam, Netherlands. Abstract EP1021
2. Montalban X, Wolinsky JS, Arnold DL, et al. Safety and efficacy of evobrutinib, a Bruton Tyrosine kinase inhibitor, in relapsing multiple sclerosis over 2.5 years of the open-label extension to a phase 2 trial. Presented at: 2022 CMSC Annual Meeting; June 1-4; National Harbor, Maryland. Abstract DMT02
3. Kuhle J, Kappos L, Montalban X, et al.Evobrutinib significantly reduces relapses and MRI outcomes in patients with multiple sclerosis: association with baseline neurofilament light chain levels. Presented at: CMSC Annual Meeting, 2022; June 1-4; National Harbor, Maryland. Abstract DMT18