Evobrutinib Maintained Over Long-Term Period, With BID Dosing Regimen Providing Maximal Efficacy

Xavier Montalban, MD, PhD

Findings from an ongoing open-label extension study (NCT029775349) assessing EMD Serono’s investigational agent evobrutinib in patients with relapsing multiple sclerosis (MS) showed treatment benefits and an acceptable tolerability profile for over a 3.5-year treatment period. The data also revealed that twice-daily (BID) dosing was more effective on clinical end points than once-daily (QD) evobrutinib.

These data were presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, by Xavier Montalban, MD, PhD, chair of neurology at the Vall d-Hebron University Hospital. In the original double-blind portion of the study, Evobrutinib, a highly selective central nervous system-penetrant Bruton tyrosine kinase (BTK) inhibitor, was compared with dimethyl fumarate (Tecfidera; Biogen), a previously approved anti-CD20 therapy.

To date, these were the first released results on evobrutinib at 3.5 years. In total, 213 of the original 267 patient cohort entered the OLE, 72.8% (n = 155) of which completed at least 228 weeks of treatment. In comparison, investigators observed a pooled annualized relapse rate (AAR) of 0.10 for evobrutinib 75 mg BID dose compared with 0.18 for 75 mg QD dose. Notably, at 228 weeks, the pooled ARR for evobrutinib remained low, at 0.13.

The trial was built so that patients with relapsing MS (n = 267) received placebo, evobrutinib 25 mg QD, 75 mg QD, 75 mg BID, or open-label dimethyl fumarate (120 mg BID for the first week, 240 mg BID thereafter). Those on placebo switched to evobrutinib 25 mg QD after week 24. Following week 48, patients were given the choice to enter the OLE, where they received evobrutinib 75 mg QD and later switched to 75 mg BID.

Safety of evobrutinib continued at week 228, with treatment-emergent adverse events (TEAEs) reported in 83.6% (n = 178) of patients, and severe/opportunistic infections of at least grade 3 reported by 5.2% (n = 11) of the cohort. Treatment-related TEAEs were found in 28.2% (n = 60) of individuals, with 3.3% (n = 7) reporting serious treatment-related TEAEs.

Previously reported data on evobrutinib from the phase 2 study and its OLE showed reductions in neurofilament light (NfL), a marker of neuroaxonal damage, compared with placebo over a 2.5-year period. Led by Jens Kuhle, MD, the analysis showed decreased NfL levels in a dose-dependent manner during the 12-week double-blind period, with reductions maintained up to week 144.²

READ MORE: Open-Label Analysis Highlights Long-Term Safety of BTK Inhibitor Tolebrutinib

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.

Evobrutinib is currently being evaluated in 2 pivotal phase 3 studies, both expected to conclude in September 2023. The trials—evolutionRMS 1 (NCT04338022) and evolutionRMS 2 (NCT04338061)––are multicenter, randomized, parallel-group, double-blind, double- dummy, active-controlled studies comparing evobrutinib and teriflunomide (Aubagio; Sanofi) in adults with relapsing MS. In April 2023, the FDA placed the EVOLUTION trials on hold because of liver injuries reported, although those taking the drug for more than 70 days were allowed to complete the treatment. Because recruitment was finished, no individuals had to leave the trial, and results are still expected to be read out by end of 2023.³

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REFERENCES
1. Montalban X, Wolinsky JS, Arnold DA, et al. Efficacy and Safety of Bruton’s tyrosine kinase inhibitor evobrutinib for relapsing multiple sclerosis over 3.5 years of treatment: an ongoing phase 2 open-label extension. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 003752
2. 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
3. Initiation of new patients on evobrutinib paused in the US; fully enrolled phase 3 evobrutinib studies continue. News release. April 12, 2023. Accessed April 21, 2023. https://www.emdgroup.com/en/news/evobrutinib-12-04-2023.html