BTK Inhibitor Evobrutinib Demonstrates Long-Term Safety in Open-Label Extension

At the end of the open-label extension period, 77.5% of patients reported treatment-emergent adverse events and 27.7% had a treatment-related TEAE.

Following a double-blind 48-week treatment period, evobrutinib (EMD Serono), an investigational Bruton tyrosine kinase (BTK) inhibitor, continued to show acceptable tolerability as well as maintained efficacy over a 2.5-year period in patients with relapsing multiple sclerosis (MS).

These data were presented at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, June 1-4, in National Harbor, Maryland, by Anne Cross, MD, Professor of Neurology and the Manny and Rosalyn Rosenthal – Dr. John Trotter MS Chair in Neuroimmunology at Washington University. All told, the annualized relapse rate at the end of the open-label extension (OLE) was 0.12 (95% CI, 0.07-0.20) for patients who received evobrutinib 75 mg twice daily.

The analysis presented included data on 213 patients (79.8% of the 267 randomized) with relapsing MS who completed the double-blind period (DBP) and entered the OLE. In the 48-week double-blind period (DBP), patients received either placebo (switched to evobrutinib 25 once daily at week 24), evobrutinib 25 mg once daily, 75 mg once daily, 75 mg twice daily, or open-label dimethyl fumarate (DMF) 240 mg twice daily.

Following the DBP, patients entered the OLE and were treated with either evobrutinib 75 mg once daily for a median of 48 weeks and then 75 mg twice daily. Of the 213 who entered the OLE, 164 (77%) completed at least 132 weeks of OLE. In total, 77.5% (165 of 213) of the overall cohort reported at least one treatment-emergent adverse event (TEAE) and 27.7% (n = 59) had a treatment-related TEAE, 6 of which were considered serious.

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Severe/opportunistic infections were reported by 9 patients (4.2%), including 3 that resulted in fatalities. Of them, 2 cases were COVID-19 pneumonia and 1 was Escherichia coli sepsis, both of which were not considered treatment related. At week 120 of the OLE, most patients had immunoglobulin (91%), IgA (88%), and IgM (82%) levels within reference ranges. Overall mean CD19+ B-cell levels were 0.218 x 106 cells/mL at OLE baseline and 0.122 x 106 cells/mL at OLE week 96.

Alanine aminotransferase/aspartate aminotransferase elevations were observed only in those previously treated with DMF or evobrutinib 25 mg and occurred within 12 weeks of OLE initiation. In the overall cohort, amylase and lipase increases occurred in 6 (2.8%) and 24 (11.3%) patients, respectively, but without clinical signs and symptoms.

Previously, data from this phase 2 study were presented at the 2019 annual meeting of the American Academy of Neurology which showed 75-mg evobrutinib to be associated with significantly fewer gadolinium-enhancing (Gd+) lesions from week 12 to week 24 compared to placebo in adults with relapsing MS. That data showed that from Weeks 12 to 24, the baseline adjusted rate ratios for the total number of lesions over time compared with placebo were 1.45 (= .32), 0.30 (P = .005), and 0.44 (P = .06) in the 25-mg, 75-mg once daily, and 75-mg twice-daily groups, respectively.2

EMD Serono has 2 ongoing trials—evolutionRMS 1 (NCT04338022) and evolutionRMS 2 (NCT04338061)—comparing the efficacy and safety of evobrutinib to teriflunomide (Aubagio; Sanofi), another previously approved disease-modifying agent. Both multicenter, randomized, parallel-group, double-blind, double-dummy, and active-controlled in design, the studies were originally intended to evaluate evobrutinib against interferon beta-1a, but switched to teriflunomide after the company saw an opportunity to evaluate the drug in an even head-to-head comparison.

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REFERENCES
1. 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
2. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. 2019;380:2406-2417. doi: 10.1056/NEJMoa1901981.