On the heels of successful long-term data, evobrutinib seeks to maintain its high efficacy in 2 pivotal phase 3 clinical trials.
EMD Serono's investigational, oral, highly selective Bruton tyrosine kinase (BTK) inhibitor evobrutinib is the focus of 2 pivotal phase 3 trials in relapsing multiple sclerosis (MS) that are expected to conclude in September 2023. Evobrutinib is unique in its mechanism, as BTK inhibition is thought to suppress antibody-producing cells, which research suggests may hold therapeutic benefit in certain autoimmune diseases.
Fernando Dangond, MD, MBA, therapeutic area head of global clinical development in neurology and executive medical director at EMD Serono, told NeurologyLive®, “The novelty of the BTK inhibition pathway is that it tackles 2 important cells that have been involved in the pathobiology of MS––B cells and myeloid cells––without directly affecting T cells. It decreases the ability to produce cytokines in B cells.”
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 in adults with relapsing MS (FIGURE). Originally, the investigators intended to evaluate the study drug against interferon β-1A, but switched the comparator to teriflunomide after EMD Serono saw an opportunity to evaluate the drug in an even head-to-head comparison.
“When we saw that the efficacy of the 75-mg dose was so high, we reconvened and decided that we could switch to another oral comparator, which would be more attractive for those interested
in enrolling because the drug would be going up against an already approved oral agent,” Dangond said.
Both studies have an estimated target enrollment of 930 patients, with a primary end point of annualized relapse rate (ARR) after 96 weeks of treatment. Secondary end points include time to first 12- or 24-week confirmed Expanded Disability Status Scale (EDSS) progression over 96 weeks; number of gadolinium-enhancing (Gd+) T1 lesions and new or enlarging T2 lesions at weeks 24, 48, and 96; change from baseline on the Patient Reported Outcomes Measurement Information System (PROMIS) MS Physical Function and PROMIS Fatigue MS Short Form scores. Further secondary end points include adverse events; clinically significant change from baseline in vitals, laboratory, or electrocardiogram measures; and concentrations of and change in immunoglobulin levels.
Eligible patients must be diagnosed with relapsing-remitting or secondary progressive MS with relapses and have an EDSS score of 0 to 5.5 at screening and baseline, and have 1 or more documented relapses within the 2 years prior to screening.
Long-term data from the phase 2, randomized controlled trial (NCT02975349) showed that twice daily treatment with 75-mg evobrutinib was associated with an AAR of 0.11 (95% CI, 0.04-0.25) at week 48 of the double-blind period and 0.12 (95% CI, 0.06-0.22) for the full 108-week treatment period.1
"We saw early on that there was an effect on annualized relapse rate. This is what we see with the most potent agents and [disease-modifying drugs] out there in the market,” Dangond said.
Across a cohort of 213 patients, the drug was considered well tolerated and maintained its known safety profile over the open-label extension period. Transient elevated liver aminotransferases, which investigators reported in the 48-week double-blind period, were not observed in the extension.2
Data from the first 24 weeks of that trial, published in 2019,3 showed treatment with evobrutinib was associated with significantly fewer Gd+ lesions from week 12 to 24 compared with placebo. Furthermore, from weeks 12 to 24, the baseline adjusted rate ratios for the total number of lesions over time compared with placebo were 1.45 (P = .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.
“We are now in a competitive arena,” Dangond said. “Multiple companies want to bring their BTK inhibitors to MS after we were the first to demonstrate that there’s efficacy in MS. We are doing our best to recruit as fast as we can.”