Evobrutinib Shows Long-Term Efficacy and Safety in Phase 2 Study

Xavier Montalban, MD, PhD, professor of Medicine, Department Division Director, Neurology, University of Toronto, director of the MS Centre at St. Michaels Hospital, Canada, and Chairman and Director Neurology-Neuroimmunology Department and Neurorehabilitation Unit, Multiple Sclerosis Centre of Catalonia, Vall dHebron University Hospital, Barcelona, Spain

Xavier Montalban, MD, PhD

Data presented at the 2020 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC 2020) suggest that the efficacy and safety of 75-mg evobrutinib is maintained over the long-term in the treatment of patients with relapsing multiple sclerosis (MS).¹

Those who received EMD Serono’s investigational, oral, highly selective Bruton's Tyrosine Kinase (BTK) inhibitor had an annualized relapse rate (ARR) of 0.11 (95% CI, 0.04—0.25) at Week 48, and 0.12 (95% CI, 0.06–0.22) for the full 108-week period. Evobrutinib was also considered generally well-tolerated, maintaining its known safety profile during the open-label extension period, with transient elevated liver aminotransferases, which was reported in the 48-week double-blind period, not observed in the extension.²

The phase 2 randomized controlled trial (NCT02975349) was conducted by Xavier Montalban, MD, PhD, chairman and director, Neurology-Neuroimmunology Department and Neurorehabilitation Unit, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, and colleagues, and included 213 patients (79.8% of the 267 randomized) who were treated for 108 weeks, which consisted of the 48-week main study and 60-week open-label extension.

“The 108-week efficacy and safety data for evobrutinib through the double-blind and the OLE period are very robust,” Montalban said in a statement. “This, combined with the high selectivity of evobrutinib, suggests that evobrutinib may offer a promising approach to MS treatment.”

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The double-blind period consisted of 48 weeks in which patients received 25-mg or 75-mg once-daily evobrutinib, 75-mg twice-daily evobrutinib, open-label dimethyl fumarate (240 mg twice daily), or placebo for the first 24 weeks. After the first 24 weeks, all cohorts continued with the original treatment assignment until 48 weeks, save for placebo patients, who switched to 25-mg once-daily evobrutinib. After Week 48, all patients could enter the open-label extension. In the 60-week extension period, treatment was initially 75-mg once-daily evobrutinib (median, 48 weeks) before switching to 75-mg twice-daily evobrutinib.

"These data demonstrate evobrutinib has a sustained and high impact on annualized relapse rate over 108 weeks," said Luciano Rossetti, MD, head, Global Research and Development, EMD Serono, in a statement. "Greatest efficacy was clearly associated with BTK occupancy, and this further validates our choice of dose for the phase 3 program. We are also encouraged by evobrutinib's breadth of consistent safety data, including no increase of serious infections in more than 1200 patients up to 2 years."

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 multiple sclerosis (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 (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.³

Overall, 267 patients were randomized: 54 to the placebo group, 52 to evobrutinib 25-mg, 53 to evobrutinib 75-mg once daily, 54 to evobrutinib 75-mg twice daily, and 54 to the comparator group. From Weeks 12 to 24, the total number of Gd+ lesions were 3.85 ±5.44 in the placebo group, 4.06 ±8.02 in the evobrutinib 25-mg group, 1.69 ±4.69 in the evobrutinib 75-mg once-daily group, 1.15 ±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78 ±22.05 in the dimethyl fumarate group.

At Week 24, patients randomized to 25-mg, 75-mg once daily, and 75-mg twice-daily evobrutinib experienced a respective total of 13, 3, and 2 relapses. In comparison, the dimethyl fumarate and placebo groups experienced 5 and 9 relapses, respectively. The unadjusted annualized relapse rate (AAR) was 0.37 in the placebo group (95% CI, 0.17 to 0.70), 0.57 in the evobrutinib 25-mg group (95% CI, 0.30 to 0.97), 0.13 in the evobrutinib 75-mg once-daily group (95% CI, 0.03 to 0.38), 0.08 in the evobrutinib 75-mg twice-daily group (95% CI, 0.01 to 0.30), and 0.20 in the dimethyl fumarate group at Week 24.

These new data from CMSC 2020 were also accepted for presentation at the European Academy of Neurology (EAN) 2020 annual meeting. Additionally, 2 phase 3 randomized clinical trials evaluating the efficacy and safety of evobrutinib in patients with relapsing MS are set to begin this year, according to EMD Serono.²

Those new trials, dubbed EVOLUTION RMS 1 (NCT04338022) and EVOLUTION RMS 2 (NCT04338061) are multicenter, randomized, parallel-group, double-blind, double-dummy, active-controlled studies of evobrutinib with teriflunomide in participants with relapsing MS. Both trials are assessing ARR after 96 weeks of treatment as the primary end point. Secondary end points will include the appearance of new or enlarging T2 lesions assessed by MRI scans and progressing disability as measured by the Expanded Disability Status Scale (EDSS).

For more coverage of CMSC 2020, click here.

REFERENCES

1. Montalban C, Arnold DL, Weber MS, et al. Efficacy and Safety of the Bruton’s Tyrosine Kinase Inhibitor (BTKI) Evobrutinib in Relapsing Multiple Sclerosis over 108 Weeks: Open-Label Extension to a Phase 2 Study. Int J MS Care. 2020;22(2 Suppl). Late-Breaking Abstract.

2. New Late-Breaking Data at EAN Indicate Evobrutinib is the First BTK Inhibitor to Report Efficacy and Safety in MS Over 108 Weeks [press release]. Rockland, MA: EMD Serono; Published May 23, 2020. Accessed May 26, 2020. biospace.com/article/releases/new-late-breaking-data-at-ean-indicate-evobrutinib-is-the-first-btk-inhibitor-to-report-efficacy-and-safety-in-ms-over-108-weeks

3. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. Published online May 10, 2019. doi: 10.1056/NEJMoa1901981.