#ECTRIMS2018 – Evobrutinib Seen to Lower Active Brain Lesions in Phase 2 Trial

Merck KGaA announced that evobrutinib, its oral candidate for relapsing multiple sclerosis (MS), was able to safely and significantly reduce active brain lesions over 24 weeks of treatment, according to results of a Phase 2 study sponsored by the company.

The data were part of the late-breaking news session at the recent 34th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Berlin, given in the presentation, “Primary analysis of a randomized, placebo-controlled, phase 2 study of the Bruton’s tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis.” 

Evobrutinib is an investigational oral inhibitor of Bruton’s tyrosine kinase (BTK), a signaling protein believed to be important for the proper development and functioning of a number of immune cells, including B-cells and macrophages.

In the double-blind, randomized, placebo-controlled, Phase 2 study (NCT02975349) the therapeutic effectiveness of low (25 mg once daily), mid (75 mg once daily), and high (75 mg twice a day) doses of evobrutinib were compared to treatment with Tecfidera (dimethyl fumarate) or a placebo in people with relapsing MS.

In total,  patients were treated for 48 weeks. Those in the placebo group were given placebo for 24 weeks, then switched to a low dose of evobrutinib for another 24 weeks. 

Nearly all enrolled (244 of 267) completed 24 weeks of treatment, and the study met its primary endpoint — a reduction in lesion number at that time period. Evobrutinib at 75 mg, either given daily or twice a day, was seen to significantly reduce the number of active brain lesions (referred to as T1 lesions on MRI) at weeks 12, 16, 20, and 24, when compared with placebo.

The mean number of active lesions in patients taking evobrutinib at 25 mg once daily, 75 mg once daily, or 75 mg twice daily dropped as the dose rose — 4.06, 1.69, and 1.15, respectively, at weeks 12 to 24. In the placebo group, the mean number of active lesions was 3.85.

Such results suggest that evobrutinib’s therapeutic effect has a dose-response relationship, with a 75 mg daily or twice a day (total 150 mg) dose leading to a significant benefit, but not a 25 mg daily dose.

According to Merck, evobrutinib treatment also led to clinically relevant reductions in annualized relapse rates (mean relapse rate per year). In patients given 75 mg once or twice a day, relapse rates were 0.13 and 0.08, respectively, while in the placebo group it was 0.37.

Moreover, new or larger T2 brain lesions (referring to the total lesion load, both old and new) per scan were significantly lesser with evobrutinib. The mean number of lesions at 75 mg twice a day was 2.19 in patients, 3.41 in those on 75 mg once a day, 6.52 with 25 mg, and 5.96 in the placebo group. 

Evobrutinib was seen to be well-tolerated. No cases of infection, infestation, or low lymphocyte count were reported to be associated with the treatment. The most common treatment-related adverse event was an increase in the levels of liver enzymes, indicating a possible injury to the liver, and particularly evident in people treated at the highest, twice daily dose. But all these events were reversible and asymptomatic, the study reported.

“We are among the first to evaluate a BTK inhibitor for chronic autoimmune diseases, and we continue to be highly encouraged by the results we’ve seen in patients with relapsing MS thus far,” Luciano Rossetti, global head of research and development at Merck KGaA, said in a news release.

“We look forward to further exploring the potential of evobrutinib in future clinical trials,” Rossetti added.

Data is not yet available on the full 48 weeks of treatment, or comparing the effects of treatment with Tecfidera versus evobrutinib, or Tecfidera versus placebo.

“The results of this study highlight the potential of BTK inhibitors as an oral disease modifying treatment for relapsing MS,” said Xavier Montalban, a neurologist and professor of medicine at the University of Toronto, and director of the MS Centre at St. Michael’s Hospital.

“These findings suggest that the dual mechanism of action of evobrutinib, which impacts pathogenic adaptive and innate immune cells in multiple sclerosis, could translate into clinical efficacy,” Montalban added. 

The compound is the first BTK inhibitor demonstrating clinical activity in relapsing MS, according to Merck KGaA. The company is also investigating evobrutinib as a possible treatment for two other autoimmune disorders, systemic lupus erythematosus and rheumatoid arthritis.

Multiple Sclerosis News Today spoke with Jerry S. Wolinsky, a neurologist and MS specialist, at ECTRIMS 2018 about his work in this evobrutinib study, and his views on MS treatment in general. According to the researcher, evobrutinib is a  promising candidate therapy for MS. To read the interview, please use this link.