Open-Label Extension: BTKI in Relapsing MS Over 108 Weeks

Xavier Montalban, MD, PhD: I was the first author on the paper on efficacy and safety of the BTK [Bruton’s tyrosine kinase] inhibitor evobrutinib in relapsing-remitting multiple sclerosis over 108 weeks. That’s an open-label extension to the phase 2 study.

You probably remember that BTK plays a role in the B-cell microphage signaling, and evobrutinib has a dual mode of action. One side impacts B cells and myeloid cells, and the CNS [central nervous system]. So from the mechanistic point of view, it is quite an interesting molecule.

In a phase 2 study that was published last year in The New England Journal of Medicine, in patients with relapsing MS [multiple sclerosis], evobrutinib significantly reduced the cumulative number of patients with T1-weighted gadolinium-enhancing lesions compared to placebo, including weeks 12 to 24 of treatment, and was generally well tolerated.

Now what we wanted to do is to assess the long-term efficacy and safety in the open-label extension of this study. If you remember the phase 2 study, in the 48-week, double-blinded period, patients received evobrutinib 25 mg or 75 mg once daily. Also we had another group of 75 mg twice daily, and then we had open-label dimethyl fumarate or placebo for the first 24 weeks.

At 24 weeks, we had our primary end point, it was an MRI primary end point of course, gadolinium-enhancing lesions. All arms continued with the original treatment until 48 weeks, except placebo, who were switched to 25 mg once per day. And then at week 48, and this is the open-label extension part of the study, all patients were initially treated with 75 mg once daily. And then when we realized that 75 mg twice a day was better, we switched all patients to 75 mg twice per day.

At the end, I think the important data are that 80% of patients completed 108 weeks of treatment, which is very good in my opinion. And for patients who received evobrutinib at 75 mg twice per day in the double-blinded period, the annualized relapse rate was 0.11, which is very low, at week 48, and 0.12 for the 108-week period.

Evobrutinib after this period was generally well tolerated. The safety profile was maintained during the 60-week observational extension period, and nothing very serious appeared from the safety point of view.

I think that the data were quite encouraging, and I wouldn’t say there was a lack of safety issues, but in general, it was well tolerated and no serious signals were observed. And the good efficacy prompted us to design 2 phase 3 randomized trials evaluating the efficacy of evobrutinib in patients with relapsing MS against dimethyl fumarate on this occasion.

I would like to comment that I feel very fortunate. I think we are very lucky. I have been discussing 3 different abstracts using 3 different molecules for the treatment of multiple sclerosis. And 2 out of the 3 are really powerful molecules. They have already demonstrated efficacy in relapsing multiple sclerosis, and 1 of them in progressive multiple sclerosis. The third abstract shows how attractive, how promising a new molecule with a completely different mechanism of action can be.

I think we all know that we are living in a very special time in the treatment of multiple sclerosis. And I feel very happy knowing how many opportunities our patients with MS have nowadays to treat their condition.