#ECTRIMS2022 – 3-year Data Show Evobrutinib Safely Lowers Relapses

MS therapy candidate found safe, effective with long-term use in trial

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term use of the investigational BTK inhibitor evobrutinib among people with relapsing forms of multiple sclerosis (MS) continues to maintain MS relapse rates, and keep MRI lesion activity low.

That’s according to up to 3.5 years of data from a Phase 2 trial (NCT02975349) and its open-label extension (OLE) phase, which are evaluating the therapy against a placebo and the approved MS treatment Tecfidera (dimethyl fumarate).

The findings were shared by Patrick Vermersch, MD, PhD, vice president of research in biology and health at the University of Lille, in France, at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held last week virtually and in Amsterdam.

The research leading up to the poster, “MRI and clinical outcomes of evobrutinib, a Bruton’s tyrosine kinase inhibitor, in relapsing multiple sclerosis over 2.5 years of the open-label extension to a Phase 2 trial,” was funded by EMD Serono, known as Merck KGaA outside North America, which is developing evobrutinib.

“Disease progression is a top concern in the MS community,” Vermersch said in a Merck press release. “In this longest-running and most extensive analysis of any BTK inhibitor in development for [relapsing] MS, evobrutinib maintained disease stability for up to three and half years.”

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Testing evobrutinib in patients

An oral immune-modulating treatment, evobrutinib works by blocking the activity of the Bruton’s tyrosine kinase (BTK). This protein is essential for the function of certain classes of immune cells, including B-cells and macrophages, which drive the inflammation that damages nerve cells in MS.

By stopping BTK, evobrutinib is expected to dampen excessive immune activation and slow neurodegeneration in MS.

The Phase 2 trial enrolled 267 adults with relapsing-remitting MS and active secondary progressive MS. Participants were randomly assigned to one of five groups.

Three groups received evobrutinib at various doses — 25 mg once daily, 75 mg once daily, or 75 mg twice daily — while one group received a placebo. One group was given Tecfidera, an approved oral MS treatment marketed by Biogen.

Patients assigned to evobrutinib or Tecfidera received daily oral treatment for 48 weeks, or about one year. Those on a placebo received it only for 24 weeks, or about six months, after which patients were switched to evobrutinib, at the once daily 25 mg dose, for the remaining half of the trial.

Top-line results showed that the highest dose of evobrutinib — 75 mg twice daily — was superior to a placebo at reducing the number of inflammatory brain lesions after 24 weeks of treatment, meeting the trial’s main goal.

Relapse rates also were lowered with this dose. Patients receiving 75 mg evobrutinib twice daily had a rate of 0.08 relapses per year after 24 weeks and 0.11 relapses per year after one year of treatment. In turn, those in the placebo group had an average of 0.37 relapses per year after 24 weeks. Notably, 79% of patients in that evobrutinib group remained relapse-free after 48 weeks.

After completing the Phase 2 trial, 213 people (80%) chose to enter the OLE. All received 75 mg evobrutinib once daily for a mean of 49.8 weeks before switching to the 75 mg twice daily dose. The OLE will be following patients for about six years — totaling up to seven years of treatment for those initially assigned evobrutinib.

Previous updates demonstrated that evobrutinib continued to be generally safe and well-tolerated, and maintained its benefits over 2.5 years in the OLE. At the ECTRIMS congress, Vermersch now provided an update on the 160 participants who completed at least 144 weeks of treatment (about 2.7 years) in the OLE.

For patients who had received evobrutinib at its highest dose in the initial trial, this meant a total treatment duration of 192 weeks, or a little over 3.5 years.

Results showed that clinical outcomes remained stable, with patients initially assigned to the highest dose maintaining a relapse rate of 0.13 relapses per year over the OLE. Among the entire group of participants, relapse rates reduced from 0.19 to 0.09 after all patients switched from 75 mg once daily to twice daily.

Similarly, disability level and MRI lesion activity, including inflammatory and new and enlarging lesions, remained low and stable throughout follow-up.

“These data demonstrate the long-term benefit of evobrutinib in both MRI and clinical manifestations of [relapsing MS],” the researchers wrote.

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Therapy also lowers NfL levels

In a second poster presentation, data demonstrated that the highest dose of evobrutinib led to sustained reductions in neurofilament light chain (NfL) — a biomarker of nerve damage — after 12 weeks in the initial trial compared with a placebo. These reductions were maintained over a period of up to 144 weeks of follow-up.

An association also was observed between NfL levels and and MRI lesion activity, with lower NfL levels linked to fewer inflammatory brain lesions as a reduced number of new or enlarging lesions.

The poster, titled, “Evobrutinib, a Bruton’s tyrosine kinase inhibitor, decreases neurofilament light chain levels over 2.5 years of treatment in patients with relapsing multiple sclerosis,” was presented by Jens Kuhle, MD, PhD, of the neurologic clinic and policlinic at the MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel.

“This is the first time that evidence of sustained efficacy out to three and a half years could be shown with a BTK inhibitor in [relapsing] MS,” said Jan Klatt, senior vice president, head of development unit of neurology and immunology at Merck.

“Combined with our previous data demonstrating reduced volume of slowly expanding lesions … and reduced neurofilament levels, a marker of neuronal injury, we are confident evobrutinib has the potential to offer best-in-class efficacy for people living with [relapsing] MS,” Klatt added.

Evobrutinib is now being tested in two identical Phase 3 trials — EVOLUTION RMS1 (NCT04338022) and EVOLUTION RMS2 (NCT04338061) – which are collectively enrolling about 1,800 people with relapsing forms of MS at sites globally. There are 279 study locations for EVOLUTION RMS1 and 278 clinical sites for EVOLUTION RMS2.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ECTRIMS Forum 2022 Oct. 26–28. Go here to see the latest stories from the conference.