Q&A: Evobrutinib reduces blood neurofilament light levels in patients with MS

Evobrutinib, a Bruton’s tyrosine kinase inhibitor that targets B cells and myeloid cells, significantly decreased blood neurofilament light levels as early as 12 weeks in patients with MS, with sustained reductions through 24 weeks.

The findings showed that evobrutinib has a “beneficial effect” for decreasing neuroaxonal damage in MS, according to the study abstract. Researchers presented the results at the American Academy of Neurology annual meeting, which was held virtually.

The present study was a post hoc analysis of a phase 2, placebo-controlled trial that examined the efficacy of evobrutinib (Merck KGaA) on blood levels of neurofilament light (NfL) chain levels. The trial included four treatment groups: evobrutinib 25 mg once per day, 75 mg once per day, 75 mg twice per day or placebo. Researchers evaluated neurofilament light levels and included patients in the post hoc analysis who had measurements from baseline and at least once between baseline and 24 weeks.

Healio Neurology spoke with Jens Kuhle, MD, PhD, study author and head of the MS center at the University Hospital Basel in Switzerland, to learn more about the study results and the potential role for evobrutinib in MS.

Healio Neurology: What prompted this research?

Kuhle: Only recent developments of highly sensitive detection methods now allow us to reliably measure NfL in blood samples, even in healthy controls. Blood NfL is a biomarker that may allow monitoring of disease activity and treatment response with higher sensitivity than current gold standard of treatment monitoring in MS, clinical examination and MRI. Elevated blood NfL levels are a specific indicator of neuroaxonal injury and predict future brain atrophy and disease worsening in patients with MS.

An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice. This is an endeavor recently concluded in more than 10,000 serum samples from more than 5,000 healthy controls in our laboratory.

Healio Neurology: Have researchers tried to treat MS with Bruton’s tyrosine kinase inhibitors before?

Kuhle: Treating patients with MS with Bruton’s tyrosine kinase (BTK) inhibitors is currently being studied. So far, there are no BTK inhibitors approved for the treatment of MS, but preclinical and clinical data suggest that evobrutinib has the potential to inhibit MS mechanisms involved in disease activity and progression. The results on blood NfL, coupled with the previously published and presented attributes of central nervous system penetration as well as very high BTK occupancy, show that there is a strong potential for evobrutinib and BTK inhibition to play an important role in the treatment of people living with MS.

Healio Neurology: Can you provide a brief overview of the study results?

Kuhle: The data presented at AAN provide key insights into the role evobrutinib may play in modulating the clinical course of MS and further suggest that BTK inhibition with evobrutinib may reduce tissue damage associated with MS. In a post hoc analysis of the phase 2 placebo-controlled trial of evobrutinib in patients with relapsing MS (RMS), we evaluated 166 patients, with NfL values taken at baseline and at least one NfL value post-baseline.

The largest relative reductions of NfL levels were observed with evobrutinib 75 mg taken twice per day at weeks 12 and 24 compared with placebo. As elevated NfL is associated with clinical disability and brain atrophy in MS, these results, combined with the previous clinical trial data that demonstrated a reduction in T1 gadolinium-enhancing lesions and annualized relapse rates, further support the hypothesis that BTK inhibition with evobrutinib may impact both inflammatory and progressive aspects of MS within the CNS. Evobrutinib is the first BTK inhibitor to demonstrate reduction of NfL in patients with MS.

Healio Neurology: Did the study result in any surprising or unexpected findings?

Kuhle: We were hoping and expecting to find that evobrutinib was able to significantly reduce blood NfL levels, which predicts future brain atrophy and may have implications also for developing disease progression in patients with RMS. The findings from this analysis are encouraging and show a strong potential for evobrutinib in the treatment of people living with MS.

Healio Neurology also spoke with Davorka Tomic, executive medical director of global clinical development in neurology for Merck KGaA, regarding the next steps for evobrutinib. She described the new phase 3 studies of evobrutinib.

Healio Neurology: What are the next steps for this agent?

Tomic: Evobrutinib is currently being evaluated in phase 3 trials following the positive results of the phase 2 clinical trial, which was previously published in The New England Journal of Medicine. The two new trials, EVOLUTION RMS 1 and 2, are multicenter, randomized, parallel-group, double-blind, double-dummy, active-controlled studies of evobrutinib vs. teriflunomide, in participants with RMS. Each trial’s primary endpoint is annualized relapse rate over 96 weeks of treatment. Secondary endpoints include confirmed disability progression as measured by the Expanded Disability Status Scale, Patient-Reported Outcomes Measurement Information System related to physical function and fatigue and number of lesions on brain MRI.

Reference:

Kuhle J. The effect of evobrutinib, a BTK inhibitor, on blood neurofilament light chain levels in relapsing multiple sclerosis. Presented at: American Academy of Neurology Annual Meeting; April 17-22, 2021 (virtual meeting).