NeuroVoices: Jens Kuhle, MD, on Evobrutinib’s Association With Neurofilament Light Levels

Jens Kuhle, MD, PhD

As the toolbox of disease-modifying therapies for patients with multiple sclerosis (MS) has expanded in recent years, many clinicians are excited to learn more about a new investigational class of medications called Bruton tryosine kinase (BTK) inhibitors. One such therapeutic, evobrutinib (EMD Serono), has shown to have an acceptable safety profile maintained over a 2.5-year period in patients with relapsing MS in a phase 2 randomized trial (NCT02975349).¹

A new such analysis presented at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, June 1-4, in National Harbor, Maryland, evaluated the prognostic value of baseline blood neurofilament light (NfL) levels on clinical relapse and MRI lesion activities, and further assessed the treatment effect of the investigational agent. Patients were grouped by high dose evobrutinib 75 mg once daily or 75 mg BID or placebo/low dose evobrutinib 25 mg once daily, with geometric mean baseline NfL levels as either high (≥11.36 pg/mL) or low (<11.36 pg/mL).²

In a cohort of 162 patients, those with high NfL had higher disease burden at baseline as well as higher levels of clinical relapses and MRI activity over 24 weeks. Additionally, the odds of qualified relapse were significantly reduced for the high dose group vs placebo/low dose, when stratified by baseline NfL levels (odds ratio, 0.12; P = .0028). Regardless of baseline NfL, patients on the high dose group had a significant reduction in the cumulative number of gadolinium enhancing T1 lesions or new or enlarged T2 activity compared with placebo/low dose.

As part of a new iteration of NeuroVoices, lead investigator Jens Kuhle, MD, PhD, head, MS Center, and senior physician, University Hospital Basel, sat down at the meeting to discuss the findings. He provided further context on the value of NfL and how it can be used to assess neurodegeneration, as well as the idea behind raising dose levels to improve efficacy of BTK inhibitors.

NeurologyLive^®: What were the major findings from this analysis?

Jens Kuhle, MD: Neurofilament light chain is a neuron-specific protein that can quantify axonal injury in serum or plasma samples by using highly sensitive technology. In this trial, we saw that higher doses of evobrutinibreduced serum neurofilament light levels after 6 months. In the presentation, we saw that patients with higher serum neurofilament levels at baseline developed more clinical and MRI disease activity over the next months; however, treatment effect was visible in patients with high or low neurofilament light levels at baseline. The 2 main messages are that neurofilament light is highly prognostic for disease activity, and that the treatment has an effect on this important fluid biomarker, leading towards normalization of increased levels.

Is it time to solely consider higher doses to improve efficacy?

The evidence or knowledge so far of BTK inhibitors on NfL levels is limited. I think it’s fair enough to say evobrutinib is the first BTK inhibitor that investigated serum NfL levels, so it’s certainly something to further look into. Also, we need to extensively investigate the effects of BTK inhibitors on focal inflammation and on potentially mechanisms leading to progression in MS. We need to question that if this treatment leads to reduced NfL levels, is it potentially independent of the effect of lesions, potentially going toward neuroprotection, and protecting the nervous system from that neurodegeneration.

Although investigational, what are the role of BTK inhibitors right now?

That’s the difficult and important question. Obviously, that has not been answered yet. BTK inhibitors, as brain penetrant protein molecules, are an attractive treatment and potentially protecting neurodegeneration from happening. There are plenty of ongoing studies on all kinds of BTK inhibitors and we’re looking forward to being able to answer these questions in the future. Currently, it’s too early to know, but it will be down the road. Right now, it has to do with our difficult outcome measures in MS, essentially relying heavily on clinical examination vs potentially having sensitive and precise fluid biomarkers in the future that could facilitate trial design.

How does the MS community view neurofilament light? What potential does it have?

I am relatively surprised at the uptake of neurofilament light towards clinical practice. I’m meeting more and more colleagues who are actually using it in clinical practice. For example, in Canada, this biomarker is regularly used to treat patients. There is broad acceptance and uptake, although there is still some insecurity on how to use this biomarker. Things will be clarified in the next years, I believe, but it’s an important milestone to be able to use such a fluid biomarker in selected situations, and sometimes even broadly used. It’s quite the dynamic uptake.

The good thing is the straightforward specificity of neurofilament light. It’s neuron-specific and completely unspecific to the mechanisms leading to their destruction. But this unspecified part can also be a benefit in some situations where you want to quantify neuronal degeneration. In the context with reliable data, I believe we can capture these small subtle increases in neurofilaments, as compared with focal inflammatory events. That’s an important step forward for clinical application.

What has been your overall thoughts on this year’s CMSC Annual Meeting?

It’s a pleasure to meet again after a long, difficult time. My main takeaway from this meeting is that NfL has been taken up in other countries and hospitals. It’s a nice broad meeting with a range of specialists to general practitioners that gives this meeting a special flavor.

Transcript edited for clarity. Click here for more coverage of CMSC 2022.

REFERENCES
1. Montalban X, Wolinsky JS, Arnold DL, et al. Safety and efficacy of evobrutinib, a Bruton Tyrosine kinase inhibitor, in relapsing multiple sclerosis over 2.5 years of the open-label extension to a phase 2 trial. Presented at: 2022 CMSC Annual Meeting; June 1-4; National Harbor, Maryland. Abstract DMT02
2. Kuhle J, Kappos L, Montalban X, et al.Evobrutinib significantly reduces relapses and MRI outcomes in patients with multiple sclerosis: association with baseline neurofilament light chain levels. Presented at: CMSC Annual Meeting, 2022; June 1-4; National Harbor, Maryland. Abstract DMT18