#ECTRIMS2018: Study Proposes Serum Neurofilament Light Threshold to Identify RRMS Patients at Risk of Worsening

Relapsing-remitting multiple sclerosis (RRMS) patients with serum neurofilament light chain (sNfL) levels higher than a proposed threshold have a higher risk of disease activity, and worsened disability, lesions and brain shrinkage in the long term, according to a new study.

The research, “Serum neurofilament light (NfL) for disease prognosis and treatment monitoring in multiple sclerosis patients: is it ready for implementation into clinical care?,” was presented Thursday at the 34^th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Berlin, Germany.

The data was presented by Peter Calabresi, MD, from Johns Hopkins Hospital, Baltimore.

sNFL has been suggested as a potential disease biomarker. It is a protein exclusive to nerve cells, and one of the major byproducts found in cerebrospinal fluid and blood after nerve cells’ death.

In patients with RRMS, sNfL levels correlate with disease activity, help predict long-term clinical and imaging outcomes, and are reduced by disease-modifying treatments (DMTs). However, a standardized assay (method) and clinically meaningful cut points (limits) validated with real-world data are still required to integrate sNfL into clinical practice.

The study, sponsored by Biogen, aimed to define sNfL levels relevant to disease severity classification and treatment monitoring in RRMS patients. For this purpose, the team used samples and data from more than 1,000 patients enrolled in four of Biogen’s Phase 3 clinical trials.

sNfL levels were measured with two methods, using the Single Molecule Array (SIMOA, Quanterix) Advantage kit or a laboratory method. According to Calabresi, the SIMOA assay is a “technically validated, sensitive, preferred and widely used assay for evidence generation.”

In the ADVANCE trial of Plegridy (peginterferon beta-1a) in 594 RRMS patients (NCT00906399), sNfL was measured at baseline, every three months for two years, then every six months for two more years. In the CHAMPS study of Avonex (interferon beta 1a) in 319 patients with clinically isolated syndrome — which often precedes MS development — it was assessed at baseline and week 48.

In the MSCRG trial of Avonex in 164 RRMS patients, sNfL levels were measured at years three and four; and in the SENTINEL study (NCT00030966) of Tysabri (natalizumab) in 122 participants with RRMS, at baseline and week 96.

The results showed that baseline sNfL levels correlated with the number of brain lesions and accumulation of new lesions on magnetic resonance imaging (MRI) over time. sNfL levels were consistently low in patients without evident of disease activity, but were elevated in those with active disease, especially in those with high rates of brain atrophy, or shrinkage.

A sNfL level higher than 16 pg/mL indicated high probability of disease activity over the following year, and was associated with worse clinical and imaging outcomes in the long term, worse Expanded Disability Status Scale score (a measure of disability) at 12 years, greater lesion volume at 10 years, and brain shrinkage at five years.

Treatment with DMTs lowered sNfL levels, especially with Tysabri, which lowered sNfL levels in 96% of the patients.

“These findings support the clinical relevance of sNfL levels and establish relevant cut points for disease severity stratification and treatment monitoring in RRMS patients,” the researchers said.

“Establishing a standardized method and widely accessible assay, as well as validating sNfL in prospective and real-world cohorts, are essential next steps for implementation of sNfL into clinical practice,” Calabresi said.

Of note, 11 of the study’s authors are employees of Biogen. Four more received research support and/or consulting, steering committee, advisory board and speaker fees from the same company.