Evidence Mounts for Promise of MS Serum Biomarker

BERLIN — Despite a couple of caveats, multiple studies continue to support the use of serum neurofilament light chain (sNfL) as a biomarker of disease activity and treatment response among people with multiple sclerosis (MS).

One trial that combined data from four phase 3 studies, for example, shows that sNfL levels correspond to disease severity and treatment response. Another research team looked at two different phase 3 trials and found that baseline sNfL levels predict disability progression and brain atrophy.

These reports were among 32 studies on "neurofilament light" presented here at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018.

However, experts cautioned that levels of neurofilament — a scaffolding protein shed by neurons and axons during injury — are not specific to multiple sclerosis. Stroke, amyotrophic lateral sclerosis, or head trauma, for example, also can boost sNfL levels. In addition, levels tend to increase with age.

"This is a simple blood test. That's the real breakthrough — we've known before that neurofilaments are related to brain injury," Tobias Derfuss, MD, professor of medicine and senior physician in the Departments of Neurology and Biomedicine at University Clinic in Basel, Switzerland, told Medscape Medical News.

Historically, NfL measurements came from a sample of cerebral spinal fluid, which limited its clinical utility over time. "You cannot do lumbar punctures every 6 months. The patients refuse," he added.

"We can measure [NfL] now in serum because the techniques have improved," Derfuss said. Serial measurements can help identify disease progression or suboptimal response to disease-modifying therapy.

The Swiss Experience

Tobias and colleagues presented a retrospective study demonstrating that when MS treatment is effective, sNfL levels decrease 3 to 6 months later, indicating less ongoing damage to neurons and axons.

sNfL levels at baseline also predicted disease activity in the next 1 or 2 years. "If the level was high, it indicated your risk was increased to develop a relapse, to have disability progression." They also found correlations with relapses, MRI activity, and Expanded Disability Status Scale (EDSS) progression.

The investigators reported that sNfL independently increased with age (2.1% per year; 95% CI: 1.4 - 2.7; P < .001), EDSS score (5.7% per step; CI, 1.6 - 9.9; P = .006), and a recent (< 120 days) relapse (19.4%; CI, 0.1 - 42.5; P = .05).

In contrast, sNfL decreased with time on DMT (-3.2% per year [-0.9; -5.5], P = .006).

Each 10 pg/mL higher baseline sNfL level — corrected for age, EDSS, and previous on-treatment relapses — was associated with a 29% increase in relapse rate in the following 2 years (IRR, 1.29; CI, 1.16 - 1.43; P < .001).

When asked how sNfL assays might fit into clinical practice, Derfuss said, "I think it will not substitute for MRI or a neurologic exam, but it will be an additional factor that can be used in measuring or assessing the treatment response early on."

Backed by Researchers in Baltimore

Along with other US and international co-authors, Peter Calabresi, MD, director of the Multiple Sclerosis Center at Johns Hopkins Medicine, Baltimore, Maryland, presented data from four phase 3 clinical trials aiming to illuminate the clinical utility of sNfL, as well as determine cut-off values for stratifying patients by risk.

"There remains a need for clinical validation of sNfL, not just at the cohort level but at the level of individual patients," he said here at the meeting.

By combining data from the ADVANCE, CHAMPS, MSCRG, and SENTINEL studies, Calabresi and colleagues assessed sNfL levels from 1199 patients with relapsing-remitting MS. They found, for example, that a cut-off value of 16 pg/mL could indicate disease activity.

"Levels that are less than 16 [pg/mL] were associated with high probability of not having gadolinium-enhancing lesions," Calabresi said. In contrast, "if you have a patient with levels consistently high over 1 year, they have significantly higher risk for brain atrophy and new lesions."

In addition, sNfL greater than 16 pg/mL also was associated with long-term outcomes as measured by EDSS progression (12 years; P < .05), T2 lesion volume (10 years; P < .00001), and brain atrophy (5 years; P < .00001).

Similar to Derfuss' study, Calabresi reported a role for sNfL in gauging treatment response. DMT treatment was associated with sNfL levels below the 16 pg/mL cut-off in 96% of patients.

Brain Atrophy Findings From Basel

While most sNfL studies focus on relapsing-remitting MS, researchers know relatively little about this serum biomarker in patients with the progressive form of MS.

"There is an urgent need for better markers to help us select patients for treatment in progressive MS and to assess treatment [response] as soon as possible," said Ludwig Kappos, MD, of the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel in Switzerland.

To learn more, he and his colleagues evaluated 1452 people with secondary progressive MS from the EXPAND study and another 378 people with primary progressive MS from the INFORMS trial.

At baseline, sNfL levels were significantly higher among secondary progressive MS patients than primary progressive MS patients (32.1 vs 22.0 pg/mL; P < .001).

Researchers also looked at brain volume loss over time. "Higher serum neurofilament light levels at baseline were associated with higher rates of brain volume loss in both patients with secondary progressive and primary progressive MS," Kappos said.

A baseline sNfL level greater than 60 pg/mL was associated with greater brain volume loss, −0.8%, compared with −0.2% among those with values less than 30 pg/mL; this finding was significant at 12 months in the secondary progressive MS study (P < .0001).

At the same time, in the primary progressive patients, the brain volume loss was −0.8% and −0.4%, respectively (P = .0044).

Acknowledging the possible confounder of age, Kappos added, "We see secondary progressive MS patients had higher NfL levels than primary progressive MS patients at the same age."

Baseline sNfL values also significantly correlated with baseline gadolinium-positive lesions and T2 lesion counts in this study.

"NfL has shown value to predict disease and correlates well with other markers we know and use," Kappos said.

"We've heard a lot about neurofilament light, especially in serum," Robert J. Fox, MD, a neurologist and researcher at the Mellen Center, Neurological Institute at the Cleveland Clinic in Ohio, said during an overview on neuroprotection trials at ECTRIMS 2018.

"We are just starting to look at serum neurofilament light data in the SPRINT-MS trial, and what is surprising to us is that a number of patients had relatively stable neurofilament levels that suddenly went up very high," he said.

When a patient with stable sNfL levels throughout most of the study had a spike at week 96, the result correlated with a jump in disease activity and MRI findings, Fox said. "We saw new T2 lesions at week 96 in a patient who was stable at week 48," for example.

Future studies could incorporate sNfL levels as endpoints to assess treatment response and other factors in people with MS. In addition, presenters at ECTRIMS 2018 called for researchers and clinicians to agree on a standardized assay to measure sNfL because multiple options are currently available.

Also, they called for more evidence to determine the optimal cut-off values for predicting which patients with MS are likely to experience greater disease activity or worse treatment response.

Biogen sponsored Calabresi's study. Novartis Pharma funded Kappos' study. Derfuss receives speaker fees, research support, travel support, and/or serves on advisory boards or steering committees for Novartis Pharma, Merck, Biogen, Teva, Bayer-Schering, GeNeuro, Mitsubishi Pharma, MedDay, Roche, and Genzyme. He also receives research support from Biogen, Novartis, Swiss National Research Foundation, University of Basel, and Swiss MS Society. Calabresi receives consulting fees from Biogen and grants from Biogen, MedImmune, Annexon, Teva, Genzyme, and Novartis, Baltimore, US. Kappos' institution, University Hospital Basel, received steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, sanofi aventis, Santhera, Teva, and Vianex, and royalties for Neurostatus-UHB products for research purposes only. The research of the MS Centre in Basel is supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, Swiss National Research Foundation, European Union, and Roche Research Foundations. Fox receives personal consulting fees from Actelion, Biogen, EMD Serono, Genentech, Novartis, and Teva; serves on advisory committees for Actelion, Biogen, and Novartis; and receives clinical trial contract and research grant funding from Biogen and Novartis.

European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Abstracts 158, 262, and 286. Presented October 11-12, 2018.

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