Serum Neurofilament Light Protein Highly Anticipated Tool for MS

Nancy A. Melville

March 05, 2019

UPDATED March 11, 2019 // DALLAS — Mounting evidence on the reliability of blood-derived neurofilament light protein (NfL) in predicting disease activity and treatment response in multiple sclerosis (MS) is raising hopes among experts about its utility as an invaluable, easily accessible prognostic tool in the near future.

NfL, when derived from cerebrospinal fluid (CSF), has already been validated as representing a highly specific marker of neuronal damage and a longitudinal predictor of the course of disease. However, the need to perform a lumbar puncture hinders its use as a routine tool in clinical practice.

But advances in the development of high-sensitivity assays such as the single-molecule array (SIMOA) are allowing for key biomarkers such as NfL to make the critical transition from CSF to blood-based measures.

"We are already at the point of being able to use peripheral serum-based NfL on a group level," said David Leppert, MD, senior research associate at the department of neurology, University Hospital Basel, Switzerland, in discussing the issue here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019.

"We are still not at the individual level yet, but I am very positive that we will have a breakthrough in the next two to three years for individual use of NfL," he said.

Among research helping to push the field closer to that goal by validating the prognostic efficacy of serum NfL is a study published online March 5 in Neurology, in which Leppert and his colleagues evaluated data on NfL in the blood samples of 589 patients with relapsing-remitting multiple sclerosis (RRMS) using the SIMOA assay.

The patients were participants in two phase 3 clinical trials, the 2-year FREEDOMS trial evaluating MS drug fingolimod versus placebo, and the 1-year, active-controlled TRANSFORMS trial evaluating interferon-beta-1a. Patients' NfL levels were compared with those of 35 healthy controls of similar age.

The results showed that the RRMS patients in the FREEDOMS and TRANSFORMS trials had higher NfL levels at baseline compared with those of healthy controls (30.5 and 27.0 vs 16.9 pg/mL; P = .0001) and their baseline NfL levels correlated with the T2 lesion load and number of gadolinium-enhancing T1 lesions observed on MRI (P < .0001 for both).

After adjustment for potential variables, the NfL values ranged from 22.9 pg/mL in patients without gadolinium-positive lesions to 75.5 pg/mL in patients with more than 3 gadolinium-positive lesions in the FREEDOMS trial, and in corresponding levels of 22.8 pg/mL and 62.2 pg/mL in the TRANSFORMS trial (P < .0001 both trials).

In addition to being associated with new or enlarging T2 lesions (ratio of mean, 2.64 [1.51-4.60]; P = .0006), high NfL levels were associated with relapses (rate ratio, 2.53 [1.67-3.83]; P < .0001), brain volume loss (difference in means, -0.78% [-1.02 to -0.54]; P < .0001), and risk for worsening of confirmed disability (hazard ratio, 1.94 [0.97-3.87]; P = .0605).

Treatment with fingolimod was associated with a reduction in blood-derived NfL within 6 months of treatment initiation compared with placebo (0.73 [0.656-0.813]) and with treatment with interferon-beta-1b (0.789 [0.704-0.884]).

The higher NfL levels seen even in patients without enhancing lesions compared with healthy controls underscore the potential importance of NfL as a marker of disease changes that may otherwise be elusive with MRI, the authors said.

"This finding suggests that NfL levels also reflect ongoing neuronal damage and loss independent of detectable 'inflammatory' activity by contrast-enhancement in MRI, possibly as a brain-diffuse inflammation occurring in normal-appearing grey and white matter," Leppert and his colleagues write in their report.

"This assumption is further supported by the correlation between NfL levels and an objective measure of neuroaxonal damage, brain and spinal cord volume loss in a recent study by our group, and by the predictive value of baseline NfL for brain volume loss after 2 years on study in the FREEDOMS trial."

"Together, these results suggest that NfL in blood is likely to reflect an integral measure of recent and ongoing neuronal damage, over weeks, and possibly months."

In his talk, Leppert noted other studies, including the EXPAND trial, which showed that as many as 46% of patients with secondary progressive MS had higher NfL levels despite no lesions on MRI, and the INFORMS trial, in which 18% of patients with primary progressive MS had no apparent lesions.

Although blood-derived NfL has advantages over CSF-derived measures, there are also benefits integrating NfL and MRI measures, the current standard to quantitate brain atrophy in MS, Leppert noted in his talk.

Importantly, MRI is, by nature, retrospective, costly, and, as such, not ideal for longitudinal monitoring of disease, either in clinical trials or routine practice, he said.

"MRI is the measuring of a structural deficit of the past, while NfL is measuring in real time what the axonal damage is that is occurring and leads to a more comprehensive report," Leppert said.

"However, NfL will not replace MRI in MS workup; the two measures are complementary," he noted.

Among the key gaps in evidence that remain to be better understood before blood-derived NfL can go mainstream in individual treatment are the need for more prospective studies that correlate with MRI and better validation and optimization of an assay, which are currently underway, Leppert said.

"We need data on the normal values per age," he told Medscape Medical News.

"As NfL is increasing physiologically with age, we need a normal database to define whether a certain value in a patient is actually pathologic or not."

Reference biomarkers are needed to provide better context to NfL values, and the role of comorbidities also needs to be better understood, Leppert said.

"We need to define the impact of comorbidities, as NfL is blind for the cause of neuronal damage, for instance when a person has two diseases, such as MS and cerebrovascular embolism."

Although validation of the SIMOA assay is underway, and other assay platforms for NfL are in development, individual measurements of NfL are already offered to patients in some selected sites, however only as basic parameters.

"Without normal values being defined yet, it is only possible to provide relative judgements, for instance (if a measure) is 'high,' or is higher/lower compared to a prior measurement," Leppert said.

"The Neurologist's C-Reactive Protein"

In a separate talk at the meeting, Gavin Giovannoni, PhD, professor of neurology at the Blizard Institute, Queen Mary University of London, United Kingdom, underscored the potentially powerful role that serum NfL could play in MS.

"I think our C-reactive protein is coming and it's going to be in the form of peripheral blood NfL," he said, in reference to an editorial he published on the issue in the journal Brain in 2018, titled "Peripheral Blood NfL Levels: the Neurologist's C-Reactive Protein," based on the study published by Leppert and colleagues.

Giovannoni said he already has seen important benefits with CSF NfL in routine clinical practice.

"It's going to be a great biomarker to have in clinical practice," Giovannoni said. "We are already using CSF-derived NfL levels in our center and it's amazing when you start getting NfL results on your desktop, how it affects your decision making."

He described an example of how NfL was useful at his center in a case that involved a female patient with active MS who strongly believed she was experiencing a flare-up but showed no clinical evidence of a relapse or new lesions on MRI of the brain and spinal cord.

A lumbar puncture showed her CSF-derived NfL levels to be as much as three times higher than normal, and she was subsequently switched to a different high-efficacy therapy.

Without the patient's NfL measures, the outcome could have been much different, Giovannoni told Medscape Medical News.

"Without the CSF-derived NFL result, this patient would have been told this was a pseudo or minor relapse and given no treatment," he said.

"In fact, this triggered a reassessment of her clinical state and a change in her treatment."

He added that the case underscores that "NFL may be a great way of determining a true relapse from a pseudo-relapse and on the football pitch a minor head injury from a moderate head injury."

Giovannoni noted that "as a prognostic and treatment response marker, [NfL] really separates the men from the boys in reference to the effects of high-efficacy disease-modifying therapies (DMTs) in reducing NfL levels compared to lower efficacy therapies."

"I suspect we will soon be ordering blood NfL levels several times a year and maybe even more frequently to monitor MS disease activity."

In such cases, the treatment target will be to normalize NfL levels and keep the area under the curve (AUC) as low as possible, Giovannoni said, but he noted that even in those cases the measure would not necessarily be used in isolation but in conjunction with other factors.

"For example, a low or normal NfL level would not trump other poor prognostic factors as NfL is only intermittently raised."

As a marker of neuronal damage in general, NfL has implications in neurodegenerative diseases beyond MS, and, as reported by Medscape Medical News, changes in serum NfL were shown in research published in Nature Medicine last month to possibly predict neurodegeneration years before the onset of Alzheimer's disease.

Leppert has been Therapeutic Area Head at Novartis Neuroscience Development Unit. Giovannoni has served on advisory boards for AbbVie, Atara Bio, Biogen, Canbex, Sanofi Genzyme, Genentech, GlaxoSmithKline, Merck Sharp & Dohme, Merck Serono, Novartis, Roche, Synthon BV, and Teva.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. Presented March 1 and 2, 2019.

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