#ECTRIMS2018 – Serum Neurofilament Light Show Promise as Biomarker, But Not There Yet, Neurologists Say

Despite its lack of specificity to multiple sclerosis (MS) in particular, monitoring patients with a blood biomarker — serum neurofilament light (sNfL) — may hold promise as a relatively easy way to assess treatment response and brain damage, according to MS experts.

But there’s considerable work still to be done — including finding a suitable assay, or qualitative test — that would allow neurofilament levels to be readily monitored in patients’ blood to determine how they are progressing or responding.

In interviews with Multiple Sclerosis News Today at the 34^th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), neurologists Robert Fox, Jerry S. Wolinsky, and Bernd Kieseier discussed the recent results of studies of sNfL in MS, as well as technological advances and challenges.

Finding blood biomarkers that allow for quick, effective, and sensitive monitoring clearly remains a research goal — a grail of sorts that’s been chased for decades.

Bernd Kieseier, medical director of Value Based Medicine group at Biogen. (Photo courtesy of Biogen)

Kieseier, medical director within the Value Based Medicine group at Biogen, noted that unlike the swollen joints and reddened skin that marks disease status in rheumatoid arthritis, determining inflammation in MS requires knowing what’s happening in the brain — and that’s “kind of hidden.”

Clinicians now rely on magnetic resonance imaging (MRI) to assess brain inflammation, but it is “rather expensive and cumbersome, and take quite a bit of time and effort,” said Fox, a neurologist at Cleveland Clinic. An ideal alternative would be a blood test that could be taken during a routine clinic visit, he said, unlike an MRI or collecting spinal fluid.

Neurofilament light levels capture structural proteins that are unique to neurons. They rise in both the cerebral spinal fluid and blood in response to nerve cell injury, and are known to be more sensitive in spinal flood than blood serum.

Work presented at ECTRIMS showed that NfL levels correlate with the number of relapses and are differentially affected by different therapies. Another presentation reported that relapsing-remitting MS (RRMS) patients with sNfL levels higher than 16 pg/mL showed a higher risk of disease activity, and worsened disability, lesions, and brain shrinkage in the long-term.

But that 16 pg/mL number is far from a set level that would valid for all patients at all sites, said Kieseier, who took part in the study. That’s because it was drawn using a specific assay — the Simoa assay, by Quanterix — and different assays give different values. He also doubted Simoa would ever come into common use for MS.

Simoa, in Kieseier’s opinion, is too “tricky” and complex a scientific assay for doctors outside a clinical trial to use, requiring as it does a “very expensive machine that you have to run everyday or recalibrate.” It’s also expensive, with each assay carrying a roughly $50 price tag.

That lack, however, does not undercut the value of sNfL, he added, because “physicians know how to read lab values,” they just need an easier way of accurately getting them. 

Which leaves sNfL “our leading candidate biomarker for treatment response” in MS, Fox said, provided a test with less variability could be found.

Robert Fox, a neurologist with the Cleveland Clinic. (Photo courtesy of Cleveland Clinic)

Both he and Kieseier mentioned that other companies, such as Siemens, are working to advance NfL-based assays.

The neurologists also referred to a study that showed NfL’s ability to capture changes for the worse in patients who stopped taking Tysabri (natalizumab, marketed by Biogen). “It turns out that when [NfL] rises, it’s a rather specific marker for return to disease activity.”

It “nicely correlates,” Kieseier said, with falling sNfL levels evident at the start of Tysabri’s use.

Still, “it’s not a sensitive marker,” Fox added. “There were quite a few patients who had return of MRI disease activity, but did not elevate their [sNfL level].”

The researcher also noted that the biomarker may work better for relapsing MS forms, compared to progressive forms. NfL “may be too noisy, because it also reflects when there’s disease activity and new lesions — and we see new lesions [only] from time-to-time in MS. So I’m not sure we yet have a purely progressive biomarker.”

Wolinsky, a professor emeritus in the department of neurology at the McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth) agreed.

NfL, he said, “obviously is a non-specific response to neuronal injury.” As an example, he mentioned “the dozens of concussions” taking place in football games over the course of a weekend in the U.S., which will — without question — raise NfL levels in the players’ blood and spinal fluid. NfL levels also go up in small vessel diseases linked to diabetes and hypertension, he added.

Jerry Wolinsky, professor emeritus in the Department of Neurology at UT Health. (Photo by MS News Today)

So, although not specific to MS, NfL is a valid indicator of tissue damage that might be “used to monitor your therapy more frequently than, say, doing imaging,” Wolinsky said. “I wouldn’t think it replaces imaging, but allows more frequent use.”

Lack of specificity also means that NfL levels could increase with comorbidities rather than with MS progression itself, leading to variable levels, Wolinsky said, which could hamper studies into such progression.

NfL “may be a harder marker to use than I had hoped, especially in blood [sNfL],” he said — it holds promise, but it’s also another example of nature playing with science. As example he cited the excitement that surrounded early reports of  myelin basic protein — a clear MS biomarker — being evident in urine. But, Wolinsky added, the researcher was always careful to call what he was seeing in patients’ urine “myelin basic protein-like” — and “like” turned out not to be myelin basic protein at all.

“This [neurofilament light] will turn out to be what it is, but it may not turn out to be as super sensitive to new damage as we hoped, and it certainly won’t turn out to be specific” a biomarker as hoped, Wolinsky said.

Neurofilament light, specifically as seen in the blood, shows promise because if offers information about “damage happening in the brain. That’s all we [neurologists] want to know,” Kieseier said.

If rising NfL levels are evident — suggesting greater inflammation and tissue damage — they can then request an MRI scan. And, if highly active disease is confirmed, they’ll look to start treating a person with a more aggressive therapy, he added.

He also thinks a good assay, and possibly wide use of NfL as a biomarker — and possibly a blood biomarker — may be only two years away, “but that’s a positive assumption.”

But it’s also a guess based on the wide-ranging of sNfL levels in the blood, point to nerve injury in those football players that Wolinsky mentioned — or any sort of head trauma — as well as in MS patients and people with Alzheimer’s or another neurodegenerative diseases marked by damage to neurons.

“If you would have a marker that would tell you that this patient not under perfect control, this would be a game-changer,”  Kieseier said. “In a perfect world, we’d say to patient, ‘go get a scan every three months.'” But the world isn’t perfect, particularly in poorer than richer countries, and decisions made on inadequate knowledge do affect treatment.

“Excitement is huge, and everyone wants” sNfL to work as a quick, easy and accurate biomarker,  Kieseier said. “This is where we have to go.”