COMMENTARY

Making Sense of Neurofilament Light in MS

Stephen Krieger, MD

Disclosures

August 20, 2019

This transcript has been edited for clarity.

Stephen Krieger, MD: Hi. I'm Dr Stephen Krieger from Mount Sinai in New York.

James Stankiewicz, MD: And I'm Dr Jamie Stankiewicz from Brigham and Women's Hospital Partners MS Center in Boston.

Krieger: We're here at the American Academy of Neurology (AAN) meeting in Philadelphia to talk about some of the new work in multiple sclerosis (MS) that I think has been of interest to both of us.

One topic that I've seen really exploding in the MS field is the work in neurofilament light chain protein, which is a new serum blood test that may give us insight into predicting disease activity, progression, and even prognosis in patients with MS.

What have you seen in neurofilament work that has caught your eye?

Stankiewicz: I think the things that have been presented at this meeting in regard to neurofilament light are really fascinating. I think this really challenges us to rethink the extent to which the way that we stage the disease has meaning in terms of relapsed-remitting disease; progressive, secondary progressive; and primary progressive.

The thing that really impressed me was a presentation by Dr Hans-Peter Hartung. In this presentation, he looked at the results of the ASCEND trial, which is a trial conducted with natalizumab in secondary progressive MS, and demonstrated that when you look at the patients who received natalizumab versus those who received placebo, there was significantly less neurofilament light in people who'd received the drug, suggesting that the protein is associated with chronic neurodegeneration in MS.[1]

The thing that's so fascinating about that is when you consider the ASCEND trial as a whole, there was no clinical benefit at 2 years when you looked at the primary and secondary outcome measures. I think the really fascinating question to ask is what that is telling us.

Interestingly, the ASCEND trial showed that there did seem to be some clinical split at 3 years of natalizumab therapy, but that was when the patients transitioned to the open-label part of the study. I think it begs the question of whether or not we, as neurologists, have the ability to control inflammation and new damage to the nervous system, and whether or not that's going to help a progressive population or if it's like what you've suggested with your topographical model, which is that prior damage eventually will catch up to people and gradually worsen.

Krieger: That's something the topographical model gets at, which is that progression may insidiously reveal old damage already done. It's something that I know Gavin Giovannoni has talked about as therapeutic lag, particularly in progressive populations.[2] That was one of the concerns about the ASCEND trial.

It's interesting that the neurofilament levels came down with natalizumab treatment even though we didn't see a clear clinical signal. Maybe neurofilament is telling us something more sensitive about the effect of a drug in a progressive population, which is even more sensitive than we saw with clinical data alone.

Stankiewicz: I have to say that I sat back at the end of the presentation, and I had a moment where I thought about, given this, whether or not I would treat patients with natalizumab who are "progressive." I think it's a really interesting question to ask. I don't know what the answer is.

I don't know that we've converged as a field around this, but is this as simple as, patients can respond to these drugs and derive benefit? We may not see it immediately, so maybe we need to follow patients for a longer period of time to be able to realize the benefit with some of these drugs.

Maybe neurofilament light gives us the ability not to have to look over 1-2 years, but to have some—I don't know if "confidence" is the right word—but maybe some data to support the idea that we really may be benefiting patients even though we can't see it in the traditional metrics. And this calls into question the sensitivity of these metrics.

Krieger: It would be almost an early indicator that a drug is having the desired effect. We saw that in another presentation at the AAN. Peter Calabresi presented neurofilament data from a whole array of relapsing-remitting MS studies, demonstrating that high levels of neurofilament predicted lesion burden over time, atrophy, and whether a patient was a responder to therapy.[3]

In patients on drug, the neurofilament levels were very much curtailed. That's in a relapsing population where we know the drugs work. It's interesting that Hans-Peter Hartung's presentation implies that we may have the same effect in patients with progressive disease.

Stankiewicz: Yes. Obviously, one of the points that Dr Calabresi and others have made is that we still need further standardization around this assay. Ultimately, we need to be able to reach a point where we can send samples to a CLIA-certified lab and know the agreed-upon levels at which, potentially, you might think that the patient is undergoing neuronal damage.

I don't know what the right answer is, but I wonder if we, as neurologists, are following and treating neurofilament light and we treat to a target to keep it below a certain level that we've defined, whether or not we might be doing much better for our patients than we are doing now with what I would consider somewhat arbitrary distinctions between progressive and relapsing disease.

Fundamentally, at its core—to me, at least—MS is a progressive, degenerative condition that starts early in life—around ages 20-40 years in many of our patients.

Krieger: Well, I think that's a very good point. I think the neurofilament data do give us new insight.

Reporting about neurofilament light from the AAN meeting, I'm Stephen Krieger from Mount Sinai in New York, and I'm very happy to have been joined by Dr Stankiewicz from Boston. Thank you so much.

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