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NeuroVoices: Bruce Cree, MD, PhD, MAS, FAAN, on the Importance of Biomarker Studies in NMO and Role of NfL, GFAP

Disease Spotlight | <b>Disease Spotlight: NMOSD</b>

The clinical research director of the UCSF Multiple Sclerosis Center provided perspective on several analyses from the N-MOmentum trial that highlight the clinical use of biomarkers in NMO and NMOSD.

At the 2022 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, October 26-28, in Amsterdam, the Netherlands, multiple analyses from the phase 3 N-MOmentum trial (NCT02200770) of inebilizumab (Uplizna; Horizon) were presented. In one particular assessment, the FDA-approved drug for neuromyelitis optica spectrum disorder (NMOSD) was shown to effectively deplete CD19+ b-cells, including plasmablasts and plasma cells, which have been found to play a crucial role in the underlying pathophysiology of the disease.

The study, led by Bruce Cree, MD, PhD, MAS, FAAN, showed increases in plasma cells seen in over half (57%; 12 of 21) of placebo participants at the time of attack relative to baseline compared with 20% (4 of 20) and 16% (3 of 19) for total CD20+ b-cells and CD27+ memory b-cells, respectively. No significant increases in b-cell subsets at the time of attack were seen in inebiluzumab-treated patients relative to the preceding visit. To the surprise of the study investigators, significant increases in aquaporin-4 (AQP4)-IgG titer were observed at the time of attack in the placebo group relative to baseline (P = .02) but not in those treated with inebiluzumab (P = .76); however, changes in AQP4-IgG from baseline to attack were not significantly different between treatment groups (P = .15).

Moreover, the results also showed that at the end of the randomized control period, 37% (59 of 159) of participants on inebilizumab demonstrated at least a 2-fold decrease in AQP4-IgG titers from baseline compared with 18% (9 of 50) of those on placebo (P = .01). As part of new iteration of NeuroVoices, NeurologyLive® sat down with Cree to discuss these unique findings. Cree, the clinical research director of the UCSF Multiple Sclerosis Center, provided commentary on the importance of these studies, the role of biomarkers in neuromyelits optica and NMOSD, and how specific biomarkers like glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) will be used going forward.

NeurologyLive®: What was presented here, and what should the clinical community take away from the data?

Bruce Cree, MD, PhD, MAS, FAAN: There are some post hoc studies from the inebilizumab trial in neuromyelitis optica. This study has previously been published and has shown to substantially reduce the risk of attacks in neuromyelitis optica, to prevent disability from occurring, and to have effects on radiographic measures of disease activity by MRI, as well as to prevent hospitalizations. One of the interesting features of this study was that there were a lot of additional biomarker analyses built in. Some of the data presented to this meeting is looking at some of those biomarkers, in particular, one of interest is looking at a gene signature from peripheral blood, specifically at plasma cells. Now, plasma cells are some of the antibody-producing cells. They are a little bit different from B-cells, whereas B-cells mature into plasma cells. But we were able to utilize gene expression technology to look at plasma cell signatures in NMO (neuromyelitis optica).

What we found, I think, was actually very interesting. What we saw in the placebo-treated group was that plasma cell gene signature expression increased before attacks, went even higher up during the course of a clinical attack, and then came back down. In the actively treated group, we didn't see the exact same pattern. In fact, the level of expression of the plasma cell gene signature stayed fairly constant with inebilizumab treatment. This is kind of interesting because it gets the basic biology of what's going on in NMO. A role of plasma cells certainly make sense, but to my knowledge, this is one of the first times that that's actually been shown using prospective serially acquired data. It's just kind of one of the interesting things. When you build the opportunity to investigate biomarkers into these clinical trials—things you might not even know that you're going to investigate before you do the study—if you are thinking ahead and planning to include acquisition of biologically relevant material, you might find something interesting about the disease state itself.

Another complement to that particular poster showed that levels of anti-aquaporin-4 antibodies also seemed to increase a little bit during attacks. And that was long term treatment with inebilizumab; those levels of antiaquaporin-4 antibodies begin to decrease. Now, I don't think we have studied the cohort for long enough to know whether those antibody levels go away completely. And if they do go away completely, how many people that might be. So there's some unanswered questions that we're going to have to try and address with other studies.

Is NMOSD in a similar situation to MS where additional biomarkers are needed to track disease progression?

There were additional biomarkers that had been studied in the context of the N-MOmentum clinical trial. In particular, we were looking at serum GFAP (glial fibrillary acidic protein), which is a component of astroglia cells. We showed that at the time of acute attacks, the levels of GFAP that you can measure in the blood go sky high. So it is a marker of acute damage to astroglia cells. Astroglia cells can contain GFAP and when they get damaged, they release the GFAP. That GFAP gets into the spinal fluid, and eventually, some of that gets into the blood. With this very sensitive system that we now—a quantarex assay—you can detect very tiny amounts of this brain substance in peripheral blood. We did that in in the clinical trial and found that serum GFAP levels go very high at the time of attack.

They are also elevated more over baseline in patients who are at risk for having an attack, those who are about to have an attack. And so, there are a couple of applications that come out of this right away. If we had serum GFAP available as a genuinely available blood test, we could measure this in all of our patients. If we could get the turnaround time for getting an answer back on the GFAP level, we could even turn it potentially into a point of care study. The difference there is that we did this all by research, we get all the samples, send them off to the lab, get the answer back. But in clinical practice, you need your answers in real time. And so if we had a kit where we could measure serum GFAP, in the emergency department of the patient coming in who's got an optic neuritis or myelitis, where we weren't sure what was going on, it would be a rapid way of being able to distinguish a patient who's having an attack, versus somebody who's having worsening of symptoms for some other reasons, such as a fever or other type of illness.

Are there any other results from this study that you feel are particularly important?

Another observation from the N-MOmentum trial I think that is very important was looking at serum neurofilament light levels. Right now, serum neurofilament light is the belle of the ball, you'll see hundreds of posters and presentations at ECTRIMS on use of serum neurofilament light in MS. But in NMO, again, there's potential for clinical application. What we found is that in MMO, for patients having attacks, not only does GFAP go up, but serum neurofilament light goes up too. It turns out GFAP is a better measure of acute attack, but the degree of serum neurofilament light level at the time of attack is predictive of disability. The higher the level of serum neurofilament light, the worse outcome patients are likely to have.

Why is this important? Well, if we were able to measure it, again, get a result back in real time, we might be more aggressive with the management of that patient in terms of how to reduce the severity of attack. Right now, steroids are the standard, and we use lots of corticosteroids in high dose for treatment of NMO attacks. We also use plasmapheresis. I would say that if you saw a patient who has a very high level of serum neurofilament light, you might want to move on to plasma freezes in conjunction with use of corticosteroids right away, as opposed to waiting for several days. There are potential for application of these biomarkers in NMO. I think it's very exciting. That work on serum neurofilament light is now being prepared for publication, it's out it's been out for review, and we'll see if we can get it through the last steps but I think that type of work is very interesting. And again, has the potential to be clinically informative, in the real-world setting.

Transcript edited for clarity. Click here for more NeuroVoices.

1. New analysis of Uplizna (Inebilizumab-cdon) phase 3 trial data demonstrates importance of reducing plasmablasts to help prevent neuromyelitis optica spectrum disorder (NMOSD) attacks. News release. Horizon. October 26, 2022. Accessed November 1, 2022. https://ir.horizontherapeutics.com/news-releases/news-release-details/new-analysis-upliznar-inebilizumab-cdon-phase-3-trial-data