In this podcast, Dr Coyle discusses the "final word" on neuromyelitis optica spectrum disorder in multiple sclerosis from the ECTRIMS/ACTRIMS MSVirtual2020 meeting.

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Patricia K. Coyle, MD, is a professor in the Department of Neurology at Stony Brook University in New York; director of the Stony Brook MS Comprehensive Care Center; and section editor of multiple sclerosis on Neurology Learning Network.

Transcript:

Christina Vogt: Hello, everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today, I'm joined by Dr. Patricia K. Coyle, who is a professor of neurology and director of the Stony Brook MS Comprehensive Care Center at Stony Brook University in New York.

Dr Coyle will be sharing the final word from MSVirtual2020 on neuromyelitis optica spectrum disorder in the context of multiple sclerosis.

Patricia K. Coyle, MD: This is Dr Pat Coyle, and I'm discussing the final word from MSVirtual2020 on neuromyelitis optica spectrum, or NMO spectrum disorder. As we know, for many years, this was considered a variant of MS, but it's not MS. It's a distinct neuroimmune syndrome and astrocytopathy that's connected with IgG2 aquaporin-4.

We now have 3 FDA-approved treatments for NMO spectrum disorder. We have eculizumab, which is a humanized anti-complement 5 monoclonal antibody. We have satralizumab, which is a humanized anti-interleukin 6 receptor antibody, and inebilizumab, which is a humanized anti-CD19 monoclonal antibody.

There were 2 presentations at MSVirtual2020 that gave further information on the pivotal phase 3 eculizumab trial, the PREVENT trial. Now, as you recall, this entered 143 aquaporin-4-positive NMO spectrum disorder patients. They could be on immunosuppressive therapy—actually, 76% of the cohort were on immunosuppressive therapy—that could include steroids, azathioprine, and mycophenolate. There was only a 3% rate of relapses in the eculizumab versus 43% in the placebo arm. Remember, about three-quarters of the patients were on a form of immunosuppression.

They continued an open-label extension through 192 weeks. This particular abstract looked at those quarter of individuals that were not on immunosuppression. In other words, they were looking at monotherapy. They were only on eculizumab or placebo. That translated to a total of 33 patients that were on eculizumab through the open-label extension that extended out to 192 weeks vs 13 individuals that were initially on placebo treatment and then switched over.

They asked, what was the relapse rate using eculizumab as monotherapy? It remained precisely extremely low. Only 1 of 33 individuals on eculizumab alone (no immunosuppression) had an attack vs 7 of the 13 that were on basically no underlying immunosuppression.

The bottom line is that eculizumab works as monotherapy for NMO spectrum disorder, aquaporin-4-positive individuals, of course. You really don't need the additional immunosuppression to be effective.

There was another relook at the eculizumab PREVENT study, and this was in NMO spectrum disorder patients that had been on rituximab, a chimeric anti-CD20, previously. They had to be off it for longer than 3 months.

The concern was, would that influence the efficacy, or would it make patients more vulnerable to infections? In this study, actually, 26 of those that were randomized to eculizumab had been previously on rituximab compared to 20 of 47 individuals that were randomized to placebo.

Now, rituximab historically was more common in participants from the United States and was less common in Asian individuals with NMO spectrum disorder. It turned out that the prior history of rituximab—you saw still a decrease in relapses of those on prior rituximab. Then, randomized to eculizumab, there was only 1 attack out of 26 individuals, 3.8%, compared to 7 of 20 of those that were randomized to placebo—that was 35%. There was no increase in infections, so that was very reassuring to people.

Satralizumab, another FDA-approved agent for NMO spectrum disorder, aquaporin-4-positive, actually had 2 phase 3 trials, SAkuraStar, a monotherapy, and SAkuraSky, a combination therapy. Satralizumab was positive in this study.

This particular analysis looked at the severity of relapses. They looked at more severe relapses as measured by those that increased the expanded disability status scale, or EDSS, 2 points or greater. In the case of optic nerve attacks, it changed the visual functional severity score 2 points or greater. This would be a more severe attack.

First of all, what you saw was attack rates of 26% in the satralizumab arm, 27 of 104 patients, compared to 46% who relapsed in the placebo arm, 34 of 74. When we looked at more severe attacks, 19% of the satralizumab breakthrough attacks were severe compared to 35% of those attacks on placebo.

In the optic neuritis, the more severe optic neuritis was seen in 25% of those on satralizumab vs 39% of those on placebo. That was basically a 79% relative reduction in severe relapses. Satralizumab not only decreases relapses, but it also decreases the severity of relapses.

Another study was more a basic science-type study, but it looked at the ependymal cells. You recall that the ependymal cells are from ectoderm. They're epithelial-based cells. They line the ventricles, and they actually have beading cilia. They help to make some of the CNS and some of the spinal fluid and really help to move things around and passage neurotransmitters and other factors. They also line the central canal of the spinal cord.

It turns out they express aquaporin-4. Now, aquaporin-4 is a water channel on the astrocyte foot process. It is the target in classic NMO spectrum disorder. The individuals are typically aquaporin-4 IgG antibody-positive. Well, the ependymal cell also has aquaporin-4.

They looked at 2 distinct in vitro models. The first was a rat culture of ependymal cells, and the second was actually slicing out from an adult rat the lateral ventricle. They did histopathologic studies. What they found was that antibodies, IgG2 aquaporin-4, actually disrupted, structurally damaged the ependymal cells in both of these models.

What they suggested in NMO spectrum disorder was that the astrocyte may not be the only target, but the aquaporin-4 IgG may be targeting ependymal cells as well, and that may be responsible for some of the action. I think that this will affect how we think about aquaporin-4 NMO spectrum disorder.

We had another abstract that looked at serum levels of gliofibrolariacid protein, or GFAP, and S100B protein. These are both astrocyte markers and neurofilament light protein. That is a marker of axon and neuron damage.

You had an ELISA assay to measure S100B levels in the blood compartment, and you had SAMOA ultrasensitive assays that can detect low levels for the GFAP and the neurofilament light protein.

They took NMO spectrum disorder patients who they had longstanding serial specimens on over a number of years, and they investigated levels of GFAP, S100B, and neurofilament light protein in the blood. They were looking for blood markers of a breakthrough attack, a clinical attack.

They didn't find that S100B was helpful, and they didn't find that neurofilament light protein was helpful. They did find that GFAP was helpful. Elevated levels of GFAP predicted a future breakthrough relapse. I think this will be very, very, very, very helpful in the future. Obviously, it's a preliminary study, but it needs to be explored further.

The final abstract that I want to talk about was actually pertinent to both NMO spectrum disorder and MOG-associated disorder, or MOGAD. We know that, particularly in aquaporin-4-positive NMO spectrum disorder, you get granulocyte infiltration into the CNS, including neutrophils.

In fact, you can have a large proportion of neutrophils in the spinal fluid, and that's supposed to be a suggestive feature for NMO spectrum disorder. What they were looking at was neutrophil spinal fluid biomarkers. They looked at 4: elastase, myeloperoxidase, matrix metalloproteinase-8, and a substance called neutrophil gelatinase-associated lipocalin, or NGAL. Now, these assays are ELISA assays, so they're pretty easy to set up, and they're 4-hour assays. You have an answer in 4 hours.

They looked at patients with acute relapsing MS with NMO spectrum disorder in the setting of an attack, and with MOG-associated disease, or the so-called MOGAD. They evaluated the spinal fluid in the setting of the acute attack.

What they found was that finding these neutrophil spinal fluid biomarkers differentiated both NMO spectrum disorder and MOG, MOGAD, from acute relapsing MS; that you found all 4 neutrophil markers increased in the CSF in NMO spectrum disorder; and 3 of the 4 increased in MOGAD; and you didn't find that in acute relapsing MS. This was true even in aquaporin-4-negative NMO spectrum disorder patients.

What they're suggesting is that, if you have a patient with an acute attack, and maybe you don't have their aquaporin-4 antibody data or MOG antibody data, and it's going to take a couple of weeks to come back, a panel of analysis of neutrophil/granulocyte biomarkers seemed to distinguish NMO spectrum disorder and MOGAD from acute relapsing MS.

The turnaround of these particular assays is very rapid in terms of a couple of hours. In addition, interestingly, they also found that elevated spinal levels of GFAP, gliofibrolariacid protein, and S100B, the astrocyte markers, differentiated acute NMO spectrum disorder from acute MOGAD.

We may see in the future a panoply of CSF markers that can actually be very, very helpful for us in identifying, even at the first attack, who has NMO spectrum disorder or MOGAD compared to relapsing MS.

Christina Vogt: Thanks again for joining me today, Dr Coyle. For more podcasts like this, visit neurologylearningnetwork.com.   

References:

1. Global perspectives on neuromyelitis optica spectrum disorders. Talk presented at: ECTRIMS/ACTRIMS MSVirtual2020; September 11-13, 2020; Virtual.
2. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4–positive neuromyelitis optica spectrum disorder. N Eng J Med. 2019;381:614-625. doi:10.1056/NEJMoa1900866
3. Levy M, Berthele A, Kim HJ, et al. Efficacy and safety of eculizumab in patients with neuromyelitis optica spectrum disorder previously treated with rituximab: findings from the phase 3 PREVENT Study (1788). Neurology. 2020;94(15 suppl.). https://n.neurology.org/content/94/15_Supplement/1788
4. Yamamura T, Kleiter I, Fujihara K, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Eng J Med. 2019;381:2114-2124. doi:10.1056/NEJMoa1901747
5. Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 2020;19(5):402-412. doi:10.1016/S1474-4422(20)30078-8
6. Leppert D. Neutrophil granulocyte markers in cerebrospinal fluid differentiate NMOSD and anti-MOG antibody associated disease from MS in acute disease phase. Paper presented at: ECTRIMS/ACTRIMS MSVirtual2020; September 11-13, 2020; Virtual.