Anastasia Vishnevetsky, MD, an immunology fellow at Brigham and Women’s Hospital, provided insight on the latest research initiatives in MOG-antibody associated disease, including the potential for the first FDA-approved therapy.
Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) is an autoimmune disorder discovered in 2007 that causes inflammation and potential damage in the optic nerve, spinal cord, brain and/or brainstem. Unlike multiple sclerosis (MS) and aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD), in which multiple clinical attacks characterize relapsing forms of disease, individuals with MOGAD can have either monophasic or relapsing course.
Each year, in April, the clinical community, including those at the Seigel Rare Neuroimmune Association (SRNA) and Sumaira Foundation, celebrate MOGAD Awareness Month as a way to highlight the disorder and continue conversations to further treatment. MOGAD incidence is 1.6-3.4 per million people per year, and prevalence is estimated at 20 per million, although these numbers are expected to rise with the increase in recognition and availability of testing, including identification of patients with mild disease, monophasic disease, and atypical presentations.
There have been advances in the diagnosis and care for MOGAD, most notably through a recently published diagnostic criteria, led by an international panel of pediatric and adult neurologists, neuroimmunologists, and researchers. As part of MOGAD Awareness Month, NeurologyLive® sat down with Andrea Vishnevetsky, MD, an immunology fellow at Brigham and Women’s Hospital, to discuss the current understanding of the disease and the needed efforts to raise awareness. She spoke specifically about hot topics in MOGAD-related research, the potential for a first FDA-approved therapy, and how the clinical community learns from diseases like MS and NMOSD. Additionally, she provided context on conversations around neurodegeneration, remyelination, and why there is still much to learn about the moments following a relapse.
NeurologyLive®: What is the public’s understanding of MOGAD? What sorts of positive impacts can greater awareness create?
Anastasia Vishnevetsky, MD: The non-clinician public's awareness of this disease is relatively low, as this is a rare disease. That's not unexpected, and that will be very hard to change. But I do think that it's important to improve awareness of MOGAD as a condition amongst clinicians. I was in medical school within the last 10 years, and we did not learn about MOGAD at all because we didn't know that MOGAD existed at that time. Most clinicians who are practicing today didn't learn about MOGAD in their training. Unless you're really embedded in a place where there are experts in MOGAD, or seeing a lot of these patients and hearing about the latest research, this isn't something that your regular family medicine doctor or primary care doctor, or even just general neurologist, will have heard about during their training. That's where I think it's important to increase awareness of this.
Hammering home some of the differences between MOGAD and MS, but kind of grouping it as a general conceptualization, is helpful. Thinking about it as something that used to be considered part of MS and was only recently discovered to be a separate disease. Most clinicians do have a conceptualization of MS as a neuroinflammatory condition with distinct events and relapses. Saying that we've brought this subtype out from the MS and into its own disease is important. Increasing awareness amongst optometrists and ophthalmologists is important. Amongst ophthalmology, there's quite a bit of awareness about MOGAD, but a lot of our patients first go to their optometrists with some blurry vision and thinking that they need their glasses changed—things like that. In most cases, they get the appropriate referral to ophthalmology or neuro ophthalmology and then make their way over to neurology after that if they're presenting with optic neuritis.
In medical schools, we need to make sure that MOGAD is part of the conversation when clinicians are learning about neurology. That's an important change because I think MOGAD is more common than we've realized in the past. It's newer than NMOSD, and it doesn't have FDA approved treatments yet. I work together with Michael Levy, MD, PhD, in the MGH neuroimmunology clinic, and our patients with MOGAD outnumber our patients with NMO now. And that includes both aquaporin-4-positive and seronegative patients. We have new patients with MOGAD every single week. As we test more, we're going to discover more of these patients, which I think will kind of increase awareness of it as well.
Are there as many conversations about treating neurodegeneration and remyelination in MOGAD as there is in MS and other related disorders?
A lot of the research on remyelination, not so much degeneration, that's being done in MS will be applicable to MOGAD. The reason I say not as much degeneration is because in MOGAD, we don't see a degenerative aspect outside of relapses. When patients with MOGAD have disability, it's driven by those relapses. In MS, sometimes disability and progression is driven by relapses, but sometimes there's no discrete relapses, and patients just get steadily worse. That part is what we really struggle with in multiple sclerosis. With MOGAD, that's kind of off the table.
If we fully prevented relapses, based on what we know now, we would kind of prevent disability accumulation. But MOGAD is such an interesting case because the recovery from relapses is much more dramatic. Many to most still have some disability that most of the time we can see, and they can at least feel or associate with their relapses. But at the worst of the attack, patients with MOGAD are often severely affected: they can barely move their legs if they have a myelitis, or they can barely see out of one or both eyes if they have an optic neuritis. They go from really low recovery, usually lower than patients with multiple sclerosis, to what would be almost a miraculous or very dramatic recovery towards the end of the relapses, although they can still be very affected. That's just an interesting thing.
It raises questions for me: what's different about the attacks with MOGAD? Why's that recovery so much more impressive? Why do they respond so well to steroids? Seemingly on the opposite end of the spectrum, unfortunately, patients with NMOSD who often have more limited recoveries. That's the baseline of how MOGAD is different. I think a lot of the remyelination research from MS can be extrapolated to MOGAD. I don't think there's any specific research that I'm aware of, that's looking at remyelination in MOGAD excluding MS or looking specifically in the MOGAD kind of realm, but I think that MS is just a bigger kind of population. First [if] we show a proof of concept that’s effective in that population, I think a lot of that will be transferable to MOGAD, which I think is lucky for this smaller patient population to be able to connect to some of the larger research efforts in this other space.
What types of future MOGAD-related research is compelling to you?
Big picture, there's two large phase 3 clinical trials looking at patients specifically with relapsing MOGAD, so they must have had at least a second attack. That's the point where we often think about or start maintenance therapy. One of those trials, named Meteoroid, evaluates satralizumab, an IL-6 receptor blocker. It’s recruiting now in a lot of locations, including at MGH in Boston. It includes patients who have active MOGAD who have had a relapse within the last year or 2 relapses within the last 24 months. This is a trial that, if successful, would hopefully lead to FDA approval. I have high hopes that it will be successful just based on our experience with a kind of closely related medication, tocilizumab. Satralizumab has the benefit of being a once-a-month injection. It’s easy to administer at home.
We have some once-a-month injectable medications in the MS space and they're very popular with patients. No more going to infusion centers and things like that. The other phase 3 clinical trial assesses rozanolixizumab, which has been shown to be effective for myasthenia gravis, another kind of antibody driven disease. Rozanolixizumab tries to mimic some of the pathophysiology of IVIG, essentially, targeting the FcRn receptor and increasing turnover of antibodies and increasing destruction of potentially pathogenic antibodies. Given our success with IVIG, I also have high hopes for this clinical trial. There's some potential down the line to use this more in an acute setting as well because IVIG is both used in acute and maintenance treatment.
Those [two trials] are kind of big picture. Everyone's excited about those. I am particularly excited about some research looking into the first MOGAD attack. There’s just so much practice variability and such lack of clarity about what we should do, and what's best for patients in that situation. I let the patient give their input, but I think it would be a lot better if I had better data to present to the patient before asking for their input. It's not really fair to a patient to say, “hey, what do you want to do? We don't have that much information to guide you.”
There are some clinical trials being conducted out of France looking at early versus delayed treatment. They are looking at azathioprine and rituximab. As I mentioned, practice varies and experience varies in different locations. Those are the agents they chose, but I think the question of whether it’s better to treat patients upfront after the first attack, and are we doing them a disservice by waiting, or vice versa, is an important one. There's no one who really knows the answer to that, which is the time when you should be doing clinical trials. There's some research in that space looking at, how many patients are relapsing early after their first attack? How many patients are having clustered attacks, or polyphasic attacks where they seem to be getting better and then get worse again? Should we be treating them for longer after the first attack? And we kind of too wedded to our old paradigms that come from multiple sclerosis, where we treat them for a few days and we're done, and then wait for for an additional relapse.
Transcript edited for clarity.