The director of Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology provided context on challenges within the NMOSD space and what’s next following the first-approved therapies.
The first clinical descriptions of neuromyelitis optica spectrum disorder (NMOSD) emerged over a century ago when 2 clinicians documented a series of patients with a monophasic course of bilateral optic neuritis and myelitis. Over time, significant variation in the presenting features, clinical course, and the degree of accumulated disability in patents with presumed NMOSD made its distinction from multiple sclerosis and other demyelinating disorders clearer. The field took another leap of progress with the identification of the aquaporin-4 antibody, which further distinguished these patients and led to the first approved therapies in 2019.
Alexion Pharmaceuticals’ eculizumab (Soliris), a first-in-class complement inhibitor, was the first to gain FDA approval in June 2019 and was supported by the phase 3 PREVENT study, which showed that 98% of those who received treatment were relapse-free at 48 weeks. The FDA then approved inebilizumab (Uplizna; Horizon Therapeutics) in June 2020 and satralizumab (Enspryng; Genentech) in August 2020. All 3 therapies, while different in mechanistic action, are indicated to treat only patients with NMOSD who are aquaporin-4 (AQP4)–positive.
Despite the influx of new therapies, there has been limited research regarding new agents within the clinical pipeline, according to Sean Pittock, MD. Pittock, director, Center for Multiple Sclerosis and Autoimmune Neurology, noted that industry leaders may be swayed to focus on other autoimmune disorders that currently have no treatment options available. He sat down with NeurologyLive to provide an overview of the NMOSD pipeline, reasons for the struggle in generating new trials, and challenges clinicians still face in the diagnostic setting.
Sean Pittock, MD: There are many companies who have drugs that probably would work for NMO. The problem is that it’s a relatively rare disease that affects maybe half a million people worldwide, and the potential to do placebo-controlled trials is significantly reduced now because of these 3 FDA-approved drugs. It’s going to be difficult for drug companies to step into the space and prove efficacy. Maybe they can prove equivalency to efficacy, but it’s going to be difficult to design trials in the future as we move forward.
I think there’s a rush by many industry and pharma groups to look at the potential use of their drug in the space of autoimmune neurological disease, but not necessarily in that specific small space. For example, there’s a condition called MOG-AD (myelin oligodendrocyte glycoprotein antibody disease) which has some overlap with NMOSD. It’s a very different disease that’s associated with a milder phenotype. At the same time, it’s still a relapsing condition that can cause optic nerve damage, vision loss, and spinal cord inflammation. It’s probably an antibody-mediated disease. The types of drugs that work for NMOSD may work in that disease as well. That’s an exciting area.
There’s this whole group of diseases called autoimmune encephalitis or autoimmune inflammatory disorders in the brain. Many people will know NMDA receptor encephalitis because of the Brain on Fire book, which brought the disease to the general public. There are many conditions like that. We don’t have FDA-approved drugs for those conditions. And so, there’s been this explosion in the last couple of decades regarding antibody biomarkers, whether those be antibody biomarkers of antibody-mediated inflammatory brain diseases or having more cytotoxic T-cell-mediated brain diseases. There are all those diseases out there.
In terms of randomized controlled trials in the inflammatory central nervous system space, excluding multiple sclerosis, there’s been very few. In fact, there’s only been those 4 major randomized controlled trials and a couple more in the space of autoimmune encephalitis. An intravenous immunoglobulin trial we did with Grifols showed that IV IgG can help patients in the acute setting of encephalitis with Lgi2 on our Caspr2 antibodies. That’s about it. And so, there’s a huge need for drugs for all those devastating and disabling conditions. We have a lot of work to do, but it’s a very exciting time to try to move this field forward.
When I talk about NMOSD, I talk about the disease that’s associated with aquaporin-4 antibodies. Initially, the disease was generally misdiagnosed as multiple sclerosis. In fact, I would say about 90% of patients were misdiagnosed as MS before we educated the neurological community on the entity. They were treated with MS drugs that made their condition worse, so it was highly problematic. Now, because of the biomarker and the availability of testing for that biomarker, most MS physicians are aware of NMOSD. You need to think about NMOSD when discussing Optic neuritis or longitudinal sense of transverse myelitis. You also need to test the patient’s water channel antibody. Because the water channel antibody is so specific, along with the fact that you’re 85% sensitive, it proved itself as a helpful biomarker.
There are very few biomarkers that are essentially 100% specific. I’m not particularly concerned with that condition, especially in the US where testing is accessible. Outside of the US where testing is limited, this is more problematic. Additionally, there are good assays to test for AQP4 antibodies. With respect to other disorders, for example, MOGAD, there is a much more problematic situation. The diagnosis of MOGAD is generally made in the context of the presence of MOG antibodies. MOG antibodies of low titer are highly problematic in the sense that low positive titers are commonly false positive. In the context of a high titer of MOG antibodies, they’re not going to be helpful, but in low titer MOG antibodies, you need to be careful. You could potentially misdiagnose a patient with multiple sclerosis with MOGAD because we know about 2% to 3% of patients with multiple sclerosis have a false positive low titer MOG antibodies. There is a potential for misdiagnosis and those types of disorders, as well as in many of the autoimmune encephalopathies because the antibody tests are sometimes more problematic. Assays are not perfect.
Transcript edited for clarity.