18-20 - NEUROLOGY CONGRESS - Neuromyelitis optica spectrum disorder: is there hope on the horizon?

Following a presentation on neuromyelitis optica spectrum disorder (NMOSD) at this year’s European Academy of Neurology (EAN) meeting in Budapest, we spoke to Professor Friedemann Paul at the Charité and Dr Kristina Patterson of Horizon Therapeutics.

What is neuromyelitis optica spectrum disorder (NMOSD) and how does it impact patients?
Kristina Patterson (KP): NMOSD is a rare, debilitating neurological disease that can impact vision, motor skills such as the ability to walk and the brain. It can occur at any time, and the attacks are relatively severe – patients rarely recover completely and prognosis can be quite unpredictable. The majority of patients suffer severe degeneration a few years after diagnosis, with around half fully requiring the use of wheelchairs. As such, it’s incredibly important not just to accurately diagnose this condition, but to also get patients the appropriate care as soon as possible.

Friedemann Paul (FP): It’s important to mention that NMOSD is not multiple sclerosis (MS). Many patients have a history of being misdiagnosed with MS, but it’s a distinct condition with a distinct pathobiology and that has to be treated differently.

Drug treatments that work for MS don’t work for NMOSD – in fact, they can make things worse and can even exacerbate attacks. In terms of current treatments for NMOSD, since 2019, we’ve now seen approval for four immunotherapies that are designed specifically to prevent attacks, including one that targets an inflammatory cytokine-IL6 and another that targets plasma cells, plasma blasts, B cells and anti-CD19 monochrome antibody anabolism.

NMOSD often presents with other rheumatological disorders and sometimes patients experience a rheumatological disorder prior to being diagnosed with NMOSD. However, this also leads to false and late diagnosis, so it’s very important to work closely together with rheumatologists, ophthalmologists and other internal medicine colleagues.

What is also important is that some patients with NMOSD have concomitant myasthenia gravis, which is a neuromuscular disease. It’s not fully clear as to why these comorbidities are common, but there does appear to be an underlying propensity to autoimmune conditions in NMOSD sufferers, which is not present in MS sufferers. It’s therefore important to not only educate and teach neurologists about this condition, but also teach ophthalmologists and dermatologists, as these are who many patients will first be seen by. Correct identification of NMOSD as early as possible is vital to patient care.

Why is there often an overlap in diagnosis between NMOSD and MS?
FP: Both diseases can manifest with similar features and symptoms, like vision loss caused by optic neuritis and myelitis, as well as pain policies and other ambulation problems. MS is significantly more prevalent than NMOSD, so unfortunately most neurologists are inclined to do the more logical diagnosis of the more frequent condition, leading to NMOSD often being overlooked. This can be massively damaging for patients as NMOSD attacks are a lot more severe than MS attacks, with patients often suffering from complete vision loss and complete loss of ambulation, becoming wheelchair-bound or bedridden.

Why does precise B-cell targeting present a promising approach to developing new treatments?
KP: B cells play a critical role in NMOSD, not just in terms of producing auto-antibodies and these cells express CD19 (a key protein in the workings of NMOSD), but also in activating other immune cells. Their role in NMOSD is therefore very central to the disease. One of the defining characteristics of inebilizumab (Uplizna) – compared to other B-cell-based therapies – in addition to targeting CD19 antibodies-expressing cells, is that it has been engineered to overcome genetic variation that can otherwise impact the efficacy of B-cell therapies.

FP: We know that cells of the B-cell lineage, like B cells or plasma blasts and plasma cells, release pathogenic auto-antibodies (such as aquaporin-4) that then enter the central nervous system and attack astrocytes. This is where the aquaporin-4 water channels are located, which means that when these B cells such as plasma cells and plasma blasts are depleted, there is a certain chance of reducing auto-antibody production and preventing damage to the astrocytes, thereby limiting the impact of NMOSD.

This can be further influenced by static polymorphism, which has an influence on how efficiently natural killer (NK) cells can bind to inebilizumab and then deplete B cells and plasma cells. Inebilizumab has a higher antibody dependent cell mediated cytotoxicity, so has a higher capacity to interact with NK cells and thus deplete B cells and plasma cells.

Horizon Therapeutics’ Uplizna (inebilizumab) received EU approval in April 2022. Has this approval helped make HCPs more aware of NMOSD?
KP: It’s quite interesting – the answer is both ‘yes’ and ‘no’. The year that Uplizna was approved become known as ‘the year of NMOSD’ – more and more people became aware of the condition, how to identify and diagnose it, and what treatments are available for it. Several therapies appeared on the market that year, meaning that awareness of NMOSD was raised for both practitioners and undiagnosed sufferers.

This elevated awareness improves the ability for patient care tremendously as it helps to counteract the misdiagnosis of NMOSD. Patients with NMOSD have a high risk of being misdiagnosed with MS and treatments for MS can actually worsen NMOSD symptoms. As such, proper diagnosis as early as possible is vital, and the elevated awareness created by multiple treatments being released at the same time has helped. And having more treatment options available for patients is always a good thing.

What are some best practices that companies can adopt when investigating new treatments for less common diseases?
KP: When operating in the rare disease space, the best thing that any company can do is to listen to the patients. Partnerships with patients are incredibly important as they are the ones who are ultimately impacted by the condition and any treatments. Their input is valuable all the way from trial design to the eventual commercialisation of the drug. Having the perspective of patients who are involved throughout the process ensures that all decisions are made with evidence that they’ll benefit the patient, which is ultimately the goal of any therapy development endeavour. There are a multitude of ways to get involved with patients and gain their feedback.

One way is to partner with advocacy groups, as this gives you insight into quality of life, expectations and other information that might get lost behind clinical endpoints. Once a treatment to stop symptoms, such as NMOSD attacks, has been identified, the next steps should be gaining this vital patient insight.

Have recent advancements in technology, such as the growing prevalence of artificial intelligence (AI), aided in developing new understandings of and treatments for NMOSD?
FP: They have been useful, especially in developing new kinds of algorithms that would be applicable to individual patients, and this is likely to continue into the future as well. There are already groups working on this that would integrate, for example, biosignatures, clinical signatures and imaging features and would combine them into a prediction algorithm that can, hopefully, help with treatment decisions and tailored therapies.

The goal would be to develop a means to work out which of the three current treatments for NMOSD would be most applicable for the individual patient. As it currently stands, each of the three available treatments has different pros and cons, and individuals can have different responses to each. By utilising biomarkers and biosignatures that can easily and effectively be identified using the aforementioned algorithm, this can allow for patients to receive the most pertinent treatment as early as possible.

How do you see the NMOSD landscape evolving over the next five years?
KP: Today there are several approved NMOSD therapies, which was unimaginable previously, even as recently as ten years ago. It’s really exciting, both for us as therapeutics developers and for the whole pharma landscape, that therapies for such rare diseases are becoming more common. Therapies develop from clinicians working with patients to discern which treatments are best suited to them. There are a lot of different factors that can go into such a decision, including dosing frequency and tolerability, so the future of NMOSD treatments – and treatments for all rare diseases – will rely on the ability to more effectively personalise treatments and therapies to patients.

FP: My expectations are for there to be three emerging fields. The first focus is on the cause of the disease, as this has not been fully elucidated. We know that there are auto-antibodies and that plasma cells make these antibodies, but we do not know what the initial trigger is. More research therefore will be needed to go into the interactions with environmental factors, along with potential signatures in the microbiome and how that, in turn, relates to environmental factors.

The second focus, with regards to treatment, is around the sub-clinical disease activity. We know that the disability in NMOSD stems from its devastating attacks. While we don’t think there is progression between attacks, as in MS, we see from imaging studies that there is more subtle tissue damage over time. We need to learn more about this and understand how this could inform treatment decisions.

The third complex aspect is increasing the prevalence of symptomatic therapy. NMOSD has a host of symptoms that can impact patients’ lives, including fatigue, cognitive problems, depression, sleep problems and pain. Approaches to therapy that help to alleviate all of these symptoms is therefore most relevant for patients. If they had to choose, then they will most likely choose these symptomatic therapies over others, so there is a pressing need to increase research in this field as well.