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What’s new in NMOSD? Updates on biomarkers and therapies

In recent years, significant advancements have been made in the management of neuromyelitis optica spectrum disorder (NMOSD). The introduction of targeted therapies has revolutionized treatment by reducing relapse rates and improving long-term outcomes. Additionally, advances in early diagnosis and personalized medicine approaches have led to more tailored treatment strategies, enhancing the overall management of NMOSD.

Biomarkers Therapy of Acute Attacks Prevention of Relapses What's next in NMOSD?

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune demyelinating disease of the central nervous system that preferentially affects the spinal cord and optic nerve. Repeated acute attacks are a typical characteristic of NMOSD. The frequent and severe relapses lead to early and incremental disability. Therefore, limiting the frequency and severity of relapses is the main goal of disease management.1,2

The pathophysiologic processes and inflammatory cascade in NMOSD are complex and not fully understood. Aquaporin‐4 immunoglobulin G (AQP4‐IgG) antibodies are found almost exclusively in patients with NMOSD. AQP4-IgG contributes to the pathogenesis of NMOSD through binding to AQP4 channels on astrocytes, leading to activation of the complement cascade, which causes granulocytes and lymphocyte infiltration. This eventually leads to astrocyte and oligodendrocyte injury, followed by demyelination and neuronal loss.1,3 However, not all patients with NMOSD have AQP4-IgG, which suggests that the pathogenesis of NMOSD may be multifactorial. In fact, previous studies have reported up to 20%-30% of patients clinically diagnosed with NMOSD are persistently AQP4-IgG negative.4

Based on NMOSD’s diagnostic criteria, NMOSD can be categorized into two pathophysiological entities depending on the presence or absence of AQP4-IgG. In AQP4-IgG-negative patients, it is required to detect myelin oligodendrocyte glycoprotein (MOG)‐IgG to determine or exclude MOG‐IgG‐associated disease (MOGAD).2 There are also a small number of double-seronegative NMOSD patients, and current thinking suggests that these cases are caused by unknown autoantibodies or are variants of multiple sclerosis.5

Biomarkers

 

Due to the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response, reliable and sensitive biomarkers in NMOSD are urgently needed. The identification of biomarkers able to assess disease activity, monitor treatment responses and determine prognosis promises to improve the diagnostic accuracy and individualized care of NMOSD.6,7

There are currently a number of biomarkers under investigation, the most promising of which include neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). NfL is a neuronal intermediate filament protein that increases in the CSF and blood proportionally to neuroaxonal damage.8 GFAP is an astrocytic intermediate filament, high levels of which reflect astrocyte injury.9

N-MOmentum (NCT02200770), a recent Phase II/ III trial, investigated the efficacy and safety of inebilizumab, an anti-CD19 monoclonal antibody, in participants with NMOSD. A further analysis of the trial’s results aimed to investigate relationships between serum levels of putative biomarkers GFAP, NfL, tau, and ubiquitin C-terminal hydrolase L1 (UCHL1) and disease activity/disability, providing insight into the effects of inebilizumab on these biomarkers.7 In total, 1260 serial and NMOSD attack-related samples from 215 participants were provided for biomarker concentration analysis. During attacks, increases in serum levels were observed in all four biomarkers. Serum NfL (sNfL) had the strongest correlation with EDSS scores at attack (Spearman R2=0.40; p=0.01), suggesting that its assessment during an attack could inform about attack severity and potentially guide therapeutic interventions. Additionally, participants with EDSS score worsening at follow-up had elevated sNfL (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02).7

 

Although sNfL was shown to be the best predictor for disability worsening during and after attacks, serum GFAP (sGFAP) was the best predictor of future attacks.7

Friedemann Paul, MD, Charité – University Medicine Berlin, Berlin, Germany, comments on the correlation found between sGFAP and the risk of relapse: “sGFAP might be a valuable biomarker for disease monitoring, both in terms of predicting attack risk as well as disability progression.” The analysis also found that inebilizumab-treated participants had smaller biomarker elevations compared with placebo. At the end of the randomized controlled period, sNfL levels were significantly lower with inebilizumab than with placebo (22% vs. 45%; OR, 0.36 (95% CI 0.17 to 0.76); p=0.004).7

Therapy of Acute Attacks

In NMOSD, accumulation of physical impairment is relapse dependent, which makes acute relapse treatment and relapse prevention crucial to minimize residual deficits and disability accumulation. In the context of treatment of NMOSD acute attacks, time is of the essence. Retrospective cohort studies have shown that early treatment initiation is associated with better clinical outcomes. Glucocorticoids, such as methylprednisolone, are often employed as the first line of therapy for acute treatment due to their wide availability and simple administration. For relapses refractory to steroids or when steroids are contraindicated, plasmapheresis is often used and can be considered a first-line treatment for patients refractory to steroids in previous relapses.5

Prevention of Relapses

There are currently multiple approved treatments for relapse prevention, including traditional DMTs such as azathioprine, mycophenolate mofetil (MMF), and rituximab. More recently, developments in NMOSD relapse prevention research led to the FDA approval of three new drugs in 2019, thought to be the “year of NMOSD”.

Satralizumab

One such drug is satralizumab – a monoclonal antibody that inhibits IL-6 signaling by binding to soluble and membrane-bound IL-6 receptors. Two key randomized, double-blind, placebo-controlled Phase III trials were involved in the approval of satralizumab – SAkuraSky study (NCT02028884) and SAkuraStar study (NCT02073279). In the SAkuraStar trial patients were randomized receive satralizumab monotherapy or placebo, while in the SAkuraSky trial, patients were randomized to receive satralizumab in addition to baseline immunosuppressive treatment or placebo. Both of these clinical trials had similar results, with SAkuraStar finding the number of patients who experienced protocol-defined relapses was significantly lower in the satralizumab group compared to the placebo group (30% vs. 50%; HR, 0.45 (95% Cl 0.23 to 0.89); p=0.018).10

In the SakuraSky trial, 20% of patients receiving satralizumab had a protocol-defined relapse, as compared with 43 % of patients receiving placebo (HR, 0.38 (95% CI 0.16 to 0.88); adjusted p=0.02).11 No differences in the incidence of serious adverse effects or adverse effects leading to withdrawal were found in either study. Therefore, SAkuraStar and SAkuraSky present indisputable evidence that satralizumab is a safe and efficacious drug for NMOSD relapse prevention.

Eculizumab

Eculizumab is another recently approved drug for the prevention of relapses in NMOSD. Eculizumab is a monoclonal antibody that inhibits C5, a terminal complement protein, and prevents its cleavage into pro-inflammatory C5a and C5b, and hence inhibits the formation of the membrane attack complex. The PREVENT study (NCT01892345) was a multicenter, randomized, double-blind trial where NMOSD patients were randomized to receive either intravenous eculizumab or placebo. Results demonstrated an adjudicated annualized relapse rate of 0.02 in the eculizumab group, compared to 0.35 in the placebo group (RR, 0.04 (95% CI 0.01 to 0.15); p<0.001).12

Inebilizumab

Inebilizumab is a monoclonal antibody that binds CD19, leading to B-cell depletion. Inebilizumab was approved after the positive results of the multicenter, randomized, double-blind, placebo-controlled Phase II/III trial called N-MOmentum study (NCT02200770). Relapses occurred in only 12% of participants receiving inebilizumab, compared to 39% of those receiving placebo (HR, 0.272 (95% CI 0.150 to 0.496); p<0.0001), showing a clear reduction in risk of an NMOSD attack.13

Friedemann Paul, MD, Charité – University Medicine Berlin, Berlin, Germany, comments on the long-term outcomes of inebilizumab treatment in AQP4-IgG positive (AQP4+) NMOSD participants from the N-MOmentum trial with a history of immunosuppressant therapy as compared to those without. In this analysis, participants who received inebilizumab were grouped by no history of immunosuppression therapy (naïve) or prior azathioprine and/or MMF therapy. Safety and efficacy profiles were similar in treatment-naïve participants and those who had previously received azathioprine or MMF.14

 

 

Ravulizumab

Despite recent approved treatments, research into the prevention of NMOSD relapses continues to be of high priority. One particularly promising drug is ravulizumab, a recombinant monoclonal antibody that inhibits the AQP4-Ab-induced terminal complement C5b-C9 deposition. The CHAMPION-NMOSD trial (NCT04201262) was a Phase III, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with AQP4+ NMOSD.

 

The availability of eculizumab precluded the use of a concurrent placebo control; therefore, the placebo arm from the PREVENT trial was used as an external comparator. Michael Levy, MD, PhD, Massachusetts General Hospital and Harvard Medical School, Boston, MA, discusses the CHAMPION-NMOSD trial results as well as the prespecified analyses of the trial. Overall, no relapses were observed in the ravulizumab group, compared to 20 relapses in the placebo group (relapse risk reduction [RRR], 98.6%; p<0.0001). The annualized relapse rate (ARR) of those on ravulizumab was 0.00 (upper 95% CI, 0.04), which was superior to a predefined comparator ARR (0.25; p<.0001). Safety measures were similar between the two groups, with most treatment-emergent adverse effects being mild or moderate.15 Ravulizumab binds the same complement component 5 epitope as eculizumab, but its longer half-life enables an extended dosing interval. This is more convenient for patients, meaning that infusion is only needed every 8 weeks rather than every 2 weeks.

Ravulizumab was recently approved in the European Union for the treatment of adult patients with NMOSD who are AQP4+, and regulatory reviews are ongoing in additional countries, including in the United States.16

What's next in NMOSD?

 

In recent times, our understanding of NMOSD’s pathophysiology has brought significant advancements to its management, leading to the approval of new and safe medications. These newer drugs specifically target various elements of the autoimmune cascade in NMOSD patients. However, the suitability of different drugs for individual patients remains unclear, and in this context, personalized medicine could hold immense importance in the future of NMOSD treatment. Additionally, reliable biomarkers are necessary to predict relapses and disease severity. Kazuo Fujihara, MD, PhD, Fukushima Medical University School of Medicine, Fukushima, Japan, shares his views on some of the unmet needs within the treatment and diagnosis of NMOSD, highlighting the need for quality-of-life measures to be included in diagnostic and treatment outcome measures.

 

Written by Lottie Julian
Reviewed by Marta Palhas

References

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  2. Shi M, Chu F, Jin T, Zhu J. Progress in treatment of neuromyelitis optica spectrum disorders (NMOSD): Novel insights into therapeutic possibilities in NMOSD. CNS Neurosci Ther. 2022 Jul;28(7):981-991.
  3. Kawachi I, Lassmann H. Neurodegeneration in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2017 Feb;88(2):137-145.
  4. Carnero Contentti E, Lopez PA, Pettinicchi JP, et al. What percentage of AQP4-ab-negative NMOSD patients are MOG-ab positive? A study from the Argentinean multiple sclerosis registry (RelevarEM). Mult Scler Relat Disord. 2021 Apr;49:102742.
  5. Held F, Klein AK, Berthele A. Drug Treatment of Neuromyelitis Optica Spectrum Disorders: Out with the Old, in with the New?. Immunotargets Ther. 2021 Mar;10:87-101.
  6. Melamed E, Levy M, Waters PJ, et al. Update on biomarkers in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm. 2015 Aug;2(4):e134.
  7. Aktas O, Hartung HP, Smith MA, et al. Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder [published online ahead of print, 2023 May 23]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2022-330412.
  8. Khalil, M., Teunissen, C.E., Otto, M. et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol.2018 Aug;14, 577–589.
  9. Misu T, Takano R, Fujihara K, et al. Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker. J Neurol Neurosurg Psychiatry. 2009 May;80(5):575–7.
  10. 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 May;19(5):402-412.
  11. Yamamura T, Kleiter I, Fujihara K, et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 Nov;381(22):2114-2124.
  12. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 Aug;381(7):614-625.
  13. Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019 Oct;394(10206):1352-1363.
  14. Paul F, Marignier R, Lindsey J, et al. Safety and efficacy of inebilizumab in AQP4+ NMOSD participants with history of immunosuppression treatment prior to N-Momentum Study. [published online ahead of print, 2023 Apr 25]. Neurology. 2023; 100(17 Supplement 2).
  15. Pittock S, Barnett M, Bennett J, et al. Efficacy and safety of ravulizumab in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: Outcomes from the Phase 3 Champion-NMOSD trial. [published online ahead of print, 2023 Apr 28]. Neurology. 2023;100(17 Supplement 2).
  16. Ultomiris approved in Japan for the prevention of relapses in patients with neuromyelitis optica spectrum disorder (NMOSD). [Press Release] 26 May 2023. Accessed: 11 July 2023.
The content of VJNeurology is intended for healthcare professionals