Treating NMOSD: Where Do We Go After Complement Inhibition's Success?
Newly approved treatments in neuromyelitis optica spectrum disorder have shown efficacy in recent years, yet unaddressed concerns voiced by clinicians and patients living with the disease remain.
Farrah Mateen, MD, PhD
Credit: Massachusetts General Hospital
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder whose pathogenesis includes antiaquaporin-4 (AQP4) immunoglobulin G (IgG), making it a key biomarker for diagnosis and treatment success. Until early 2024, there were 3 FDA approved therapies for the treatment of patients with AQP4+ NMOSD: eculizumab (Soliris; Alexion), inebilizumab (Uplizna; Horizon Therapeutics), and satralizumab (Enspryng; Genentech). Eculizumab, a complement inhibitor, was the first approved treatment in June 2019. Inebilizumab, an anti-CD19 agent, received approval in June 2020, and then satralizumab, an anti-interleukin-6 (IL-6) receptor, was approved later that same year. In March 2024, the FDA approved ravulizumab-cwvz (Ultomiris; Alexion), a terminal compliment C5 inhibitor, making it the fourth approved therapy for NMOSD.
In conversations with NeurologyLive®, experts in the field have shared their excitement about these treatments, but have also expressed their concerns chief among them being the issue of accessibility. These treatments can be expensive, and some are only available in select countries where they have been approved by regulators. Another concern is that even though there are approved and effective treatments, other treatments may be more effective, with one avenue potentially being gene therapy. In short: research on new therapies cannot stop because of the current successes.
“A great deal of progress has been made since the discovery of the AQP4 antibody, only approximately 20 years ago now. There are multiple FDA treatments that are all immune based. This has led to many NMOSD patients being relapse-free after their initial attack and has changed the field. There is a lot of interest from biotechnology and pharmaceutical companies in NMOSD and the patient voice is being amplified through dedicated foundations. All of this makes being a neurologist treating NMOSD, being able to offer real options to patients, very exciting,” Farrah Mateen, MD, PhD, associate director of the Multiple Sclerosis and Neuromyelitis Optica Unit at Massachusetts General Hospital, told NeurologyLive.
Michael Levy, MD, PhD
Credit: Harvard Medical School
Another expert, Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School, echoed Mateen’s sentiment about the positive effects of these approvals. He told NeurologyLive that the key effect of these new medicines has been that the treatment failures in NMOSD have dropped drastically.
“Once diagnosed with NMOSD, patients who can access any one of the 4 approved medications are very likely to respond. The consequence of a response is that the disease goes into remission and no additional neurological disability accrues. This is a stark difference from life with NMOSD before effective drugs, such as in 1999 when the mortality rate from NMOSD was 30% in 5 years,” Levy, who also serves as the chairman for the medical advisory board at The Sumaira Foundation, said.
The success in NMOSD has also provided hope for related disorders, such as myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), in which some of these treatments are now being evaluated in clinical trials. Hamza Coban, MD, assistant professor of neurology at University of Connecticut School of Medicine, told the International Journal of MS Care (IJMSC), a sister publication of NeurologyLive, that the progress been “an incredible achievement [for the] community. It’s very challenging to develop effective treatments for rare disorders, but NMO has been an inspirational success among rare diseases. I’m excited about the MOGAD trials which are currently underway, I expect we will see some positive results.”
Data on Treatment Success
Eculizumab
The FDA approval of eculizumab came after a 6-month priority review based on data from the PREVENT trial,( NCT01892345) which demonstrated safety and efficacy of eculizumab in adults and met its primary end point of prolonging time to first relapse and reducing risk of relapse.1 Those data, which were presented at the 2019 Annual Meeting of the American Academy of Neurology and simultaneously published in the New England Journal of Medicine,2 solidified eculizumab as a promising treatment option for patients with the disease.
The PREVENT trial was a randomized, double-blind, placebo-controlled trial of 143 adults with AQP4-IgG+ NMOSD. The participants (91% women) were randomly assigned to receive either intravenous eculizumab (900 mg weekly for 4 weeks, followed by 1200 mg every 2 weeks) or matched placebo. Baseline annualized relapse rate for the previous 24 months was 1.99 ±0.94, and median scores on the Expanded Disability Status Scale (EDSS), modified Rankin scale, and Hauser Ambulation Index showed moderate to severe disability.
The primary end point of adjudicated relapse occurred in 3 of 96 patients (3%) in the eculizumab group compared with 20 of 47 patients (43%) in the placebo group (HR, 0.06; 95% CI, 0.02-0.20; P <.001). The median time to first relapse was not reached in the treatment group but occurred at 103 weeks in the placebo group; most relapses were myelitis. The most common adverse events (AEs) observed in the trial were upper respiratory tract infection, nasopharyngitis, diarrhea, back pain, and dizziness. Serious AEs included pneumonia, cellulitis, sepsis, and urinary tract infection. Notably, no cases of meningococcal infection were reported.
Inebilizumab
The FDA granted approval of inebilizumab, designed to bind with high affinity to CD19 and deplete a broad range of B cells, as a monoclonal antibody treatment for adult patients with NMOSD who are AQP4-IgG+.3 The agency based its approval on findings from the phase 2/3 N-MOmentum pivotal trial (NCT02200770) that assessed the safety and tolerability of inebilizumab in patients with NMOSD. In the trial, 21 of 174 (12%) participants who received inebilizumab had an attack compared with 22 of 56 (39%) patients who received placebo (HR, 0.272; 95% CI, 0.150–0.496; P <.0001). Notably, 87.6% of patients in the AQP4-IgG+ group remained relapse-free during the 5-month period post-treatment.4
The N-MOmentum study was a multicenter, double-blind, randomized, placebo-controlled trial with an open-label extension period (OLE). Eligible participants were randomly placed (3:1) to receive 300 mg intravenous (IV) inebilizumab or placebo on days 1 and 15. All patients who completed the double-blind period (n = 230) received inebilizumab 300 mg IV for at least 2 years in the OLE. Presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, 2-year data from the OLE of the N-MOmentum showed that inebilizumab continued to provide benefits similar to those seen in the randomized controlled period (RCP).5
In comparison, 60.7% those on placebo remained attack-free in the RCP vs 83.4% of those who crossed over to active treatment in the OLE. At OLE baseline, mean EDSS scores were lower in the group randomized to inebilizumab compared with those originally in the placebo group (3.82 [SD, 1.76] versus 4.16 [SD, 1.71]). By OLE week 78, patients randomized to either group demonstrated lower EDSS scores than recorded at baseline (inebilizumab: –0.24 [SD, 0.87]; placebo: –0.12 [SD, 0.73]).
A separate analysis evaluated the long-term safety outcomes with inebilizumab during the OLE. Treatment-emergent AE (TEAE) incidence rates per 100 person-years were 304.5 and 251.4 in the placebo and inebilizumab groups, respectively. Urinary tract infection (UTI) was the most common TEAE (placebo: 14.9%; inebilizumab: 7.2%), followed by nasopharyngitis (placebo: 7.1%; inebilizumab: 6.9%) and upper respiratory tract infection (placebo: 4.7%; inebilizumab: 5.7%).
Satralizumab
The FDA approved satralizumab, a humanized monoclonal recycling antibody against the IL-6 receptor, for use in adult patients with AQP4-IgG+ NMOSD. It was also the first of the NMOSD therapies to allow for at-home administration.6 Satralizumab’s approval was based on robust data from the phase 3 SAkuraStar (NCT02073279) and SAkuraSky (NCT02028884) clinical trials, which combined included more than 170 patients who were randomly assigned to receive satralizumab 120 mg or placebo. In SAkuraSky, patients added treatment to baseline immunosuppressive therapy. All patients received a loading dose of the study drug at baseline, week 2, and week 4, followed by 4-week treatment intervals. The primary end point in both studies was time to protocol-defined relapse. Notably, both studies included a population of patients who were AQP4-IgG antibody positive and negative to accurately reflect clinical practice.
In SAkuraStar, 30% of patients treated with satralizumab monotherapy experienced relapse compared with 50% of those who received placebo (HR 0.45; 95% CI, 0.23—0.89; P =.018).7 Among those who were AQP4-IgG+, a 74% reduction in relapse risk was observed. In the overall satralizumab-treated population, 76.1% and 72.1% were relapse-free at 48 and 96 weeks, respectively, compared with 61.9% and 51.2% with placebo. Data from the AQP4-IgG seropositive subgroup showed that 82.9% and 76.5% were relapse-free at 48 and 96 weeks compared with 55.4% and 41.1% with placebo, respectively.
In total, 92% (n = 58) of those in the satralizumab group experienced an AE compared with 75% (n = 24) of the placebo group. Serious AEs were similar between groups; only 1 event led to study drug discontinuation in the treatment group.
In SAkuraSky, the overall population saw a 62% reduction in the risk of relapse (HR 0.38, 95% CI, 0.16-0.88; P =.0184), while the group of AQP4-IgG seropositive patients experienced a 79% reduction in relapse risk (HR 0.21, 95% CI, 0.06-0.75; P =.0086).8 Results showed 88.9% and 77.6% of patients in the total population were relapse-free at 48 and 96 weeks, respectively, compared with 66% and 58.7% of patients in the placebo group. Among AQP4-IgG seropositive patients, 91.5% treated with satralizumab were relapse-free at 48 and 96 weeks compared with 59.9% and 53.3% of patients in the placebo group. The most common AEs observed were upper respiratory tract infection, nasopharyngitis, and headache.
Ravulizumab-cwvz
In September 2023, the FDA issued a complete response letter to Alexion for the supplemental biologics license application (sBLA) for ravulizumab-cwvz in the treatment of NMOSD. In its response, the agency requested modifications to enhance the Risk Evaluation and Mitigation Strategy program and did not need any additional analysis or reanalysis of the phase 3 CHAMPION-NMOSD study (NCT04201262), the supporting trial for ravulizumab-cwvz’s sBLA.9
In May 2022, ravulizumab-cwvz met its primary end point of time to first on-trial relapse in CHAMPION-NMOSD, with no relapses observed in 58 patients with NMOSD over a median treatment duration of 73 weeks.10 CHAMPION-NMOSD was an open-label, multicenter trial that evaluated the efficacy and safety of ravulizumab-cwvz in 58 patients with anti-AQP4 NMOSD who had at least 1 attack or relapse in the 12 months prior to the screening visit. These patients also had EDSS scores of 7 or less, had a body weight of at least 40 kg at trial entry, and were allowed to stay on stable supportive immunosuppressive therapy for the duration of the trial.
Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, additional findings from CHAMPION-NMOSD showed that ravulizumab-cwvz not only reduced the risk of relapse but also significantly lowered Hauser Ambulation Index (HAI) score worsening compared with placebo in patients with AQP4 AQP4+ NMOSD.11 In this additional analysis, patients received a weight-based intravenous loading dose of ravulizumab, then a maintenance dose on day 15 following every 8 weeks after. Eculizumab availability precluded concurrent placebo control and the PREVENT trial placebo arm was used as an external comparator. Propensity scores accounted for potential differences in patient characteristics between the arms.
All told, no patients had adjudicated relapses with ravulizumab versus 20 with placebo (relapse risk reduction [RRR], 98.6%; P <.0001). The annualized relapse rate (ARR) of those on the therapy was 0.00 (upper 95% CI, 0.04), which was superior to a predefined comparator ARR (0.25; P <.0001). There were fewer patients who experienced clinically important HAI score worsening with ravulizumab (2 out of 58 patients; 3.4%) compared with placebo (11/47; 23.4%; P = .023), demonstrated by ORs of 0.16 (95% CI, 0.03–0.77).
Treatment-emergent AEs were observed in 93.1% of patients on ravulizumab and serious AEs in 13.8% of patients. Only 2 vaccinated patients experienced meningococcal infection (2.4 out of 100 patient-years). Both recovered with no sequelae and one continued with the trial. There were no deaths were reported. The efficacy and safety data remained consistent with the primary treatment period despite the longer follow-up (median treatment duration, 90.9 weeks).
Unaddressed Issues: Where We Go From Here
The Clinician Perspective
From a clinician perspective, there are still some unaddressed issues despite the success of the approved treatments. A major holdup is that there are currently no approved treatments for patients with seronegative NMOSD. In a case report of a 35-year-old woman with treatment-resistant AQP4 IgG seronegative NMOSD, treatment with eculizumab over 8 years showed promise for seronegative NMOSD, but further research was recommended by the investigators.12 In another case report of a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as index events of seronegative NMOSD, results suggested that inebilizumab treatment may be considered in aggressive seronegative NMOSD, though similarly, more research is needed.13 In conversation with IJMSC, Coban supported this need for more research, saying, “We are still struggling to address seronegative NMOSD which seems to have a different biology behind it, yet to be discovered.”
Hamza Coban, MD
Credit: LinkedIn
Another issue is expanding the treatable patient population. According to a review published in Central Nervous System Disease, there are pending clinical trials of inebilizumab, eculizumab and satralizumab in children with NMOSD to build on the successes of the approved treatments in adults. Additionally, newer therapies are being developed to target novel NMOSD pathways,13 which could potentially address the unmet needs of pregnant patients who are more at risk of relapse. Research is also continuing on the long-term experience of treatment, as well as assessments of general risk management for potential lifelong therapies.14
In a review published in the Journal of Neurology, researchers noted that other unmet needs in NMOSD include determining the optimal immunotherapy durations, as well developing strategies for treatment cessation and de-escalation, and searching for biomarkers that indicate attack risk.14 Another subgroup of patients that researchers have noted should be considered in international and collaborative research for potential treatments are those who have double-seronegative NMOSD and MOGAD.
As for future directions for trials, Coban said, “I think next steps will be exploring CAR-T cell therapies, stem cell therapies, and immune tolerance induction for NMO in the path for a cure, along with exploring remyelination and restoration strategies. An important unmet need is treatment of symptoms associated with NMO such as fatigue, pain, spasticity, etc. Additionally, addressing issues with current [disease-modifying therapies] such as immune suppression [and] opportunistic infections should be a priority.”
Mateen said much of the same, expressing desire for treatments that can aid in repair and remyelination, and that can address symptomatic challenges, in addition to more useful biomarkers and global access to antibody testing and treatment. “Much work is needed,” she said. “There are many patients globally who still have no access to a diagnosis and treatment. Equity in NMO diagnosis and treatment deserves significant attention to ensure that the field's successes are felt among all patients. Also notable is the lack of approved treatments for the patients who phenotypically appear to have NMOSD but who do not have an identified autoantibody.”
While the approved medications are remarkably effective at preventing relapses, they come with long term consequences of prolonged immune suppression,” Levy said, explaining that the next step should be to develop more specific immunotherapies that can target immunity against AQP4. “Rather than suppress the immune system, we should strive to turn off the immune response against just AQP4,” he said.
The Patient Perspective
In clinical practice, approximately 40% of patients with NMOSD are misdiagnosed, most often receiving an incorrect diagnosis of multiple sclerosis, or similar diseases.15 According to a previous multicenter study published in the Multiple Sclerosis Journal, investigators observed a 12% frequent rate of misdiagnosis among patients with NMOSD in Latin America because of misapplication and misinterpretation of clinical and neuroradiological findings.16 Despite the recent advancements in the field of NMOSD, including approved treatments, misdiagnosis remains an prevalent issue in this rare disease community.
Sumaira Ahmed
Credit: LinkedIn
“There's still an alarming rate of misdiagnosis in our community that really needs to be addressed, specifically outside of North America. We are very privileged. What keeps me up at night is thinking about all of the patients around the world, specifically in lower middle-income countries that are being misdiagnosed or even worse, not even diagnosed with anything. They're just going blind, becoming paralyzed, and there's no rhyme or reason for it to them,” Sumaira Ahmed, a patient with NMOSD who serves as the founder and executive director of The Sumaira Foundation, told NeurologyLive.
“The way I see it, there's this recipe for a rare disease patient or maybe any patient with any ailment,” Ahmed said. “First step, you need a correct diagnosis. Then finding a doctor who knows and understands how to treat and care for these patients. That's also another unmet need. We don't have enough specialists in the world who know and understand and how to care for NMOSD and MOGAD. We need more neuroimmunologists in the field, which is an unmet need there.
“You find a doctor, that's great. Now you need a therapy that works and that works for you. Every patient is going to have a different experience, even with the approved therapy. You have to figure out what works for you physically and with your lifestyle. Everyone has different preferences, and they're entitled to that,” she said.
From there, Ahmed explained, patients need a support system. She cited that roughly 95% of patients with NMOSD are living outside of the United States, which introduces possible challenges for them regarding access to advocates. “We're very fortunate here in the US and in Canada to have advocacy groups, advocacy organizations, having the ability to go to Capitol Hill and raise all these concerns with people in power. But this is certainly not the case in other countries, another unmet need,” Ahmed said.
A major question that remains is how to elevate the patient voice in the places where they are. Without the support system of clinicians in the clinic and advocates out of it, it is difficult to produce change in care and policy. Ahmed asked, “How do we elevate the patient voice in places that matter…that will benefit our community not just for NMOSD or MOGAD, but I think for rare diseases in general?” Unfortunately, we may not have an answer to those questions right now, but it’s clear that there is work to be done, and there are many clinicians and advocates who are ready to take on that challenge.
