
==== Front
Neurol Ther
Neurol Ther
Neurology and Therapy
2193-8253
2193-6536
Springer Healthcare Cheshire

39012406
640
10.1007/s40120-024-00640-7
Original Research
Safety and Effectiveness of Satralizumab in Japanese Patients with Neuromyelitis Optica Spectrum Disorder: A 6-month Interim Analysis of Post-marketing Surveillance
http://orcid.org/0000-0001-9048-0375
Yamamura Takashi yamamura@ncnp.go.jp

1
http://orcid.org/0000-0001-9525-4254
Isobe Noriko 2
http://orcid.org/0000-0002-7140-8500
Kawachi Izumi 34
Nohara Chiyoko 5
http://orcid.org/0000-0002-8235-7569
Miyazaki Yusei 6
http://orcid.org/0009-0003-3201-305X
Tomita Minami 7
http://orcid.org/0009-0009-7261-0346
Tsumuraya Takahiko 7
http://orcid.org/0000-0002-5761-1609
Yamashita Katsuhisa 8
http://orcid.org/0000-0002-5858-0998
Nakahara Jin 9
http://orcid.org/0000-0002-2612-8948
Nakashima Ichiro 10
http://orcid.org/0000-0002-3096-4156
Fujihara Kazuo 1112
1 https://ror.org/0254bmq54 grid.419280.6 0000 0004 1763 8916 Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4 Chome-1-1 Ogawahigashicho, Kodaira, Tokyo 187-8551 Japan
2 https://ror.org/00p4k0j84 grid.177174.3 0000 0001 2242 4849 Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582 Japan
3 https://ror.org/04ww21r56 grid.260975.f 0000 0001 0671 5144 Department of Neurology, Brain Research Institute, Niigata University, Chuo-ku, Niigata, 951-8585 Japan
4 https://ror.org/04ww21r56 grid.260975.f 0000 0001 0671 5144 Medical Education Center, Niigata University School of Medicine, Chuo-ku, Niigata, 951-8510 Japan
5 https://ror.org/00v47dk08 grid.417086.c 0000 0001 0631 2329 Department of Neurology, Ebara Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, 145-0065 Japan
6 https://ror.org/00sbe8213 grid.474861.8 0000 0004 0629 3596 Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Sapporo, 063-0005 Japan
7 grid.515733.6 0000 0004 1756 470X Drug Safety Division, Chugai Pharmaceutical Co., Ltd., 1-1 Nihonbashi-Muromachi 2-Chome, Nihonbashi Mitsui Tower (Reception15F), Chuo-ku, Tokyo, 103-8324 Japan
8 grid.515733.6 0000 0004 1756 470X Medical Affairs Division, Chugai Pharmaceutical Co. Ltd., Tokyo, 103-8324 Japan
9 https://ror.org/02kn6nx58 grid.26091.3c 0000 0004 1936 9959 Department of Neurology, Keio University School of Medicine, Tokyo, 160-8582 Japan
10 https://ror.org/0264zxa45 grid.412755.0 0000 0001 2166 7427 Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, 983-8512 Japan
11 https://ror.org/012eh0r35 grid.411582.b 0000 0001 1017 9540 Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, Fukushima, 960-1295 Japan
12 Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, 963-8563 Japan
16 7 2024
16 7 2024
10 2024
13 5 13611383
28 12 2023
6 6 2024
© The Author(s) 2024
2024
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Introduction

Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD.

Methods

This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021.

Results

Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07–87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80–13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan–Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25–96.23) at 6 months.

Conclusion

In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period.

Trial Registration: UMIN Clinical Trials Registry, UMIN000041047.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-024-00640-7.

Keywords

Anti-IL-6 receptor antibody
Effectiveness
Glucocorticoids
Neuromyelitis optica spectrum disorder
Post-marketing surveillance
Relapse
Safety
Satralizumab
Chugai Pharmaceutical Co, Ltd.issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
==== Body
pmcKey Summary Points

Why carry out this study?	
The Phase 3 clinical trials of satralizumab proved the efficacy and safety of satralizumab in a limited sample size of a well-selected patient population.	
However, the effectiveness and safety of satralizumab in a broader group of patients with neuromyelitis optica spectrum disorder (NMOSD) have not been assessed.	
The hypothesis of the study was that the safety and efficacy results of satralizumab in clinical trials can be translated to patients with NMOSD in a routine clinical setting.	
What was learned from the study?	
Satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice at 6-month interim analysis, and these results are consistent with those of previous Phase 3 trials.	
The study will be continued to assess the safety and effectiveness of satralizumab in Japanese patients with NMOSD over the 6-year surveillance period.	

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic autoimmune disease, primarily affecting the optic nerve and spinal cord in the central nervous system through the aquaporin-4 (AQP4) water channel of astrocytes, ultimately resulting in paralysis and blindness [1]. The disease is characterized by a variety of symptoms including visual impairment and loss of motor, sensory, and bowel–bladder functions along with occasional incidences of nausea, emesis, and hiccups [2]. It preferentially affects adult females with a female:male ratio of 9:1 worldwide. Around 5–10% of patients with NMOSD have been diagnosed in adolescence [3]. In Japan, a nation-wide survey estimated the prevalence of NMOSD to be around 3.42 per 100,000 population in 2011 [4]. Northern Japan has a slightly higher prevalence of 4.1 per 100,000 population as per a 2016 local survey [5]. Relapses are commonly associated with NMOSD, leading to a high risk of permanent disability over a period of time. Hence, disease management is aimed to reduce the number of relapses with simultaneous reduction in disease severity [6].

Approaches to treatment include acute treatment of attack and long-term preventive or maintenance therapy. Acute relapse therapy comprises intravenous methylprednisolone, plasma exchange/immunoadsorption therapy, and immunoglobulins, while long-term maintenance therapy includes non-selective immunosuppressants and specific immune targeting agents [7]. Interleukin-6 (IL-6) levels are generally increased in the cerebrospinal fluid of patients with frequent NMOSD relapses [7]. Targeting IL-6 with suitable inhibitors has shown to decrease relapse rate in patients with NMOSD [8].

Satralizumab is a humanized immunoglobin G2 (IgG2) anti-IL-6 receptor monoclonal recycling antibody engineered to have a longer plasma half-life [7]. Previous Phase 3, randomized, double-blind, placebo-controlled clinical trials, SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279), have used satralizumab as combination therapy with immunosuppressants or as monotherapy in adults and children aged ≥ 12 years with NMOSD who are AQP4 water channel auto-antibody (AQP4-IgG) seropositive [9, 10]. These trials have shown satralizumab therapy to be efficacious in reducing the risk of protocol-defined relapse (PDR) and severe PDR when compared with placebo, and provide relevant evidence on the mechanism of action, efficacy, and safety of satralizumab. The median treatment duration with satralizumab in the double-blind periods were 107.4 and 92.3 weeks, respectively. In these trials, the eligible participants had experienced at least 1 relapse in the past 12 months and had an Expanded Disability Status Scale (EDSS) score of 0–6.5 at screening.

Moreover, in the open-label extension following the double-blind periods of SAkuraSky and SAkuraStar, the long-term efficacy of satralizumab in patients with AQP4-IgG seropositive NMOSD has shown that 71% and 73% of satralizumab-treated patients were free from annualized investigator-determined PDR (iPDR), 91% and 90% patients were free from severe iPDR, 90% and 86% had no sustained EDSS worsening, and the overall adjusted iPDR rates (ARRs) were 0.12 and 0.08, respectively [6]. The median treatment durations with satralizumab in the double-blind and extension periods were 4.4 and 4.0 years, respectively [6].

Interestingly, SAkuraMoon (NCT04660539), a single-arm, open-label study in adult participants with AQP4-IgG seropositive NMOSD who had completed the SAkuraSky and SAkuraStar trials, has shown that satralizumab was effective long term at preventing relapses, and 72% of satralizumab-treated patients were free from ARRs, 91% patients were free from severe iPDR, and 85% had no sustained EDSS worsening [11].

Based on the encouraging efficacy and tolerable safety results, satralizumab received approval on June 1, 2020, in Canada, and subsequently on June 29, 2020 in Japan, for the management and prevention of NMOSD relapse. This was followed by approval for the drug in other countries [12].

The longer plasma half-life of satralizumab has enabled an effective dose schedule of once in 4 weeks of satralizumab administered subcutaneously. In Japan, the approved dosage of 120 mg given at weeks 0, 2, and 4 as loading doses, followed by a maintenance dose of 120 mg every 4 weeks [12].

However, the Phase 3 clinical trials involved a limited sample size with a well-selected patient population. Thus, it is necessary to examine if the safety and efficacy results of satralizumab can be translated to patients with NMOSD in a routine clinical setting. This large-scale, ongoing postmarketing surveillance (PMS) study will evaluate the real-world safety and effectiveness of satralizumab over 6 years in patients diagnosed with NMOSD in Japan. In this study, we aimed to present the results of 6-month interim analysis from this ongoing study, to describe PMS safety of satralizumab in the early post-marketing period in Japan.

Methods

Study Design

This study is an ongoing observational, general drug use surveillance (All Patient Surveillance) investigating the safety and effectiveness of satralizumab in patients with NMOSD conducted across 234 centers in Japan (UMIN Clinical Trials Registry, UMIN000041047). The total surveillance period for this study is from August 26, 2020, to February 28, 2027.

The case enrollment period was from August 26, 2020 to July 31, 2021, during which patients with NMOSD scheduled to receive satralizumab were registered using a fax-based central registration system. The planned observation period is from the start date of treatment (index date) with satralizumab to August 31, 2026, (6 years after the launch of satralizumab in Japan) for each patient or until the time of treatment discontinuation in patients who discontinued satralizumab. This interim analysis was conducted when the data lock of the 6-month case report form (CRF) was completed for all patients (the end of observation period). For the patients who discontinued satralizumab during the 6-month follow-up, the date of last observation was defined as the end date.

Thus, the results reported here are of the interim analysis of all patients whose 6-month CRFs and the data clarification of the 6-month CRFs were collected (Fig. 1).Fig. 1 Study design

Study Participants

The study included all patients who used satralizumab during the registration period and whose survey forms were collected prospectively. However, data from all patients who had started using satralizumab before initiation of this surveillance were also included retrospectively. Enrolled patients received satralizumab subcutaneously in routine clinical practice. CRFs were collected from all patients who received satralizumab. The data on the patient demographics and characteristics, treatment with satralizumab, treatment with concomitant therapy (at the index date and at 6 months), relapse, and adverse events were collected.

Outcomes

The primary outcomes assessed at each time point were the proportion of patients with adverse drug reactions (ADRs) which were classified according to the International Conference on Harmonisation Medical Dictionary for Regulatory Activities Japanese edition (ICH MedDRA/J) Version 25.1; the incidence of adverse reactions (person-years method; by safety specification); and the concomitant oral glucocorticoids given as maintenance therapy. The daily oral glucocorticoid doses were recorded as categorical values and mean doses at the start of treatment, 6 months, the end of the observation period, and the end date. The secondary outcomes were time to relapse and relapse rate while being on continuous satralizumab treatment, wherein relapse was defined clinically based on the judgement of the physicians without setting any predetermined criteria. The presence or absence of relapse was recorded. For those who had a relapse, the date of the diagnosis of relapse and the treatment status for relapse were recorded.

Statistical Analysis

All analyses were descriptive. Continuous variables were summarized descriptively using mean (standard deviation [SD]), median (minimum, maximum), or median (interquartile range [IQR]) while categorical data were summarized using frequencies and percentages. No imputation of missing values was performed. Since the data after the discontinuation of satralizumab were not available, the data on oral glucocorticoid reduction were analyzed only for patients who continued satralizumab treatment. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA).

Ethical Consideration

The study was conducted in accordance with relevant regulations in Japan (Ministerial Ordinance on Good Post-Marketing Study Practice [GPSP], Ministry of Health, Labour and Welfare Ordinance Number 38, March 23, 2005).

The study protocol was reviewed and approved by The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) [13] prior to study initiation.

The study did not undergo review by the ethics committee of the participating medical institutions or follow procedures for informed consent as this was not required for PMS studies according to Japanese regulations of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices [14], to ensure the registration of all patients with NMOSD and all patients set out as approval conditions in Japan. The patient data were collected after de-identification.

Results

Study Population and Baseline Characteristics

Overall, 575 patients were registered in the PMS study (Fig. 1). Of the 571 patients whose survey forms were collected, 1 patient was excluded from the safety analysis as no consent was obtained for including the data for publication. Hence, 570 patients were included in the safety analysis set. Of these, 10 patients were excluded from the effectiveness analysis set (7 patients previously treated with satralizumab and 3 patients for whom effectiveness data were not analyzed as the details of presence or absence of relapse were unknown). Thus, 560 patients were included in the effectiveness analysis set.

Baseline characteristics for the safety analysis set are shown in Table 1 and Table S1 in the electronic supplementary material. The mean age was 52.4 years, and majority of patients were aged between 50 and 75 years (53.68%). Most patients were female (91.75%); 2 female patients were pregnant during the treatment period. About half (48.42%) the patients had comorbidities. Most (98.24%) patients were AQP4-IgG positive. Prior treatment with immunosuppressants was given to 61.22% patients and with other biologics to 7.71% patients. Most (99.29%) patients reported clinical signs and symptoms of NMOSD including acute myelitis (73.50%), optic neuritis (62.10%), symptomatic cerebral syndrome with magnetic resonance imaging (MRI) lesions of the brain typical of NMOSD (7.19%), and symptomatic narcolepsy with MRI lesions of the diencephalon (1.75%). NMOSD EDSS score (mean ± SD) was 4.19 ± 2.19. The mean ± SD time from diagnosis to index date was 7.3 ± 6.4 years. There were no relapses in 44.91% patients and ≥ 3 relapses in 8.95% patients over a period of 2 years before the index date. Most (85.96%) patients were receiving concomitant oral glucocorticoids and about half of the patients (48.59%) were receiving immunosuppressants concomitantly (Table 1 and Table S1).Table 1 Patient characteristics (analysis set, N = 570)

Characteristica	Categories	n (%)	
Sex	Femaleb	523 (91.75)	
Age (years)	Mean (SD)	52.4 (14.1)	
Comorbiditiesc	All	276 (48.42)	
Medical historyd	Yes	247 (43.33)	
History of prior treatment (immunosuppressants and other biologics)	Yes	366 (64.21)	
Immunosuppressants	349 (61.22)	
Biologics	44 (7.71)	
Details of NMOSD	
 Specific clinical manifestations of NMOSD (multiple responses)	Optic neuritis	354 (62.10)	
Acute myelitis	419 (73.50)	
An episode of the area postrema syndrome causing hiccups or nausea and vomiting that cannot be explained by other causes	71 (12.45)	
Acute brainstem syndrome	47 (8.24)	
Symptomatic narcolepsy or acute diencephalic syndrome with diencephalic MRI lesions typical of NMOSD	10 (1.75)	
Symptomatic cerebral syndrome with brain MRI lesions typical of NMOSD	41 (7.19)	
 Time from diagnosis to the index date (years)	Mean (SD)	7.3 (6.4)	
 Number of relapses within 2 years	Mean (SD)	0.9 (1.3)	
0	256 (44.91)	
1	157 (27.54)	
≥ 2	141 (24.73)	
Unknown/not specified	16 (2.80)	
 EDSS score	Mean (SD)	4.19 (2.19)	
< 3	167 (29.29)	
≥ 3– < 6	215 (37.71)	
≥ 6	160 (28.07)	
Unknown/not specified	28 (4.91)	
Status of concomitant therapy at the index date (oral glucocorticoids other than glucocorticoid pulse therapy)	Yes	490 (85.96)	
Use of concomitant therapies at index date (immunosuppressants)	Yes	277 (48.59)	
Details of concomitant immunosuppressant therapies	Azathioprine	112 (19.64)	
Tacrolimus hydrate	144 (25.26)	
Cyclosporine	11 (1.92)	
Mycophenolate mofetil	6 (1.05)	
Cyclophosphamide hydrate	0 (0.00)	
Immunosuppressants other	12 (2.10)	
All data are presented as n (%)

EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, NMOSD neuromyelitis optica spectrum disorder, SD standard deviation

an = 570 for all characteristics except time from diagnosis to the start of treatment with satralizumab (years) (n = 551), number of relapses within 2 years (n = 554), and EDSS score (n = 542)

bOf the 523 female subjects, pregnancy occurred in 2 (0.35%), and pregnancy related details of 2 (0.35%) other female subjects were unknown

cComorbidities in all excluding 1 patient with unspecified/details unknown. Comorbidities included ongoing comorbid conditions or diseases (possibly under treatment) at the index date

dMedical history included the conditions or diseases that had been cured at the index date

Treatment Using Satralizumab

The mean ± SD cumulative dose of satralizumab was 918.5 ± 275.5 mg, and median (minimum–maximum) satralizumab treatment duration was 171.0 (1–540) days. Of 570 patients, 84.56% patients were receiving satralizumab treatment, dose interruption occurred in 0.35% patients with 14.91% discontinuations, and status was unknown for 0.17% patients at 6-month follow-up. Reasons for discontinuation were adverse events (6.14%), hospital transfer (5.08%), relapse (1.40%), missed visit (0.52%), and others (1.75%).

Safety

Occurrence of ADRs

In the safety analysis set, for the overall ADRs, 76.22 (66.07–87.48) events/100 person-years occurred in 118 (20.70%) patients (Table 2). Infections were the most common ADRs with 13.58 (9.51–18.80) events/100 person-years in 28 (4.91%) patients (Table 2). The occurrence of serious infections in 570 patients of the safety analysis set by percentage and person-years method based on patient background is shown in Table 3.Table 2 Summary of adverse drug reactions by seriousness (safety analysis set, N = 570)

Event term	Serious	Total	
Number of subjects with events	Incidence % (95% CI)	Events/100 person-years (95% CI)	Number of subjects with events	Incidence % (95% CI)	Events/100 person-years (95% CI)	
Total	29	5.08 (3.43–7.22)	17.35 (12.70–23.15)	118	20.70 (17.44–24.26)	76.22 (66.07–87.48)	
Infections and infestations	18	3.15 (1.88–4.94)	9.05 (5.80–13.47)	28	4.91 (3.28–7.02)	13.58 (9.51–18.80)	
Neoplasms benign, malignant, and unspecified (including cysts and polyps)	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	
Blood and lymphatic system disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	2	0.35 (0.04–1.26)	0.75 (0.09–2.72)	
Immune system disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	3	0.52 (0.10–1.53)	1.13 (0.23–3.30)	
Metabolism and nutrition disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	5	0.87 (0.28–2.03)	1.88 (0.61–4.40)	
Psychiatric disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	
Nervous system disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	10	1.75 (0.84–3.20)	5.28 (2.88–8.86)	
Eye disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	5	0.87 (0.28–2.03)	1.88 (0.61–4.40)	
Cardiac disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	2	0.35 (0.04–1.26)	0.75 (0.09–2.72)	
Vascular disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	2	0.35 (0.04–1.26)	0.75 (0.09–2.72)	
Respiratory, thoracic, and mediastinal disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	
Gastrointestinal disorders	4	0.70 (0.19–1.78)	1.88 (0.61–4.40)	13	2.28 (1.21–3.86)	6.03 (3.45–9.80)	
Hepatobiliary disorders	2	0.35 (0.04–1.26)	1.50 (0.41–3.86)	16	2.80 (1.61–4.51)	6.79 (4.02–10.73)	
Skin and subcutaneous tissue disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	12	2.10 (1.09–3.64)	4.52 (2.33–7.90)	
Musculoskeletal and connective tissue disorders	0	0.00 (0.00–0.64)	0.00 (- – 1.39)	4	0.70 (0.19–1.78)	1.50 (0.41–3.86)	
Renal and urinary disorders	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	1	0.17 (0.00–0.97)	0.37 (0.00–2.10)	
General disorders and administration site conditions	2	0.35 (0.04–1.26)	0.75 (0.09–2.72)	22	3.85 (2.43–5.78)	10.94 (7.32–15.71)	
Investigations	4	0.70 (0.19–1.78)	1.50 (0.41–3.86)	31	5.43 (3.72–7.63)	18.86 (14.00–24.87)	
If the same event (with the same MedDRA SOC and PT code) occurred more than once but if the seriousness levels of the event were different (1 serious and other nonserious event), each event was counted separately but the total number of subjects was considered as 1

Adverse events other than “progression/relapse of NMOSD (including neuromyelitis optica)” were tabulated

CI confidence interval, MedDRA Medical Dictionary for Regulatory Activities, NMOSD neuromyelitis optica spectrum disorder, PT preferred term, SOC system organ class

Table 3 Summary of serious adverse drug reactions (serious infection)

Characteristics	Category	Number of subjects	Subjects with adverse drug reactionsa (incidenceb)	Number of eventsa	Events/100 person-years (95% CI)	
Total		570	18 (3.15)	24	9.05 (5.80–13.47)	
Sex	Male	47	4 (8.51)	4	19.28 (5.25–49.37)	
Female	523	14 (2.67)	20	8.18 (5.00–12.64)	
Pregnancy during treatment	
No	519	14 (2.69)	20	8.23 (5.03–12.71)	
Yes	2	0 (0.00)	0	0.00 (- − 530.45)	
Unknown/not specified	2	0 (0.00)	0	0.00 (- − 508.43)	
Age	< 12	2	0 (0.00)	0	0.00 (- − 397.45)	
≥ 12- < 50	233	3 (1.28)	5	4.63 (1.50–10.81)	
≥ 50- < 75	306	12 (3.92)	16	11.11 (6.35–18.05)	
≥ 75	29	3 (10.34)	3	24.35 (5.02–71.16)	
Comorbiditiesc	No	293	7 (2.38)	11	7.99 (3.98–14.29)	
Yes	276	11 (3.98)	13	10.24 (5.45–17.51)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
Medical historyd	No	320	7 (2.18)	12	8.03 (4.14–14.02)	
Yes	247	11 (4.45)	12	10.60 (5.47–18.52)	
Unknown/not specified	3	0 (0.00)	0	0.00 (- − 151.04)	
History of prior treatment (immunosuppressants)	No	221	8 (3.61)	8	7.90 (3.41–15.57)	
Yes	349	10 (2.86)	16	9.76 (5.58–15.86)	
 Azathioprine	184	7 (3.80)	10	11.48 (5.50–21.11)	
 Tacrolimus hydrate	182	4 (2.19)	7	8.15 (3.27–16.80)	
 Cyclosporine	15	1 (6.66)	3	43.72 (9.01–127.78)	
 Mycophenolate mofetil	7	0 (0.00)	0	0.00 (- − 97.21)	
 Cyclophosphamide hydrate	5	0 (0.00)	0	0.00 (- − 180.36)	
 Immunosuppressants others	19	0 (0.00)	0	0.00 (- − 42.82)	
  Mizoribine	8	0 (0.00)	0	0.00 (- − 104.28)	
  Mitoxantrone hydrochloride	3	0 (0.00)	0	0.00 (- − 249.05)	
  Methotrexate	9	0 (0.00)	0	0.00 (- − 89.94)	
History of prior treatment (biologics)	No	526	17 (3.23)	23	9.38 (5.95–14.08)	
Yes	44	1 (2.27)	1	4.98 (0.12–27.77)	
 Eculizumab	10	0 (0.00)	0	0.00 (- − 84.21)	
 Inebilizumab	0	0 (0.00)	0	–	
 Rituximab	14	0 (0.00)	0	0.00 (- − 55.63)	
 Satralizumab	7	1 (14.28)	1	34.78 (0.88–193.81)	
 Biological preparations-miscellaneous	14	0 (0.00)	0	0.00 (- − 55.56)	
  Interferon beta	1	0 (0.00)	0	0.00 (- − 728.30)	
  Interferon beta-1a (genetical recombination)	1	0 (0.00)	0	0.00 (- − 797.25)	
  Interferon beta-1b (genetical recombination)	1	0 (0.00)	0	0.00 (- − 765.54)	
  Tocilizumab (genetical recombination)	6	0 (0.00)	0	0.00 (- − 118.18)	
  Belimumab (genetical recombination)	1	0 (0.00)	0	0.00 (- − 797.25)	
  Freeze-dried sulfonated human normal immunoglobulin	1	0 (0.00)	0	0.00 (- − 797.25)	
  Human immunoglobulin	2	0 (0.00)	0	0.00 (- − 376.35)	
  Biological preparations-miscellaneous	1	0 (0.00)	0	0.00 (- − 2283.66)	
Details of NMOSD	
 Clinical manifestations of NMOSD	No	3	0 (0.00)	0	0.00 (- − 222.33)	
Yes	566	18 (3.18)	24	9.12 (5.84–13.58)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
 Core clinical characteristics (multiple responses)	Optic neuritis	354	10 (2.82)	15	9.15 (5.12–15.10)	
Acute myelitis	419	15 (3.57)	20	10.25 (6.26–15.83)	
Episode of the area postrema syndrome causing hiccups or nausea and vomiting that cannot be explained by other causes	71	1 (1.40)	1	2.91 (0.07–16.23)	
Acute brainstem syndrome	47	0 (0.00)	0	0.00 (- − 17.51)	
Symptomatic narcolepsy or acute diencephalic syndrome with diencephalic MRI lesions typical of NMOSD	10	0 (0.00)	0	0.00 (- − 70.95)	
Symptomatic cerebral syndrome with brain MRI lesions typical of NMOSD	41	3 (7.31)	3	15.38 (3.17–44.96)	
 Time from diagnosis to the index date with satralizumab (years)	< 2	113	1 (0.88)	1	1.87 (0.04–10.45)	
≥ 2 to < 5	112	2 (1.78)	3	5.72 (1.18–16.73)	
≥ 5 to < 10	152	5 (3.28)	5	7.12 (2.31–16.62)	
≥ 10	174	10 (5.74)	15	18.74 (10.49–30.91)	
Unknown/not specified	19	0 (0.00)	0	0.00 (- − 40.52)	
 Number of relapses within 2 years	0	256	6 (2.34)	8	6.75 (2.91–13.31)	
1	157	3 (1.91)	5	6.67 (2.16–15.58)	
2	90	5 (5.55)	5	12.05 (3.91–28.13)	
≥ 3	51	3 (5.88)	5	21.11 (6.85–49.26)	
Unknown/not specified	16	1 (6.25)	1	15.15 (0.38–84.44)	
 EDSS score	< 3	167	2 (1.19)	2	2.50 (0.30–9.05)	
≥ 3 to < 6	215	7 (3.25)	9	9.11 (4.16–17.29)	
≥ 6	160	8 (5.00)	11	15.18 (7.57–27.16)	
Unknown/not specified	28	1 (3.57)	2	14.28 (1.72–51.58)	
Hepatitis B virus test	No measurement	26	0 (0.00)	0	0.00 (- − 24.58)	
Measured	543	18 (3.31)	24	9.61 (6.16–14.30)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
 Results of measurement (HBs antigen)	Negative	529	17 (3.21)	23	9.42 (5.97–14.13)	
Positive	3	1 (33.33)	1	98.45 (2.49–548.52)	
Unknown/not specified	11	0 (0.00)	0	0.00 (- − 84.15)	
 Results of measurement (HBs antibody)	Negative	423	14 (3.30)	20	10.37 (6.33–16.01)	
Positive	49	2 (4.08)	2	8.65 (1.04–31.26)	
Unknown/not specified	71	2 (2.81)	2	5.95 (0.72–21.50)	
 Results of measurement (HBc antibody)	Negative	426	14 (3.28)	20	10.29 (6.28–15.89)	
Positive	32	2 (6.25)	2	12.50 (1.51–45.16)	
Unknown/not specified	85	2 (2.35)	2	5.10 (0.61–18.42)	
Status of concomitant therapy at the index date (oral glucocorticoids other than glucocorticoid pulse therapy)	No	79	2 (2.53)	3	7.71 (1.58–22.53)	
Yes	490	16 (3.26)	21	9.30 (5.76–14.22)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
Use of concomitant therapies at the index date (immunosuppressants)	No	292	13 (4.45)	14	10.33 (5.65–17.34)	
Yes	277	5 (1.80)	10	7.74 (3.71–14.24)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
Details of concomitant immunosuppressant therapies	Azathioprine	112	2 (1.78)	3	5.78 (1.19–16.91)	
Tacrolimus hydrate	144	2 (1.38)	4	5.82 (1.58–14.91)	
Cyclosporine	11	1 (9.09)	3	60.67 (12.51–177.31)	
Mycophenolate mofetil	6	0 (0.00)	0	0.00 (- − 111.44)	
Cyclophosphamide hydrate	0	0 (-)	0	–	
Immunosuppressants other	12	0 (0.00)	0	0.00 (- − 76.59)	
 Mizoribine	5	0 (0.00)	0	0.00 (- − 206.96)	
 Methotrexate	7	0 (0.00)	0	0.00 (- − 121.60)	
Status of concomitant therapy at the index date (oral glucocorticoids and immunosuppressants other than glucocorticoid pulse therapy both given at the start of the treatment)	No	24	1 (4.16)	1	8.13 (0.20–45.31)	
Yes	222	4 (1.80)	8	7.80 (3.36–15.37)	
Unknown/not specified	1	0 (0.00)	0	0.00 (- − 797.25)	
Other	323	13 (4.02)	15	10.01 (5.60–16.52)	
CI confidence interval, EDSS Expanded Disability Status Scale, HBc hepatitis B core, HBs hepatitis B surface, MRI magnetic resonance imaging, NMOSD neuromyelitis optica spectrum disorder

aAdverse events other than “progression/relapse of NMOSD (including neuromyelitis optica)” were tabulated as adverse reactions

bAll data are represented as n (%)

cComorbidities in all patients excluding 1 with unspecified/details unknown. Comorbidities included ongoing comorbid conditions or diseases (possibly under treatment) at the index date

dMedical history included the conditions or diseases that had been cured at the index date

Serious infections occurred in 3.15% patients, with an event rate of 9.05 (5.80–13.47) events/100 person-years (Table 3). There was a difference in the event rate of serious infections between those aged 12–50 years (4.63 events/100 person-years) and those aged 50–75 years of age (11.11 events/100 person-years), but the rate was considerably higher for those over 75 years of age (24.35 events/100 person-years). Furthermore, the event rate of serious infections was higher in those with longer disease duration (≥ 10 years; 18.74 events/100 person-years) and having ≥ 3 relapses in the last 2 years (21.11 events/100 person-years; Table 3).

Status of Occurrence of Safety Specifications

Safety specifications examined in the survey were infection, neutropenia/leukopenia/agranulocytosis, thrombocytopenia, hypersensitivity, hepatic function disorder, and cardiac disorder. Table S2 in the electronic supplementary material presents data on these ADRs and the time of onset of the first ADR from the index date. The mean ± SD number of days from the index date to onset of the first adverse reaction were 54.6 ± 64.9 (Table S2a). Adverse reactions were more common within first 30 days (Table S2b). Among serious infection events, the most common infections reported were respiratory infections (7/24, 29.17%) and urinary tract infections (6/24, 25.00%; Table 4). Among total infection events, the most common infections reported were skin infections (10/36, 27.78%), followed by urinary tract infections and respiratory infections (both 9/36, 25.00%; Table 4). Table S3 in the electronic supplementary material shows details of all infections reported by percentage and event rate (per 100 person-years); pneumonia and urinary tract infection were the most common infections/serious infections each reported in 3/570 (0.52%) individuals with an event rate of 1.13 per 100 person-years. One drug-related death due to septic shock was reported. Although the invasive pneumococcal infection and concomitant medications (oral glucocorticoid, tacrolimus) were considered as possible causes of septic shock, a causal relationship with satralizumab could not be ruled out.Table 4 Breakdown by sites of infectiona

Type of infections (ADRs)
System organ classb
 Preferred term	Incidence of event, n (%)	
Serious (total number of events = 24)	Total (total number of events = 36)	
Skin infection	5 (20.83)	10 (27.78)	
 Cellulitis	2	2	
 Herpes zoster	0	2	
 Paronychia	0	2	
 Breast abscess	1	1	
 Mastitis	1	1	
 Necrotizing soft tissue infection	1	1	
 Herpes simplex	0	1	
Respiratory infection	7 (29.17)	9 (25.00)	
 Pneumonia	3	3	
 Nasopharyngitis	0	2	
 Pneumonia aspiration	1	1	
 Pulmonary tuberculosis	1	1	
 Pneumococcal infection	1	1	
 Atypical mycobacterial infection	1	1	
Urinary tract infection	6 (25.00)	9 (25.00)	
 Urinary tract infection	3	3	
 Cystitis	1	3	
 Escherichia urinary tract infection	2	2	
 Vulvovaginal candidiasis	0	1	
Sepsis	3 (12.50)	3 (8.33)	
 Escherichia sepsis	1	1	
 Sepsis	1	1	
 Septic shock	1	1	
Gastrointestinal infection	0 (0.00)	2 (5.56)	
 Gastroenteritis	0	1	
 Oral herpes	0	1	
Other infection	3 (12.50)	3 (8.33)	
 Sinusitis	1	1	
 Jaw abscess	1	1	
 Medical device site abscess	1	1	
ADR adverse drug reaction; MedDRA/J Medical Dictionary for Regulatory Activities Japanese edition

aThis table only shows the breakdown by the sites of infection and the values in parentheses are the proportions

bSystem organ class and preferred term of MedDRA/J ver. 25.1

Change in Use of Concomitant Oral Glucocorticoids

The time profiles of daily oral glucocorticoid dose (distribution rate by category) from the index date to end date in the safety analysis set (570 patients) are shown in Table 5 and Figure S1 in the electronic supplementary material. The proportion of patients who received a low daily dose of oral glucocorticoid of < 10 mg/day increased substantially from 206/570 (36.14%) at treatment initiation to 294/496 (59.27%) at 6 months (Table 5 and Figure S1). During the same duration, the mean ± SD oral glucocorticoid dose (mg/day) reduced from 12.28 ± 10.17 at the index date to 8.11 ± 7.30 at 6 months for those who continued satralizumab (Table 5 and Figure S2).Table 5 Oral glucocorticoid dosage from the start of treatment to the end date

Time point	Daily oral glucocorticoid dose (mg/day), n (%)	Dose (mg/day)a	Sample size	
	0	 > 0 to < 5	 ≥ 5 to < 10	 ≥ 10 to < 15	 ≥ 15 to < 20	 ≥ 20 to < 30	 ≥ 30 to < 40	 ≥ 40 to < 50	 ≥ 50	Unknown/not specified	Mean (SD)		
At the index date	79 (13.85)	25 (4.38)	102 (17.89)	136 (23.85)	110 (19.29)	85 (14.91)	20 (3.50)	6 (1.05)	5 (0.87)	2 (0.35)	12.28 (10.17)	570	
At 6 months	83 (16.73)	55 (11.08)	156 (31.45)	112 (22.58)	63 (12.70)	20 (4.03)	1 (0.20)	0 (0.00)	1 (0.20)	5 (1.00)	8.11 (7.30)	496	
End of the observation period	94 (16.49)	61 (10.70)	179 (31.40)	131 (22.98)	75 (13.15)	20 (3.50)	5 (0.87)	1 (0.17)	1 (0.17)	3 (0.52)	8.30 (7.45)	570	
End date	11 (12.94)	7 (8.23)	26 (30.58)	21 (24.70)	13 (15.29)	1 (1.17)	5 (5.88)	1 (1.17)	0 (0.00)	0 (0.00)	9.80 (8.36)	85	
SD standard deviation

aExcluding unspecified patients

Effectiveness

The effectiveness was evaluated in terms of the relapse rate (person-years method) and time to relapse in 560 patients in the effectiveness analysis set.

Relapse Rate

The cumulative number of patients with relapse was 28 patients (relapse rate of 5.00%).

Time to Relapse

The cumulative incidence of freedom from relapse for 555 patients in the effectiveness analysis set is shown in Table 6 and Fig. 2. The Kaplan–Meier cumulative event-free rate (95% confidence interval [CI]) was 94.59% (92.25–96.23) at 6 months (sample size at 6 months; at risk: 464 patients).Table 6 Time to relapse

Time point	Sample size at risk	Cumulative no. of patients with relapse	Cumulative relapse-free rate (95% CI), %	
At the index date	555a	0	100.00 (100.00–100.00)	
6 months	464	28	94.59 (92.25–96.23)	
12 months	9	28	94.59 (92.25–96.23)	
CI confidence interval

aExcluding 5 subjects for whom the total dose of this drug was unknown/not recorded

Fig. 2 Time to relapse using the Kaplan–Meier method

Discussion

The results of this 6-month interim PMS analysis of Japanese patients provided relevant real-world evidence on the safety and effectiveness of satralizumab in Japanese patients with NMOSD. The results suggested that satralizumab treatment was well tolerated and effective in routine clinical practice.

Compared with previous Phase 3 trials of satralizumab monotherapy and combination therapy, the patient population in the present PMS was older (mean 52.4 years vs. 45.3 and 40.8 years in SAkuraStar and SAkuraSky, respectively) [15]. Our results are from an entirely Japanese population providing real-world Japanese data. In the previous pivotal clinical trials, SAkuraStar included no Japanese patients [10] while SAkuraSky included > 70% non-Japanese population [9]. Thus, these data add value to the available evidence demonstrating that the clinical trial data translate well to a real-world Japanese scenario.

ADRs

Infections were the most common events for both total ADRs. as well as serious ADRs in the present PMS. This real-life scenario is consistent with the results of a meta-analysis of 7 randomized-controlled trials and 776 patients with NMOSD using biologics (eculizumab, inebilizumab, rituximab, satralizumab, tocilizumab), wherein severe infections were the most common serious adverse events [16]. The factors that can increase the risk for serious infections in patients with NMOSD during treatment with satralizumab were being male, advanced age (≥ 75 years), longer disease duration (≥ 10 years), and a higher number of relapses in the last 2 years.

Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common. These findings from the PMS data corroborate those observed in the clinical trial setting [10, 15]. Indeed, NMOSD is characterized by neurogenic bladder due to myelitis, resulting in a higher proportion of urinary tract infections [17]. In the present PMS, all 6 patients with serious urinary tract infections had acute myelitis. Contrastingly, the PMS results of tocilizumab, an IL-6 receptor inhibitor for rheumatoid arthritis (RA), show that respiratory infections (41.69%) were the most common type of serious infection [18]. We speculate that this difference in the occurrence of type of infections may result from differences in the disease background (wherein respiratory infections are prevalent in RA) and not due to the drug [17, 19]. The mean EDSS score of 5.0 and above is associated with a higher expression of NMOSD. Patients with such EDSS scores have severe disabilities that impair full daily activities and ability to work a full day without special provisions [20].

Concomitant Oral Glucocorticoid Status

The proportion of patients receiving 10 mg/day or more oral glucocorticoid reduced from ~ 65% at the start of satralizumab treatment to ~ 40% at the end of the 6-month observation period. Even for the 85/570 patients who discontinued satralizumab, the proportion of patients receiving 10 mg/day or more oral glucocorticoid reduced to ~ 48% at the point of discontinuation. The average oral glucocorticoid dosage at the end of the observation period was 8.11 mg/day compared to 12.28 mg/day at the beginning of treatment.

Notably, research suggests that chronic use of glucocorticoids is associated with hypertension, bone fracture, cataract, nausea, vomiting, and metabolic problems like weight gain, hyperglycemia, and type 2 diabetes [21]. Specifically, a daily dose of > 10 mg or a cumulative dose > 700 mg of prednisone can increase the rate of infections [22]. Reducing the maintenance dose of glucocorticoids is often associated with increased risk of relapse. Under these circumstances, a consistent reduction in oral glucocorticoid dosage evident in this real-world PMS is impressive.

Relapse-Free Period

This study reported relapses as a physician-judged clinical relapse, whereas previous clinical trials SAkuraStar and SAkuraSky had protocol-defined relapses adjudicated by the independent clinical end-point committee [9, 10]. Thus, it might be expected that more relapses would be reported here than the protocol-defined relapses in the Phase 3 trials. The relapse rate of 5.0% over 6-month follow-up in the present PMS was comparable or lower than relapse rates previously reported in satralizumab clinical trials (relapse rates in AQP4-IgG seropositive patients in satralizumab groups of 11% and 22% in the SAkuraSky and SAkuraStar trials, respectively, over a median treatment duration of around 48 weeks [9, 10]). Furthermore, in a real-world study using clinical practice data from a Japanese claims database, the relapse rate of NMOSD (defined as prescription of acute-phase treatment) in patients using satralizumab was 4.6%, over a median duration of satralizumab exposure of 197 days [23]. As the relapse rate data in this previous real-world study are almost identical to the relapse rate in the present PMS study, the relapse-free rate of satralizumab in real-world clinical practice may be considered to be approximately 95% over a 6-month follow-up duration.

Limitations

This PMS study is an observational study and, therefore, has certain limitations including potential reporting bias and lack of a control group. The evaluations of risk factors for infections and other ADRs have not been adjusted for other variables. The study may be limited by not using EDSS and MRI as effectiveness indicators. Thus, the relapse data collected in this PMS study are not clearly defined in contrast to a clinical trial. However, it may in fact lead to overestimation of the incidence of relapse. Thus, our PMS may result in underestimation of the effectiveness. Although the duration of observation of this interim analysis of PMS data was relatively short, this PMS will continue data collection over a period of 6 years.

Conclusion

This interim analysis of satralizumab PMS study in Japan offers the first demonstration in a real-world setting that satralizumab is safe, effective, and well tolerated in preventing relapses in 570 patients with NMOSD. No new safety concerns were reported, with ADRs being consistent with the known safety profile of satralizumab. Treatment with satralizumab is possibly associated with a reduction in the concomitant use of immunosuppressive therapies. To understand the long-term effect of satralizumab in Japanese patients with NMOSD, further data will become available over the course of the 6-year surveillance period.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 349 KB)

Acknowledgements

We are grateful to the participants of this study.

Medical Writing, Editorial, and Other Assistance

The authors thank Dr. Padma Singu, PhD, and Dr. Vidula Bhole, MD, MHSc, of MedPro Clinical Research for providing medical writing support for this manuscript which was funded by Chugai Pharmaceutical Co, Ltd.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Conceptualization: Takashi Yamamura, Noriko Isobe, Izumi Kawachi, Chiyoko Nohara, Yusei Miyazaki, Minami Tomita, Takahiko Tsumuraya, Katsuhisa Yamashita, Jin Nakahara, Ichiro Nakashima and Kazuo Fujihara; Methodology, Formal analysis and investigation: Minami Tomita, Takahiko Tsumuraya and Katsuhisa Yamashita; Writing—original draft preparation: All Authors; Writing—review and editing: All Authors.

Funding

This study was funded by Chugai Pharmaceutical Co, Ltd. The journal’s Rapid Service Fee and medical writing and editorial assistance were funded by Chugai Pharmaceutical Co, Ltd.

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available as informed patient consent has not been obtained for this PMS study according to Japanese regulations.

Declarations

Conflicts of Interest

Takashi Yamamura served on scientific advisory boards for Chugai Pharmaceutical, Roche, Biogen Japan, Biogen MA, Novartis Pharma, and Mitsubishi Tanabe Pharma; received research grants from Chugai Pharmaceutical, Novartis Pharma, Biogen Japan, Chiome Bioscience, Sanofi, UCB Japan, and Mebix; and received speaker honoraria from Chugai Pharmaceutical, Biogen Japan, Novartis Pharma, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Miyarisan Pharmaceutical, Alexion Pharmaceuticals, Sumitomo Pharma, and Teijin Pharma. Noriko Isobe received speaker honoraria from Biogen Japan, Novartis Pharma, Alexion Pharmaceuticals, Mitsubishi Tanabe Pharma, UCB Japan, Takeda Pharmaceutical, Teijin Pharma, Argenx, and Chugai Pharmaceutical and research grants from Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Biogen Japan, Sumitomo Pharma, CSL Behring, Eisai, Kyowa Kirin, and Japan Blood Products Organization. Izumi Kawachi received a grant from JSPS KAKENHI (grant no. 20K07899, JP23K06923) and the MHLW Research Program on Rare and Intractable Diseases, Grant/Award (JPMH 20FC1030, JPMH 23FC1009); funding for research, travel, and/or speaker honoraria from Chugai Pharmaceutical, Novartis Pharma, Biogen, Alexion Pharmaceuticals, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Teijin Pharma, Argenx, and Daiichi Sankyo; and is a scientific advisory board member for Chugai Pharmaceutical. Chiyoko Nohara has no competing interests to disclose. Yusei Miyazaki received funding for travel and/or speaker honoraria from Alexion Pharmaceuticals, Biogen Japan, Chugai Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Novartis Pharma, Takeda Pharmaceutical, and Teijin Pharma. Minami Tomita, Takahiko Tsumuraya and Katsuhisa Yamashita are employees of Chugai Pharmaceutical. Jin Nakahara received speaker honoraria from Alexion Pharmaceuticals, Chugai Pharmaceutical, Mitsubishi Tanabe, and Roche; served as a paid consultant for Alexion Pharmaceuticals, Chugai Pharmaceutical, Horizon, Mitsubishi Tanabe Pharma, and Roche; and received research grants from Chugai Pharmaceutical, Mitsubishi Tanabe Pharma, MEXT, and MHLW. Ichiro Nakashima serves on the scientific advisory boards for Chugai Pharmaceutical, Biogen Japan, and Novartis Pharma and receives honoraria for speaking engagements with Chugai Pharmaceutical, Alexion Pharmaceuticals, Biogen Japan, Mitsubishi Tanabe Pharma, and Novartis Pharma. Kazuo Fujihara serves as an advisor on scientific advisory boards for Biogen, Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Roche, Alexion Pharmaceuticals, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco, and Abbvie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe Pharma, Novartis Pharma, Chugai Pharmaceutical, Roche, Alexion Pharmaceuticals, VielaBio, Teijin Pharma, Asahi Kasei Medical, Merck, and Takeda Pharmaceutical; and has received the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labour of Japan.

Ethical Approval

The study was conducted in accordance with relevant regulations in Japan (Ministerial Ordinance on Good Post-Marketing Study Practice (GPSP), Ministry of Health, Labour and Welfare Ordinance Number 38, March 23, 2005). The study protocol was reviewed and approved by The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) prior to study initiation. The study did not undergo review by the ethics committee of the participating medical institutions or follow procedures for informed consent as this was not required for PMS studies according to Japanese regulations of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices to ensure the registration of all patients with NMOSD and all patients set out as approval conditions in Japan. The patient data was collected after de-identification.

Prior Presentation: Part of these data was presented as a poster (P308) at “The ninth annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024” which took place between February 29 and March 2 in West Palm Beach, Florida, USA at the Palm Beach County Convention Center and the Hilton West Palm Beach.
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