Long-term effectiveness and safety of satralizumab for neuromyelitis optica spectrum disorder in a real-world clinical setting in Japan: A 2.5-year final analysis of a multicenter medical chart review (The SAkuraBeyond Study)

Abstract

Purpose:

To evaluate the real-world effectiveness and safety of satralizumab over 2.5 years using medical data charts of satralizumab-treated Japanese patients with aquaporin-4 immunoglobulin-G seropositive neuromyelitis optica spectrum disorder (AQP4[+] NMOSD).

Major findings:

Overall, 124 patients were evaluated (mean ± standard deviation: age, 51.1 ± 14.0 years; disease duration, 7.0 [6.0] years). At baseline, 72.6%, 16.9%, and 35.5% of patients received oral glucocorticoids (GCs), azathioprine (AZA), and tacrolimus (TAC), respectively. The annualized relapse rate (ARR [95% confidence interval]) decreased from 0.45 (0.34–0.58) within 52 weeks before satralizumab initiation to 0.03 (0.02–0.07) after 130 weeks of satralizumab initiation; relapse-free rate was 91.8% at 130 weeks. Nine patients had nine relapses; seven were re-administered satralizumab after relapse. At 130 weeks, 48.8% of relapse-free patients were not receiving oral GCs (89.3% received ⩽5 mg/day); mean oral GC dose reduced from 10.3 to 2.5 mg/day. In patients receiving AZA and TAC at baseline, 80.0% and 47.1% were no longer receiving AZA and TAC at 130 weeks, respectively. Serious drug reactions occurred in 9.7% of patients (serious infections, 6.5%).

Conclusion:

The real-world relapse-free rate at 2.5 years was 91.8% (ARR = 0.03) in satralizumab-treated patients with AQP4[+] NMOSD, supporting the relapse-preventive effect of satralizumab without new safety concerns.

Registration number: UMIN000050027

Keywords

Japan long-term effectiveness neuromyelitis optica spectrum disorder real-world satralizumab

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition that primarily presents with optic neuritis and transverse myelitis in the form of acute attacks. It encompasses numerous related conditions but primarily presents with optic neuritis and transverse myelitis. The pathogenesis of NMOSD is associated with aquaporin-4 immunoglobulin-G (AQP4-IgG).^1
–3 Acute relapses are treated with methylprednisolone, plasmapheresis, and intravenous immunoglobulin, whereas long-term maintenance therapy is aimed at preventing relapses and associated disability with therapies including oral glucocorticoids (GCs), azathioprine (AZA), methotrexate, mitoxantrone, cyclosporine A, mycophenolate mofetil, cyclophosphamide, and monoclonal antibodies.³

In Japan, patients with NMOSD are commonly treated with oral GCs; however, recent clinical practice guidelines assert the importance of minimizing their use.⁴ Regarding monoclonal antibodies, in Japan, satralizumab was approved (29 June 2020) as a long-term relapse-prevention therapy for children and adults with AQP4-IgG seropositive (AQP4[+]) NMOSD.⁵ This approval in Japan⁵ was based on the results of two phase 3 trials, SAkuraSky⁶ and SAkuraStar.⁷ Reports from Japan evaluating satralizumab for NMOSD from a claims database,⁸ and interim results from a real-world postmarketing surveillance (PMS)⁹ study and SAkuraBeyond¹⁰ have been published. The claims analysis showed a reduction in relapses and medication use despite a short observation period. The PMS study confirmed safety and GC dose reduction, though relapse data were limited.⁹ The SAkuraBeyond interim analysis presented data on relapse-free rates and medication reduction at 6 months, but the analysis period was short.¹⁰ However, long-term real-world evidence on the nature of NMOSD relapse in patients treated with satralizumab is limited.

SAkuraBeyond was designed to evaluate, in detail, relapse over 2.5 years among satralizumab-treated patients with AQP4[+] NMOSD in a real-world clinical setting in Japan. The 6-month interim analysis¹⁰ showed a 96.6% relapse-free rate after satralizumab treatment and was associated with dose reductions of concomitant oral GC and immunosuppressants over 6 months. Herein, we present the final effectiveness and safety results over a 2.5-year follow-up period.

Methods

Study design

SAkuraBeyond (UMIN000050027) is a multicenter (25 sites; Japan), real-world, observational study that evaluated the effectiveness and safety of satralizumab in patients with AQP4[+] NMOSD using a medical chart review. Data were evaluated 52 weeks before and 130 weeks after initiating satralizumab. The study-enrollment period was 6 months after the first patient enrollment date (Supplementary Figure 1).

The study protocol was approved (8 December 2022) by MINS as a representative Institutional Review Board review for other centers (MINS-REC-220234) and conducted in accordance with the Declaration of Helsinki, “Ethical Guidelines for Medical and Biological Research Involving Human Subjects” (Notice No. 1 [2021]; Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labour and Welfare; and Ministry of Economy, Trade and Industry [23 March 2021]),¹¹ and the “Act on the Protection of Personal Information” (27 May 2016).

Patients

Patients aged ⩾ 7 years who were initiated on satralizumab (on/after 26 August 2020; marketing date) as the most appropriate medical treatment for a recorded diagnosis of AQP4[+] NMOSD were enrolled. Written informed consent with a choice to opt out was obtained from all patients or their legal representatives. Where possible, written assent was obtained through an informed assent form for patients between ⩾7 and <16 years of age. Patients with a history of treatment with interleukin-6 receptor inhibitors other than satralizumab (e.g. tocilizumab) were excluded.

Treatment

Based on the Japanese package insert,⁵ the expected satralizumab exposure is presented in Supplementary Table 1.

Endpoints

The primary endpoints were annualized relapse rate (ARR) at week 130 and within 52 weeks before satralizumab initiation; proportion of relapse-free patients at 130 weeks after satralizumab initiation; and time to first relapse after satralizumab initiation. Other details of relapse including history of relapse within 52 weeks prior to satralizumab initiation are presented in Supplementary Table 1.

The secondary endpoints were changes in the daily dose of oral GC after satralizumab initiation during the 130-week follow-up among relapse-free patients and the number and proportion of patients in whom the dose was reduced. Similar changes in oral GC dose over 130 weeks were evaluated among relapse-free patients categorized into those treated with and without concomitant immunosuppressant therapy (IST) at baseline. Changes in oral GC dose over 130 weeks were also evaluated in patients with and without concomitant oral GC dose at baseline and in the overall population (primary population 1). The target patient populations are described in Supplementary Table 1.

Other endpoints included changes in the daily dose of ISTs, AZA (in mg/day at baseline, commonly used in Japan),⁸ and tacrolimus (TAC, in mg at baseline) during 130 weeks among relapse-free patients after satralizumab initiation and the number and proportion of patients in whom IST dose was reduced.

Exploratory endpoints included the sequence of oral GC versus IST dose reductions, dose-reduction status of pain medications, continuation rate of satralizumab, and safety assessments over 130 weeks.

Assessments

Per protocol, data were electronically captured in case report forms by the investigators from the medical chart of each patient. Relapse was defined as the onset of new or worsening of current neurological symptoms that persisted for ⩾24 hours, in the absence of confounding clinical factors, and requiring acute-phase treatments. Relapse symptoms that occurred within 30 days were considered to be part of the same relapse. Complete definitions of relapse, date and time to first relapse after satralizumab initiation, time to dose reduction of concomitant medications, satralizumab-continuation rate, and prednisolone-equivalent dose of oral GC are presented in Supplementary Table 1. Relapse severity was assessed using the modified Rankin Scale (mRS). The daily doses of oral GCs and ISTs were evaluated every 13 weeks until week 130. Pain medication data were collected every 12 weeks until week 130 and reported until week 120. Safety assessments included data on adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs (MedDRA/J Version 27.0).

Statistical analysis

The target sample size was based on estimates from the SAkuraSky study.⁶ The ARR (95% confidence interval [CI]) was calculated using the person-year method. Time to first relapse was calculated using the Kaplan–Meier method and presented as the median (95% CI; Brookmeyer and Crowley’s method).¹² Safety is reported as the incidence and incident/incidence rate/100 patient-years (PY) of AEs, SAEs, ADRs, and serious ADRs. Further details and a list of additional analyses are provided in Supplementary Table 1. Analyses were performed using SAS version ⩾ 9.4.

Results

Patient disposition

Of the 125 enrolled patients initiated on satralizumab, 124 were evaluated (primary population 1), of whom 92 continued satralizumab treatment for 130 weeks (Figure 1); reasons for discontinuation due to AEs are presented in Supplementary Table 2. Patient analysis sets and their definitions are shown in Supplementary Figure 2 and Supplementary Table 1, respectively.

Figure 1.

Patient disposition.

Baseline patient characteristics

The mean ± standard deviation (SD) (range) age of the 124 satralizumab-initiated patients was 51.1 ± 14.0 (16–87) years; almost all were female (n = 116 [93.5%]). The mean ± SD disease duration was 7.0 ± 6.0 years, with 1, 2, and 3 relapses reported in 34, 9, and 1 patient, respectively, in the past 52 weeks. The median (min, max) Expanded Disability Status Scale (EDSS) score (n = 116) was 3.0 (0.0, 8.5), and 13 patients (10.5%) were previously treated with biologics. A total of 46 (37.1%) patients had comorbidities, 90 (72.6%) were receiving a concomitant mean ± SD oral GC dose of 14.3 ± 9.3 mg/day, 92 (74.2%) patients presented with acute myelitis, and 69 (55.6%) presented with optic neuritis (Supplementary Table 3).

Among 44 patients with relapse (including the first relapse) within 52 weeks prior to satralizumab initiation, the mean ± SD duration from the last relapse to the administration of satralizumab was 96.2 ± 102.6 days.

Relapse

Based on per-protocol relapse criteria, nine relapses occurred in nine patients over 130 weeks after satralizumab initiation (relapse free, n = 115), with an ARR [95% CI] of 0.03 [0.02–0.07], which was lower than that observed within 52 weeks before satralizumab initiation (0.45 [0.34–0.58]; 55 relapses in 44 patients). At week 130 after satralizumab initiation, the overall relapse-free rate [95% CI] was 91.8% [84.7–95.6] (Figure 2). Kaplan–Meier analysis limited to the 92 patients who continued treatment at week 130 showed a relapse-free rate [95% CI] of 92.4% [84.7–96.3] (Supplementary Figure 3).

Figure 2.

Kaplan–Meier curve showing relapse-free rate, time to first relapse, and number of relapsed patients at 130 weeks after the initiation of satralizumab.

In nine patients who relapsed, five were hospitalized, and the sites of relapse were the optic nerve (n = 4), spinal cord (n = 4), and unknown (n = 1). Among them, four patients had an mRS score ⩽ 3, three had a score ⩾4, and two had an unknown score at relapse. Among two of the three patients with severe relapse, the mRS score returned to the pre-relapse score (12 weeks before relapse→at relapse→12 weeks after relapse: 0→4→0; 5→5→5; 3→5→3) (Table 1).

Table 1.

Details of nine patients with protocol-defined relapse.

Registration number	Age	Sex	Disease duration (years)	Relapse 52 weeks prior to SAT administration	Number of days of relapse after SAT	Acute-phase treatment (number of courses)	Site of relapse/major issues	Site of relapse by MRI	Hospitalization	Modified Rankin scale (inferred from medical records)			Narrowing of visual field			After relapse biotherapy	Concomitant medications at relapse
Registration number	Age	Sex	Disease duration (years)	Relapse 52 weeks prior to SAT administration	Number of days of relapse after SAT	Acute-phase treatment (number of courses)	Site of relapse/major issues	Site of relapse by MRI	Hospitalization	Relapse 12 weeks before	At relapse (worst)	Relapse week 12	Relapse 12 weeks before	At relapse (worst)	Relapse week 12	After relapse biotherapy	Concomitant medications at relapse
1	50s	Female	5	Yes	3	IVMP (1)	Optic nerve/ Vision disorder	None	Yes	2	3	2	None	None	None	SAT	AZA 50 mg
2	40s	Female	2	None	71	IVMP (1), (IVIg^a)	Spinal cord/ Vision disorder, Pain, Sensory disturbance	Yes	None	1	2	2	None	None	None	RTX	GC 10 mg/day
3	30s	Female	5	None	95	IVMP (2)	Spinal cord/ Pain, Sensory disturbance, Motor paralysis	None	None	1	2	1	None	None	None	SAT	GC 8 mg/day
4	40s	Female	6	None	111	IVMP (1), IVIg	Optic nerve/Vision disorder	None (not implemented)	None	Unknown	Unknown	Unknown	None	Yes: central scotoma	None	SAT	GC 20 mg/day
5	40s	Female	9	None	358	IVMP (2)	Spinal cord/Pain, Sensory disturbance	Yes	Yes	0	4	0	Yes: central scotoma	Yes: central scotoma	Yes: central scotoma	None	GC 15 mg/day
6	40s	Female	17	Yes	341	IVMP (2)	Optic nerve/Vision disorder, Pain	None	Yes	5 ^b	5 ^b	5 ^b	Unknown	Unknown	Unknown	SAT	GC 20 mg/day
7	50s	Female	13	Yes	469	IVMP (1), PP (3)	Unknown/Pain, Motor paralysis	None (not implemented)	Yes	3	5	3	None	None	None	SAT	None
8	40s	Female	10	None	613	IVMP (1)	Optic nerve/Vision disorder, Pain	None (not implemented)	None	Unknown	Unknown	Unknown	None	None	None	SAT, INE	None
9	50s	Female	2	Yes	714	IVMP (1)	Spinal cord/Motor paralysis	None	Yes	2	3	2	None	None	None	SAT	None

AZA, azathioprine; GC, glucocorticoid; INE, inebilizumab; IVIg, intravenous immunoglobulin therapy; IVMP, intravenous methylprednisolone pulse therapy; MRI, magnetic resonance imaging; PP, plasma purification therapy; RTX, rituximab; SAT, satralizumab.

Venilon was administered for 3 days (did not meet the dosing period specified in the drug package insert [5 days] as it was completed in 3 days due to weekends).

Documented in medical records.

Among the four patients without severe symptoms of relapse, the mRS score did not return to the pre-relapse score in one patient (12 weeks before relapse→at relapse→12 weeks after relapse: 2→3→2; 1→2→2; 1→2→1; 2→3→2).

Seven of the nine patients continued to receive satralizumab treatment after relapse. In the patient in whom satralizumab was discontinued, relapse symptoms were observed 15 days after four doses of satralizumab, and the patient was switched to rituximab (Table 1). In one patient without an mRS score, relapse occurred after discontinuing oral GC (Supplementary Figure 4e). Among the nine patients with relapse, no patient-related risk factors associated with relapse were identified when the relapse rate was categorized by patient background factors (Supplementary Figure 5). Thirteen relapses were documented in 10 patients over 130 weeks, determined by physician judgment, and some of these did not meet the relapse definition of this study.

Relapse rate by prior biologic treatment is presented in Supplementary Figure 6, and the most common reasons for initiating satralizumab among patients with a history of prior biologic therapy are presented in Supplementary Table 4.

Changes in the daily dose of oral GC over 130 weeks among relapse-free patients

After 130 weeks of satralizumab treatment, the mean ± SD oral GC dose reduced from 10.3 ± 10.4 mg/day (n = 114) at baseline to 2.5 ± 4.1 mg/day (n = 84) (Figure 3(a)). When categorized into patients treated with and without concomitant ISTs at baseline, the mean ± SD GC dose decreased from 13.2 ± 12.2 mg/day to 1.6 ± 1.8 mg/day in those without ISTs and 8.0 ± 8.1 mg/day to 3.1 ± 5.1 mg/day in those with ISTs (Figure 3(a)).

Figure 3.

Changes in the daily oral GC dose in relapse-free patients over 130 weeks of satralizumab treatment (a) overall, with IST at baseline group, and without IST at baseline group and (b) in patients with oral GC at baseline: overall, with IST at baseline group, and without IST at baseline group. Percentage of patients with oral GC dose reductions stratified by dose increments (c) of the population in panel (a) and (d) of the population in panel (b). For visual clarity, only positive error bars are plotted for standard deviation.

Oral GC was discontinued in 48.8% (41/84) of patients after satralizumab treatment at week 130 compared with 28.1% (32/114) of patients who were not on oral GCs at baseline. An oral GC dose of ⩽ 5 mg/day was achieved in 89.3% (75/84; > 0-⩽ 5 mg/day, 40.5% [34/84]) of patients after satralizumab treatment at week 130, compared with 36.8% (42/114; > 0-⩽ 5 mg/day, 8.8% [10/114]) at baseline (Figure 3(c)).

In patients treated with oral GC at baseline, the mean ± SD oral GC dose reduced from 14.3 ± 9.6 mg/day (n = 82) at baseline to 3.3 ± 4.6 mg/day (n = 61) at week 130 (Figure 3(b)). Among relapse-free patients treated with oral GC at baseline (n = 82), oral GC treatment was discontinued in 36.1% (22/61) of patients after satralizumab treatment at week 130, and an oral GC dose of ⩽ 5 mg/day was achieved in 85.2% (52/61; > 0-⩽ 5 mg/day, 49.2% [30/61]) of patients after satralizumab treatment at week 130, compared with 12.2% (10/82) of patients at baseline (Figure 3(d)).

Among relapse-free patients treated with oral GC at baseline (n = 82), those with baseline oral GC > 0-⩽ 5 mg/day (n = 10) discontinued oral GC by week 65, and among those with oral GC > 5-⩽ 10 mg/day (n = 23) and > 10-⩽ 15 mg/day (n = 30) at baseline, approximately 50.0% discontinued oral GC by week 130 (Supplementary Figure 7). Changes in the daily dose of oral GC over 130 weeks in the overall population is presented in Supplementary Figure 8.

Changes in the daily dose of ISTs over 130 weeks among relapse-free patients

After 130 weeks of satralizumab treatment, the mean ± SD AZA dose reduced from 83.8 ± 36.5 mg/day (n = 20) at baseline to 8.3 ± 18.1 mg/day (n = 15) (Figure 4(a)). Twenty patients were treated with AZA at baseline, and AZA treatment was discontinued in 12/15 patients (80.0%) after 130 weeks of satralizumab treatment (Figure 4(c)).

Figure 4.

Changes in daily dose of ISTs (overall, with oral GC at baseline group, and without oral GC at baseline group) over 130 weeks of satralizumab treatment: (a) AZA and (b) TAC. Proportion of patients with daily dose reductions of (c) AZA and (d) TAC over 130 weeks of satralizumab treatment. For visual clarity, only positive error bars are plotted for standard deviation.

The mean ± SD TAC dose reduced from 3.1 ± 0.6 mg (n = 43) at baseline to 0.6 ± 1.0 mg (n = 34) after 130 weeks of satralizumab treatment (Figure 4(b)). Forty-three patients were treated with TAC at baseline; TAC was discontinued in 16/34 patients (47.1%) after 130 weeks of satralizumab treatment (Figure 4(d)).

Sequence of GC versus IST dose reduction over 130 weeks

Among patients receiving concomitant ISTs with GCs at baseline, the dose of oral GCs was reduced before the dose of ISTs in a higher proportion of patients than the dose of ISTs before the dose of oral GCs, over 130 weeks (Supplementary Table 5). Moreover, the proportion of patients receiving satralizumab monotherapy (without oral GC and IST) increased to 32.6% at week 130 compared with 7.3% at baseline (Supplementary Table 6).

Changes in the daily dose of pain medications over 130 weeks of follow-up

Among patients receiving concomitant pain medications at baseline (n = 48), 6 and 13 patients discontinued and reduced their dose over 120 weeks, respectively (Supplementary Table 5).

Satralizumab treatment-continuation rate

Kaplan–Meier analysis revealed the satralizumab-continuation rate [95% CI] to be 83.7% [75.6, 89.3] at 130 weeks (Supplementary Figure 9).

Safety

A total of 30 SAEs occurred in 22 patients over 130 weeks. The incidence of SAEs was 17.7% (22/124), and the incident rate/100PY [95% CI] of SAEs was 11.5/100PY (8.0, 16.4). A total of 16 serious ADRs occurred in 12 patients over 130 weeks, and the incidence of serious ADRs was 9.7% (12/124) with an incident rate/100PY [95% CI] of serious ADRs of 6.1/100PY [3.7, 10.0] (Supplementary Table 7). Among the serious ADRs, 10 events of serious infections occurred in 8 patients; the incidence of serious infections was 6.5% (8/124), and the incident rate/100PY [95% CI] of serious infections was 3.8/100PY [2.1, 7.1] (Supplementary Table 7). Among the eight patients with serious infections, no patient-related risk factors associated with serious infections were identified when serious infection rates were categorized by patient background factors (Supplementary Figure 10).

One death due to myocardial infarction was reported, and its causal relationship with satralizumab was ruled out. In a 16-year-old patient, two non-SAEs (common cold and liver dysfunction) occurred, and treatment with satralizumab was continued without interruption.

AEs in monotherapy and combination therapy are included in Supplementary Table 8. AEs occurred in 14 patients (11.3%) on monotherapy and 42 patients (33.9%) on combination immunotherapy.

Discussion

This study provides valuable insights into the nature of NMOSD relapse and long-term (2.5 years) real-world outcome of relapse in patients with AQP4[+] NMOSD treated with satralizumab in Japan.

In this study, the ARR [95% CI] at 2.5 years among satralizumab-treated patients with AQP4[+] NMOSD was 0.03 [0.02, 0.07], and the relapse-free rate was 91.8%. The ARR 52 weeks prior to satralizumab initiation was 0.45, decreasing to 0.07 at 6 months after initiation, and further reduced to 0.03 at 2.5 years, suggesting a trend of decreasing ARR with the long-term administration of satralizumab.¹⁰ This trend aligns with long-term efficacy data from the clinical trials of satralizumab (120 mg every four weeks [Q4W] ± IST),¹³ SAkuraSky⁶ (relapse-/severe relapse–free rate: week 96, 85%/100%; week 192, 71%/91%), and SAkuraStar⁷ (week 96, 77%/92%; week 192, 73%/90%), indicating that real-world clinical practice demonstrates similar outcomes. Considering that the pre-administration ARR was 1.5 in SAkuraSky⁶ and 1.4 in SAkuraStar,⁷ the pre-administration ARR in this study (0.45) was lower than that reported in clinical trials. However, as the pre-administration ARR in other real-world evidence studies was also 0.74,¹⁴ it is possible that biological agents such as satralizumab are being introduced to patients with lower ARR than to those enrolled in clinical trials in real-world settings in Japan. In addition, baseline patient stability, rather than treatment effect alone, may partly explain these favorable results. Results should be interpreted cautiously as a relapse occurred on day 3 of treatment, potentially before the full effect of satralizumab was established. Another relapse occurred after oral GC discontinuation after tapering, suggesting that patients’ condition/responses should be carefully monitored while reducing the dose and after discontinuation.

The use of oral GCs in autoimmune diseases is well supported and is part of several current treatment guidelines. In addition, clinical practice guidelines for multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease 2023 in Japan state that when oral GCs are used concomitantly, the minimum necessary dose should be administered.¹⁵ Nevertheless, concerns regarding their long-term use because of their potential for clinically important AEs, particularly in diseases requiring extended treatment duration and high doses, cannot be overlooked.^16,17

Regarding oral GC dose reduction, physicians can expect substantial reductions from baseline to 2.5 years of follow-up among all patients including relapse-free patients. Oral GC was withdrawn in 48.8% of patients after satralizumab treatment at 2.5 years compared with 28.1% with no GCs at baseline. Our results show that physicians can expect to maintain a low maintenance dose of oral GCs (⩽5 mg/day) in most patients (89.3%) at 2.5 years compared with 36.8% at baseline.

Among relapse-free patients treated with oral GCs at baseline, physicians can expect patients receiving oral GCs > 0-⩽ 5 mg/day at baseline to discontinue them by week 65. Among those receiving higher oral GC doses (> 5-⩽ 10 mg/day and > 10-⩽ 15 mg/day) at baseline, approximately 50.0% are expected to discontinue them by 2.5 years. In comparison to the interim analysis results at 6 months,¹⁰ physicians can expect a further decrease in the oral GC dose at 2.5 years in all subgroups evaluated in this study. Overall, the results may have been influenced by a cautious approach to oral GC dose reduction, as this study included patients immediately after the launch of satralizumab in real-world clinical practice. In addition, long-term monitoring of side-effects and disease symptoms will be required for patients in whom GCs are withdrawn.

In patients receiving AZA > 0 mg/day at baseline, AZA could be withdrawn in most (80.0%) patients at the 2.5-year follow-up. In patients receiving TAC > 0 mg at baseline, TAC could be withdrawn in 47.1% of patients at the 2.5-year follow-up. In comparison with the interim analysis results at 6 months,¹⁰ physicians can expect a further decrease in the IST dose at 2.5 years in all subgroups evaluated in this study.

Regarding which concomitant medication to reduce first, we observed that physicians tended to reduce the dose of oral GCs before the dose of AZA or TAC over 2.5 years. In addition, this study did not include a standardized protocol for tapering IST; therefore, dose reductions were likely made at the discretion of individual physicians and patients. The most common reasons cited for initiating satralizumab were to reduce oral GC or IST doses. These findings suggest that the goal of reducing concomitant medication use was achieved to some extent with satralizumab based on physicians’ and patients’ discretion.

Based on the observation that the relapse rate was numerically lower in SAkuraSky⁶ (added to stable immunosuppressant treatment) than in SAkuraStar,⁷ and considering the clinical need to prevent relapses until the full therapeutic effect of satralizumab effect is achieved, we believe that the findings reflect a cautious tapering rather than an immediate discontinuation of concomitant medications.

Most patients could continue satralizumab treatment for 2.5 years (continuation rate: 83.7%). The primary reason for discontinuation was AEs. Over 2.5 years, 12 of 124 patients discontinued due to AEs, and 10 of these were considered ADRs. These findings suggest that satralizumab has high long-term tolerability. The rates of AEs, SAEs, and ADRs were consistent with those reported previously in open-label extension studies¹³ and an interim analysis of a PMS study,⁹ suggesting similar rates in this real-world setting. Among the 12 patients with 16 serious ADRs in this study, 10 events of serious infections occurred in 8 patients (6.5%); no patient-related risk factors were associated with serious infections when the incidence rate was categorized by patient background factors. This limitation in identifying risk factors can be attributed to the restricted number of patients available for analysis.

Severe infections are the most common serious ADRs associated with the use of biologics including eculizumab, inebilizumab, rituximab, and satralizumab.¹⁸ One death was reported, and its causal relationship with satralizumab was ruled out; no new safety signals were reported. While combination immunotherapy tends to have a higher incidence of AEs compared with monotherapy, the increased AE rates in the combination therapy group should be considered in the context of potential treatment selection bias.

This single-arm observational study has inherent limitations, including selection bias, impact of dropouts, and censored data. In addition, the definition of relapse did not include magnetic resonance imaging (MRI) evaluation, as the study employed criteria based on indicators considered highly reliable and likely to be available in a chart review. Therefore, the possibility that some cases were identified as relapses in this study without an MRI evaluation should be acknowledged. Nevertheless, it represents valuable real-world outcomes.

Conclusion

In real-world clinical settings, 91.8% of patients with AQP4[+] NMOSD remained relapse-free for 130 weeks following treatment initiation with satralizumab (ARR = 0.03). This finding reinforces the relapse-prevention effect of satralizumab, as demonstrated in phase 3 trials. In addition, oral GCs were stopped in 36.1% of patients who received GCs at baseline. By 2.5 years of satralizumab treatment, 80.0% and 47.1% of patients on AZA and TAC discontinued the medication, respectively. No new safety issues were identified. Overall, most patients remained relapse-free on satralizumab. Concomitant medications such as GCs and ISTs could be reduced or discontinued, indicating satralizumab as a suitable treatment option to target inflammation in patients with AQP4[+] NMOSD.

Supplemental Material

sj-docx-1-msj-10.1177_13524585261418536 – Supplemental material for Long-term effectiveness and safety of satralizumab for neuromyelitis optica spectrum disorder in a real-world clinical setting in Japan: A 2.5-year final analysis of a multicenter medical chart review (The SAkuraBeyond Study)

Supplemental material, sj-docx-1-msj-10.1177_13524585261418536 for Long-term effectiveness and safety of satralizumab for neuromyelitis optica spectrum disorder in a real-world clinical setting in Japan: A 2.5-year final analysis of a multicenter medical chart review (The SAkuraBeyond Study) by Kazuo Fujihara, Noriko Isobe, Katsuichi Miyamoto, Masaaki Niino, Jin Nakahara, Satoshi Hattori, Masami Tanaka, Masayuki Tahara, Akio Suzumura, Kenzo Sakurai, Nobuaki Yoshikura, Kazutaka Shiomi, Hirofumi Ochi, Eiichiro Nagata, Kazushi Deguchi, Yuji Tomizawa, Katsuhisa Yamashita, Tadashi Nagatsuka, Hiroki Adachi and Ichiro Nakashima in Multiple Sclerosis Journal

Footnotes

Acknowledgements

The authors would like to thank the patients and acknowledge all investigators and study sites (Supplementary Table 9).

Author Contributions

Kazuo Fujihara: Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing.

Noriko Isobe: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Katsuichi Miyamoto: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Masaaki Niino: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Jin Nakahara: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Satoshi Hattori: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Masami Tanaka: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Masayuki Tahara: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Akio Suzumura: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Kenzo Sakurai: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Nobuaki Yoshikura: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Kazutaka Shiomi: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Hirofumi Ochi: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Eiichiro Nagata: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Kazushi Deguchi: Writing – review & editing, Writing – original draft, Resources, Investigation, Conceptualization.

Yuji Tomizawa: Writing – review & editing,Writing – original draft, Resources, Investigation, Conceptualization.

Katsuhisa Yamashita: Conceptualization, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing.

Tadashi Nagatsuka: Conceptualization, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing.

Hiroki Adachi: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing.

Ichiro Nakashima: Conceptualization, Investigation, Methodology, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.F. serves as an advisor to the scientific advisory boards for Biogen, Mitsubishi Tanabe Pharma, Novartis, Chugai Pharmaceutical, Roche, Alexion Pharmaceuticals, Viela Bio/Horizon Therapeutics, UCB, Merck, Japan Tobacco, and AbbVie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe Pharma, Novartis, Chugai Pharmaceutical, Roche, Alexion Pharmaceuticals, Viela Bio, Teijin, Asahi Kasei, Merck, and Takeda Pharmaceuticals; and has received grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan. N.I. received speaker honoraria from Biogen Japan, Novartis, Alexion Pharmaceuticals, Chugai Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceuticals, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Kyowa Kirin, EA Pharma, FP Pharmaceutical, Mitsubishi Tanabe Pharma, UCB Japan, Japan Blood Product Organization, Argenx, Sanofi, Amgen, and Alnylam. She also received research grants for her department from Sumitomo Pharma, Chugai Pharmaceutical, and Biogen. K.M. received funding for speaker honoraria from Alexion Pharmaceuticals, Biogen, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Novartis, and Teijin. M.N. received funding for travel and/or speaker honoraria from Biogen, Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, Alexion Pharmaceuticals, Takeda Pharmaceuticals, and Novartis. J.N. reports personal fees from AbbVie, Alexion Pharma GK, Asahi Kasei Medical, Biogen, Bristol Myers Squibb, Chugai Pharmaceutical, CSL Behring, Daiichi Sankyo, Eisai, Kyorin, Mitsubishi Tanabe Pharma, Novartis, Otsuka, Roche, Takeda Pharmaceuticals, and Teijin; research scholarships from AbbVie, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, EA Pharma, Eisai, JB, Mitsubishi Tanabe Pharma, Otsuka, Shionogi, Sumitomo Pharma, Teijin, and Tsumura; and grants from the Ministry of Education, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, Biogen, and Chugai Pharmaceutical. S.H. has received speaker honoraria from Chugai Pharmaceutical. M. Tanaka has received honoraria for lectures from Chugai Pharmaceutical, Biogen Japan, Mitsubishi Tanabe Pharma, and Alexion Pharma. M. Tahara has received the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan (20FC1009) for the present manuscript since the initial planning of the work; consulting fees from Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, and Alexion Pharmaceuticals; and speaker honoraria from Chugai Pharmaceutical, Alexion Pharmaceuticals, Mitsubishi Tanabe Pharma, and Zenyaku Holdings. A.S. and N.Y. have no conflicts of interest to declare. K. Sakurai has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Alexion Pharmaceuticals, UCB Japan, Chugai Pharmaceutical, and Mitsubishi Tanabe Pharma. K. Shiomi has received funding for the present manuscript to his institution since the initial planning of the work; JSPS KAKENHI Grant Number JP24K10536 as payment made to his institution; and funding for travel and/or speaker honoraria from Chugai Pharmaceutical. H.O. has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Biogen Japan, Novartis Pharma, Mitsubishi Tanabe Pharma, Alexion Pharmaceuticals, Chugai Pharmaceutical, Nihon Pharmaceutical, Argenx, Daiichi Sankyo, UCB Japan, and Takeda Pharmaceuticals. E.N. has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Alexion Pharmaceuticals, Eli Lilly Japan, Daiichi Sankyo, and Otsuka Pharmaceuticals. K.D. has received consulting fees from Eisai, Alexion Pharmaceuticals, Daiichi Sankyo, Chugai Pharmaceutical, AbbVie, Argenx, Kyowa Kirin, Mitsubishi Tanabe Pharma, Novartis, Kowa, UCB, and Sumitomo Pharma. Y.T. has received honoraria for lectures related to satralizumab from Chugai Pharmaceutical. K.Y., T.N., and H.A. are employees of Chugai Pharmaceutical. I.N. serves on the scientific advisory boards for Chugai Pharmaceutical, Biogen Japan, and Novartis, and receives honoraria for speaking engagements with Chugai Pharmaceutical, Alexion Pharmaceuticals, Biogen Japan, Mitsubishi Tanabe Pharma, and Novartis.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Chugai Pharmaceutical Co., Ltd. We thank the study management team members at Chugai Pharmaceutical Co., Ltd. and the EPS Corporation for study management and statistical analysis, which were funded by Chugai Pharmaceutical Co., Ltd. Medical writing support was provided by Annirudha Chillar, MD, PhD, of Cactus Life Sciences (part of Cactus Communications), and was funded by Chugai Pharmaceutical Co., Ltd.

Ethical Considerations

The study protocol was approved (8 December 2022) by MINS as a representative Institutional Review Board review for other centers (MINS-REC-220234) and conducted in accordance with the Declaration of Helsinki, “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (Notice No. 1 of 2021; Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labour and Welfare; and Ministry of Economy, Trade and Industry; 23 March 2022), and the “Act on the Protection of Personal Information” (27 May 2016).

Consent to Participate

Written informed consent with a choice to opt out of the study was obtained from all patients or their legal representatives. Where possible, written assent for participation in the study was obtained using an informed assent form for patients between ⩾7 and <16 years of age.

Consent for Publication

All patients or their legal representatives were required to provide written informed consent for publication.

ORCID iDs

Kazuo Fujihara

Noriko Isobe

Katsuichi Miyamoto

Masaaki Niino

Jin Nakahara

Masami Tanaka

Masayuki Tahara

Kenzo Sakurai

Nobuaki Yoshikura

Hirofumi Ochi

Eiichiro Nagata

Katsuhisa Yamashita

Tadashi Nagatsuka

Ichiro Nakashima

Data Availability Statement

Data are available from the corresponding author upon reasonable request.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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