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SAkuraMoon

Long-Term Efficacy and Safety of Satralizumab in Patients With Neuromyelitis Optica Spectrum Disorder From the SAkuraMoon Open-Label Extension Study

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Year of Publication: 2025

Authors: Jeffrey L. Bennett, Kazuo Fujihara, Albert Saiz, ..., Takashi Yamamura

Journal: Neurology: Neuroimmunology & Neuroinflammation

Citation: Neurol Neuroimmunol Neuroinflamm 2025;12:e200450

Link: https://doi.org/10.1212/NXI.0000000000200450

PDF: https://www.researchgate.net/publication...mxpY2F0aW9uIn19

Clinical Question

What is the long-term safety and efficacy of satralizumab in patients with NMOSD who completed the pivotal SAkuraSky and SAkuraStar phase 3 trials?

Bottom Line

Satralizumab demonstrates sustained safety and efficacy over a median 6.9 years of treatment. At Week 456 (8.8 years), 67% of AQP4-IgG+ patients remained relapse-free with an adjusted ARR of 0.07. The safety profile remained favorable with no deaths and no increase in infection rates over time.

        Major Points
        Median satralizumab exposure of 6.9 years (range 0-10 years), with 48% receiving treatment for ≥7 years and 10% reaching 10 years
67% of AQP4-IgG+ patients remained iPDR-free at Week 456 (8.8 years)
89% of patients remained free from severe iPDRs (≥2 point EDSS increase) at Week 456
82% of patients did not experience sustained EDSS score worsening at Week 456
Overall adjusted ARR of 0.07 (95% CI 0.05-0.10), reduced from baseline ARR of 1.14
ARR remained consistently ≤0.20 throughout follow-up; below 0.10 after year 3
AE rates in OST period (299.4/100 PYs) were lower than double-blind periods
Infection rates (87.5/100 PYs) and serious infection rates (2.4/100 PYs) did not increase over time
No deaths, no meningococcal infections, no viral/bacterial meningitis/encephalitis reported
64% of AQP4-IgG+ patients did not require rescue therapy during the OST period

      

Design

Study Type: Phase 3b, multicenter, single-arm, open-label, rollover extension study

Randomization:

Blinding: Open-label; no blinding; iPDRs defined by prespecified objective criteria to mitigate bias

Enrollment Period: Rollover from SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279) parent studies

Follow-up Duration: Median 6.9 years (range 0-10 years); maximum 11 years for 1 patient; treatment period up to 3 years from first patient enrollment in SAkuraMoon

Centers: 53

Countries: Japan, USA, Canada, France, Germany, UK, Italy, Spain, Australia, South Korea, Poland, Turkey, Ukraine, Russia, Czech Republic, Croatia, Taiwan

Sample Size: 166

Analysis: Safety: descriptive statistics, AE rates per 100 patient-years with 95% CI using Poisson distribution; Efficacy: Kaplan-Meier analysis for time-to-event endpoints; Adjusted ARR using generalized estimating equation Poisson regression with repeated measurements, adjusted by study identifier and exposure year; SAS version 9.4

Inclusion Criteria

Completed double-blind and open-label extension periods of SAkuraSky or SAkuraStar
AQP4-IgG+ NMOSD patients from parent studies
AQP4-IgG- patients could enroll if investigator considered continued satralizumab treatment beneficial

Exclusion Criteria

Did not complete parent study OLE periods
Specific exclusion criteria detailed in supplement (eAppendix 1)

Baseline Characteristics

Characteristic	All Patients (n=166)	AQP4-IgG+ Patients (n=111)
Age - Mean (SD; range)	42.7 (13.3; 13-73) years	43.2 (13.5; 13-73) years
Sex - Female	86%	90%
Geographic region - Asia	25%	32%
Geographic region - Europe/other	40%	32%
Geographic region - North America	34%	36%
Baseline ARR - Mean (SD)	1.18 (0.55)	1.14 (0.53)
Baseline EDSS - Mean (SD)	3.80 (1.57)	3.96 (1.62)
Previous treatments for relapse prevention	49%
Previous systemic corticosteroids	24%
Previous azathioprine	15%
Previous mycophenolate mofetil	5%

Arms

Field	Satralizumab ± IST
Intervention	Satralizumab 120mg subcutaneous injection every 4 weeks; as monotherapy or with background IST (azathioprine max 3mg/kg/d, mycophenolate mofetil max 3000mg/d, or oral corticosteroids max 15mg/d prednisolone equivalent). Patients <18 years could continue OCS combined with AZA or MMF.
Duration	Up to 3 years from first patient enrollment; median exposure 6.9 years from first dose in parent studies

Outcomes

Outcome	Type	Control	Intervention
Long-term safety of satralizumab: incidence and rates of AEs, serious AEs, infections, serious infections per 100 patient-years	Primary	N/A (single-arm; compared to DB periods of parent studies)	AEs: 299.4 (95% CI 288.8-310.2)/100 PYs; Serious AEs: 8.1 (95% CI 6.4-10.0)/100 PYs; Infections: 87.5 (95% CI 81.9-93.5)/100 PYs; Serious infections: 2.4 (95% CI 1.5-3.5)/100 PYs
Time to first iPDR (investigator-reported protocol-defined relapse) - proportion iPDR-free	Secondary	N/A	Week 96: 80% (95% CI 72-87%); Week 192: 73% (95% CI 63-81%); Week 456: 67% (95% CI 56-76%)
Time to first severe iPDR (≥2 point EDSS increase) - proportion severe iPDR-free	Secondary	N/A	Week 96: 95% (95% CI 89-98%); Week 192: 91% (95% CI 83-95%); Week 456: 89% (95% CI 80-94%)
Time to sustained EDSS score worsening (≥24 weeks) - proportion without worsening	Secondary	N/A	Week 96: 94% (95% CI 87-97%); Week 192: 86% (95% CI 77-92%); Week 456: 82% (95% CI 72-89%)
Adjusted annualized relapse rate (ARR) - overall	Secondary	N/A (baseline ARR 1.14)	0.07 (95% CI 0.05-0.10)
Adjusted ARR by year	Secondary	N/A	Y1: 0.17 (0.10-0.28); Y2: 0.10 (0.05-0.19); Y3: 0.04 (0.01-0.14); Y4: 0.08 (0.02-0.26); Y5: 0.05 (0.01-0.15); Y6-10: consistently <0.10 (unadjusted)
Patients receiving rescue therapy for acute relapse	Secondary	N/A	40/111 (36%); 64% did not require rescue therapy
Number of iPDRs	Secondary	N/A	48 iPDRs in 32 patients (29%)
Number of severe iPDRs	Secondary	N/A	20 severe iPDRs in 10 patients
Any AE	Adverse	SAkuraStar PBO: 495.2/100 PYs; SAkuraSky PBO+IST: 514.3/100 PYs	162/166 (97.6%); 299.4 (95% CI 288.8-310.2)/100 PYs
Serious AEs	Adverse	SAkuraStar PBO: 14.8/100 PYs; SAkuraSky PBO+IST: 20.2/100 PYs	44/166 (26.5%); 8.1 (95% CI 6.4-10.0)/100 PYs
Severe AEs	Adverse		46/166 (27.7%); 9.6 (95% CI 7.8-11.7)/100 PYs
Fatal AEs	Adverse	0	0
AEs leading to discontinuation	Adverse		9/166 (5.4%); 1.0 (95% CI 0.5-1.8)/100 PYs; 10 events total
Infections	Adverse	SAkuraStar PBO: 162.6/100 PYs; SAkuraSky PBO+IST: 149.6/100 PYs	132/166 (79.5%); 87.5 (95% CI 81.9-93.5)/100 PYs
Serious infections	Adverse	SAkuraStar PBO: 9.9/100 PYs; SAkuraSky PBO+IST: 5.0/100 PYs	19/166 (11.4%); 2.4 (95% CI 1.5-3.5)/100 PYs
Injection-related reactions	Adverse		24/166 (14.5%); 5.6 (95% CI 4.3-7.3)/100 PYs; all nonserious, mostly mild/moderate
Potential opportunistic infections	Adverse		24 patients; 8.6 (95% CI 6.9-10.6)/100 PYs; oral herpes (5%), herpes zoster (4%)
Nasopharyngitis	Adverse		29%
Upper respiratory tract infection	Adverse		28%
Headache	Adverse		27%
Urinary tract infection	Adverse		25%
Arthralgia	Adverse		21%
COVID-19	Adverse		19%
Neoplasms	Adverse		21/166 (12.7%); 2.3 (95% CI 1.4-3.4)/100 PYs; mainly benign (uterine leiomyoma 4%)
Neutropenia	Adverse		26 events; 2.6 (95% CI 1.7-3.8)/100 PYs; mostly grade 2, transient
Meningococcal infection	Adverse		0

Subgroup Analysis

Results from parent studies showed patients originally randomized to satralizumab were more likely to remain relapse-free and less likely to experience multiple relapses compared to those originally on placebo; protective effect sustained with long-term treatment. Efficacy analyses limited to AQP4-IgG+ population (n=111) per approved indication. AQP4-IgG- patients (n=55) included in safety analyses only.

Criticisms

Open-label design introduces potential bias; mitigated by prespecified objective iPDR criteria
No external control arm in rollover study limits ability to attribute outcomes solely to treatment
Selection bias: only 66% (119/180) of parent study patients rolled over to SAkuraMoon, potentially selecting more SAT-responsive patients
Low patient exposure beyond Week 456 (year 9) limits interpretation of very long-term results
Efficacy not reported for AQP4-IgG- population due to small numbers and heterogeneity
High rate of treatment-emergent anti-drug antibodies (60% positive at cutoff), though no clear impact on efficacy or safety observed
No reliable neutralizing anti-SAT antibody assays available
Parent studies had different designs (SAkuraSky: SAT+IST vs PBO+IST; SAkuraStar: SAT monotherapy vs PBO), complicating integrated interpretation
Class IV evidence only due to open-label, single-arm design
Cannot directly compare long-term outcomes with other approved NMOSD therapies

Funding

F. Hoffmann-La Roche

Based on: SAkuraMoon (Neurology: Neuroimmunology & Neuroinflammation, 2025)

Authors: Jeffrey L. Bennett, Kazuo Fujihara, Albert Saiz, ..., Takashi Yamamura

Citation: Neurol Neuroimmunol Neuroinflamm 2025;12:e200450

Content summarized and formatted by NeuroTrials.ai.

SAkuraMoon

(2025)

Objective

To evaluate the long-term safety and efficacy of satralizumab (IL-6 receptor inhibitor) in patients with neuromyelitis optica spectrum disorder (NMOSD) from the SAkuraSky and SAkuraStar parent studies

Study Summary

• Over median 6.9 years of treatment, 67% of AQP4-IgG+ patients remained relapse-free at Week 456 (8.8 years)
• Overall adjusted ARR was 0.07, substantially reduced from baseline ARR of 1.14
• Safety profile was favorable with no deaths; AE rates decreased over time compared to double-blind periods

Intervention

Satralizumab 120mg SC every 4 weeks ± immunosuppressive therapy (no comparator arm - open-label extension)

Inclusion Criteria

Patients with NMOSD who completed double-blind and open-label extension periods of SAkuraSky or SAkuraStar trials

Study Design

Arms: Satralizumab ± IST (single-arm)

Patients per Arm: 166 (safety); 111 AQP4-IgG+ (efficacy)

Outcome

• 67% iPDR-free at Week 456; 89% severe iPDR-free; 82% without sustained EDSS worsening
• Adjusted ARR consistently ≤0.20, below 0.10 after year 3
• Infection rate 87.5/100 PYs (comparable to DB periods); serious infections 2.4/100 PYs

Bottom Line

Major Points

Median satralizumab exposure of 6.9 years (range 0-10 years), with 48% receiving treatment for ≥7 years and 10% reaching 10 years
67% of AQP4-IgG+ patients remained iPDR-free at Week 456 (8.8 years)
89% of patients remained free from severe iPDRs (≥2 point EDSS increase) at Week 456
82% of patients did not experience sustained EDSS score worsening at Week 456
Overall adjusted ARR of 0.07 (95% CI 0.05-0.10), reduced from baseline ARR of 1.14
ARR remained consistently ≤0.20 throughout follow-up; below 0.10 after year 3
AE rates in OST period (299.4/100 PYs) were lower than double-blind periods
Infection rates (87.5/100 PYs) and serious infection rates (2.4/100 PYs) did not increase over time
No deaths, no meningococcal infections, no viral/bacterial meningitis/encephalitis reported
64% of AQP4-IgG+ patients did not require rescue therapy during the OST period

Study Design

Study Type: Phase 3b, multicenter, single-arm, open-label, rollover extension study
Randomization: No
Blinding: Open-label; no blinding; iPDRs defined by prespecified objective criteria to mitigate bias
Sample Size: 166
Follow-up: Median 6.9 years (range 0-10 years); maximum 11 years for 1 patient; treatment period up to 3 years from first patient enrollment in SAkuraMoon
Centers: 53
Countries: Japan, USA, Canada, France, Germany, UK, Italy, Spain, Australia, South Korea, Poland, Turkey, Ukraine, Russia, Czech Republic, Croatia, Taiwan

Primary Outcome

Definition: Long-term safety of satralizumab: incidence and rates of AEs, serious AEs, infections, serious infections per 100 patient-years

Control	Intervention	HR/OR	P-value
N/A (single-arm; compared to DB periods of parent studies)	AEs: 299.4 (95% CI 288.8-310.2)/100 PYs; Serious AEs: 8.1 (95% CI 6.4-10.0)/100 PYs; Infections: 87.5 (95% CI 81.9-93.5)/100 PYs; Serious infections: 2.4 (95% CI 1.5-3.5)/100 PYs	-

Limitations & Criticisms

Open-label design introduces potential bias; mitigated by prespecified objective iPDR criteria
No external control arm in rollover study limits ability to attribute outcomes solely to treatment
Selection bias: only 66% (119/180) of parent study patients rolled over to SAkuraMoon, potentially selecting more SAT-responsive patients
Low patient exposure beyond Week 456 (year 9) limits interpretation of very long-term results
Efficacy not reported for AQP4-IgG- population due to small numbers and heterogeneity
High rate of treatment-emergent anti-drug antibodies (60% positive at cutoff), though no clear impact on efficacy or safety observed
No reliable neutralizing anti-SAT antibody assays available
Parent studies had different designs (SAkuraSky: SAT+IST vs PBO+IST; SAkuraStar: SAT monotherapy vs PBO), complicating integrated interpretation
Class IV evidence only due to open-label, single-arm design
Cannot directly compare long-term outcomes with other approved NMOSD therapies

Citation

Neurol Neuroimmunol Neuroinflamm 2025;12:e200450

View Original Publication →

SAkuraMoon

Long-Term Efficacy and Safety of Satralizumab in Patients With Neuromyelitis Optica Spectrum Disorder From the SAkuraMoon Open-Label Extension Study

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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