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Safety and Efficacy of Satralizumab Monotherapy in Neuromyelitis Optica Spectrum Disorder: A Randomised, Double-Blind, Multicentre, Placebo-Controlled Phase 3 Trial

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Year of Publication: 2020

Authors: Traboulsee A, Greenberg BM, Bennett JL, ..., Weinshenker BG

Journal: The Lancet Neurology

Citation: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-412. DOI: 10.1016/S1474-4422(20)30078-8

Link: https://pubmed.ncbi.nlm.nih.gov/32333898/

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1901747

Clinical Question

Does satralizumab monotherapy (subcutaneous IL-6 receptor antagonist) reduce the risk of relapse in NMOSD patients not on concomitant immunosuppressive therapy?

Bottom Line

Satralizumab monotherapy reduced relapse risk by 55% overall (HR 0.45, p=0.018), with 30% vs 50% relapsing. The benefit was driven almost entirely by AQP4-IgG seropositive patients (HR 0.26, 74% risk reduction; 22% vs 57% relapsed). In AQP4-seronegative patients, there was no benefit (HR 1.19). Together with SAkuraSky (add-on trial), this confirmed IL-6 receptor inhibition as effective specifically in AQP4+ NMOSD, supporting FDA approval of satralizumab (Enspryng) in 2020.

        Major Points
        Satralizumab reduced relapse risk 55% overall: 30% vs 50% relapsed (HR 0.45, 95% CI 0.23-0.89, p=0.018)
Relapse-free at 48 weeks: 76% vs 62%; at 96 weeks: 72% vs 51%; ARR 0.17 vs 0.41
AQP4+ subgroup: 74% risk reduction (HR 0.26, 95% CI 0.11-0.63); 22% vs 57% relapsed
AQP4- subgroup: NO benefit (HR 1.19, 95% CI 0.30-4.78); numerically more relapses on satralizumab (46%) than placebo (33%)
Secondary endpoints (VAS pain, FACIT fatigue at week 24) did not reach significance, partly due to high missing data (38% in placebo)
Safety comparable: no deaths; SAEs 19% vs 16%; infection rate per 100 patient-years actually lower with satralizumab (99.8 vs 162.6)
Companion to SAkuraSky (add-on): together confirmed IL-6 receptor inhibition as NMOSD treatment mechanism

      

Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: August 5, 2014 to April 2, 2017

Follow-up Duration: Median 92.3 weeks (satralizumab) vs 54.6 weeks (placebo); event-driven design (44 protocol-defined relapses or 1.5 years after last enrollment)

Centers: 44

Countries: United States, Canada, Bulgaria, Croatia, Georgia, Italy, Malaysia, Poland, Romania, South Korea, Taiwan, Turkey, Ukraine

Sample Size: 95

Analysis: Stratified Cox proportional hazards; relapses adjudicated by independent Clinical Endpoint Committee; NCT02073279

Inclusion Criteria

Age 18-74 years
Diagnosis of NMO by 2006 Wingerchuk criteria or AQP4-IgG seropositive NMOSD with LETM or optic neuritis
At least 1 documented NMOSD attack or relapse in the 12 months prior to baseline
EDSS score 6.5 or less at screening
No active immunosuppressive therapy (monotherapy design)
Adequate organ function (liver, renal, hematologic)

Exclusion Criteria

Clinical relapse within 30 days before baseline
Prior IL-6 pathway inhibitor, alemtuzumab, bone marrow transplant, or total body irradiation
Anti-CD20 therapy (rituximab), eculizumab, or anti-BLyS within 6 months of baseline
Anti-CD4, cladribine, cyclophosphamide, or mitoxantrone within 2 years
Investigational drug within 3 months before baseline
Active infection, interstitial lung disease, diverticulitis, or history of PML
Diagnosis other than NMO/NMOSD explaining neurological symptoms

Baseline Characteristics

Characteristic	Satralizumab	Placebo
N	63	32
Mean age +/- SD (years)	45.3 +/- 12.0	40.5 +/- 10.5
Female	46 (73%)	31 (97%)
Male	17 (27%)	1 (3%)
NMO diagnosis	47 (75%)	24 (75%)
NMOSD diagnosis	16 (25%)	8 (25%)
AQP4-IgG seropositive	41 (65%)	23 (72%)
AQP4-IgG seronegative	22 (35%)	9 (28%)
Annualized relapse rate, mean +/- SD	1.4 +/- 0.6	1.5 +/- 0.7
EDSS score, mean +/- SD	3.9 +/- 1.5	3.7 +/- 1.6
Disease duration, mean +/- SD (weeks)	317.8 +/- 340.9	214.7 +/- 201.3
Prior B-cell depleting therapy	8 (13%)	4 (13%)
Prior immunosuppressant	55 (87%)	28 (88%)

Arms

Field	Satralizumab	Control
Intervention	Satralizumab 120 mg SC at weeks 0, 2, 4, then every 4 weeks; no concomitant immunosuppressive therapy	Matching SC placebo on identical schedule; no concomitant immunosuppressive therapy
Duration	Until event-driven endpoint or open-label extension	Until event-driven endpoint or open-label extension

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first protocol-defined relapse (PDR), adjudicated by independent committee; required new/worsening symptoms >24h with EDSS confirmation at 7 days	Primary	Placebo: 16/32 (50%) relapsed	Satralizumab: 19/63 (30%) relapsed	0.45	0.018
	Secondary
	Secondary
	Secondary
	Secondary
	Secondary
Any adverse event	Adverse	24/32 (75%)	58/63 (92%)
Serious adverse events	Adverse	5/32 (16%)	12/63 (19%)
Any infection	Adverse	14/32 (44%)	34/63 (54%)
Serious infections	Adverse	3/32 (9%)	6/63 (10%)
Injection-related reactions	Adverse	5/32 (16%)	8/63 (13%)
Deaths	Adverse	0	0
AE leading to withdrawal	Adverse	1/32 (3%)	1/63 (2%)

Subgroup Analysis

AQP4+ (n=64): satralizumab 22% vs placebo 57% relapsed (HR 0.26, 95% CI 0.11-0.63); AQP4- (n=31): satralizumab 46% vs placebo 33% (HR 1.19, 95% CI 0.30-4.78, no benefit). Sensitivity analysis for unadjudicated clinical relapses: HR 0.74 (95% CI 0.41-1.35, NS)

Criticisms

Marked sex imbalance: satralizumab 73% female vs placebo 97% female (only 1 male in placebo)
Small sample size (95 patients, only 35 PDR events) with wide confidence intervals
No benefit in AQP4-seronegative patients (HR 1.19), raising concerns about use in seronegative NMOSD
Placebo-controlled without active comparator (no head-to-head vs rituximab or other established treatments)
Protocol-defined relapse definition filters out clinical relapses: unadjudicated clinical relapse HR was 0.74 (NS), much attenuated vs PDR HR 0.45
Differential follow-up duration: median 92.3 weeks satralizumab vs 54.6 weeks placebo
Industry-sponsored (Chugai/Roche) with no independent statistical analysis
Baseline age imbalance (45.3 vs 40.5 years) may bias toward lower relapse rate in treatment arm

Funding

Chugai Pharmaceutical Co., Ltd. (Roche Group) -- industry-sponsored

Based on: SAkuraStar (The Lancet Neurology, 2020)

Authors: Traboulsee A, Greenberg BM, Bennett JL, ..., Weinshenker BG

Citation: Traboulsee A et al. Lancet Neurol. 2020;19(5):402-412. DOI: 10.1016/S1474-4422(20)30078-8

Content summarized and formatted by NeuroTrials.ai.

SAkuraStar

(2020)

Objective

To evaluate satralizumab monotherapy (IL-6 receptor antagonist) for relapse prevention in NMOSD

Study Summary

• Satralizumab reduced relapse risk 55%: 30% vs 50% relapsed (HR 0.45, 95% CI 0.23-0.89, p=0.018); relapse-free at 96 weeks: 72% vs 51%
• Benefit driven by AQP4+ subgroup (HR 0.26, 74% risk reduction); NO benefit in AQP4- patients (HR 1.19); comparable safety; companion to SAkuraSky (add-on trial)

Intervention

Satralizumab 120 mg SC at weeks 0, 2, 4, then every 4 weeks vs matching placebo

Inclusion Criteria

Age 18-74, NMO/NMOSD diagnosis, >=1 relapse in prior 12 months, EDSS <=6.5, no concomitant immunosuppressive therapy

Study Design

Arms: Satralizumab 120 mg SC vs Placebo

Patients per Arm: Satralizumab: 63, Placebo: 32

Outcome

• Primary: Protocol-defined relapse: satralizumab 30% vs placebo 50% (HR 0.45, 95% CI 0.23-0.89, p=0.018)
• Relapse-free at 48w: 76% vs 62%; at 96w: 72% vs 51%; ARR: 0.17 vs 0.41
• AQP4+ subgroup: HR 0.26 (95% CI 0.11-0.63), 22% vs 57% relapsed; AQP4- subgroup: HR 1.19 (no benefit)
• Safety comparable; no deaths; SAEs 19% vs 16%

Bottom Line

Major Points

Satralizumab reduced relapse risk 55% overall: 30% vs 50% relapsed (HR 0.45, 95% CI 0.23-0.89, p=0.018)
Relapse-free at 48 weeks: 76% vs 62%; at 96 weeks: 72% vs 51%; ARR 0.17 vs 0.41
AQP4+ subgroup: 74% risk reduction (HR 0.26, 95% CI 0.11-0.63); 22% vs 57% relapsed
AQP4- subgroup: NO benefit (HR 1.19, 95% CI 0.30-4.78); numerically more relapses on satralizumab (46%) than placebo (33%)
Secondary endpoints (VAS pain, FACIT fatigue at week 24) did not reach significance, partly due to high missing data (38% in placebo)
Safety comparable: no deaths; SAEs 19% vs 16%; infection rate per 100 patient-years actually lower with satralizumab (99.8 vs 162.6)
Companion to SAkuraSky (add-on): together confirmed IL-6 receptor inhibition as NMOSD treatment mechanism

Study Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 95
Follow-up: Median 92.3 weeks (satralizumab) vs 54.6 weeks (placebo); event-driven design (44 protocol-defined relapses or 1.5 years after last enrollment)
Centers: 44
Countries: United States, Canada, Bulgaria, Croatia, Georgia, Italy, Malaysia, Poland, Romania, South Korea, Taiwan, Turkey, Ukraine

Primary Outcome

Definition: Time to first protocol-defined relapse (PDR), adjudicated by independent committee; required new/worsening symptoms >24h with EDSS confirmation at 7 days

Control	Intervention	HR/OR	P-value
Placebo: 16/32 (50%) relapsed	Satralizumab: 19/63 (30%) relapsed	0.45 (0.23-0.89)	0.018

Limitations & Criticisms

Marked sex imbalance: satralizumab 73% female vs placebo 97% female (only 1 male in placebo)
Small sample size (95 patients, only 35 PDR events) with wide confidence intervals
No benefit in AQP4-seronegative patients (HR 1.19), raising concerns about use in seronegative NMOSD
Placebo-controlled without active comparator (no head-to-head vs rituximab or other established treatments)
Protocol-defined relapse definition filters out clinical relapses: unadjudicated clinical relapse HR was 0.74 (NS), much attenuated vs PDR HR 0.45
Differential follow-up duration: median 92.3 weeks satralizumab vs 54.6 weeks placebo
Industry-sponsored (Chugai/Roche) with no independent statistical analysis
Baseline age imbalance (45.3 vs 40.5 years) may bias toward lower relapse rate in treatment arm

Citation

Traboulsee A et al. Lancet Neurol. 2020;19(5):402-412. DOI: 10.1016/S1474-4422(20)30078-8

View Original Publication →

SAkuraStar

Safety and Efficacy of Satralizumab Monotherapy in Neuromyelitis Optica Spectrum Disorder: A Randomised, Double-Blind, Multicentre, Placebo-Controlled Phase 3 Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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