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CHAMPION-NMOSD

Ravulizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder

Year of Publication: 2023

Authors: Pittock SJ, Barnett M, Bennett JL, ..., Kim HJ

Journal: Annals of Neurology

Citation: Pittock SJ, Barnett M, Bennett JL, et al. Ravulizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder. Ann Neurol. 2023;93(6):1053-1068. doi:10.1002/ana.26626

Link: https://doi.org/10.1002/ana.26626

Clinical Question

In adults with AQP4-IgG-positive neuromyelitis optica spectrum disorder, does ravulizumab (a long-acting terminal complement C5 inhibitor) reduce the risk of relapse compared with external placebo control from the PREVENT trial?

Bottom Line

Ravulizumab (long-acting C5 complement inhibitor, Ultomiris) significantly reduced relapse risk in AQP4-IgG+ NMOSD: 0/58 (0%) adjudicated relapses on ravulizumab vs 20/47 (42.6%) on the external PREVENT placebo control (HR 0.014, 95% CI 0.000–0.103; 98.6% relapse risk reduction, 95% CI 89.7–100.0%, p<0.0001). Phase 3, open-label, externally controlled trial (NCT04201262); primary treatment period ended per protocol trigger (50 weeks reached with no ravulizumab relapses). Published Annals of Neurology 2023 (Pittock et al.). 58 ravulizumab patients; median follow-up 73.5 weeks. Q8-week dosing (vs eculizumab Q2-week).

        Major Points
        Zero adjudicated on-trial relapses in ravulizumab (0/58 over 84.0 patient-years) vs 20 adjudicated relapses in PREVENT placebo (20/47 over 46.9 patient-years); log-rank p<0.0001.
HR 0.014 (95% CI 0.000–0.103), estimated using Firth penalized likelihood since 0 events in ravulizumab arm; 98.6% relapse risk reduction (95% CI 89.7–100.0%).
Time to first adjudicated on-trial relapse was the primary endpoint.
Phase 3, open-label, externally placebo-controlled trial: 58 patients received ravulizumab; the PREVENT placebo group (n=47) served as an EXTERNAL comparator — no concurrent randomization to placebo.
Ravulizumab: long-acting anti-C5 complement antibody (4 amino acid substitutions vs eculizumab enable FcRn recycling). Weight-based loading dose then Q8-week maintenance IV.
Advantage over eculizumab: Q8-week dosing vs Q2-week — major convenience improvement.
HAI worsening significantly lower: 2/58 (3.4%) ravulizumab vs 11/47 (23.4%) placebo, OR 0.155, p=0.0228.
EDSS worsening numerically lower (6/58, 10.3% vs 11/47, 23.4%; OR 0.332, p=0.0588) but not formally tested per hierarchical testing after EQ-5D endpoint failed.
AEs (>10%): COVID-19 (24.1%), headache (24.1%), back pain (12.1%), arthralgia (10.3%), UTI (10.3%). 2 meningococcal infections despite vaccination — both recovered fully with treatment.
Published Annals of Neurology 2023 (Pittock et al.). Alexion, AstraZeneca Rare Disease sponsored.
NMOSD is C5b-9/MAC-mediated astrocytopathy — complement inhibition targets core pathophysiology.

      

Design

Study Type: Phase 3, open-label, externally placebo-controlled, multicenter interventional trial

Blinding: Open-label (no blinding of patients, treating physicians, or RAC)

Sample Size: 58 patients received ravulizumab; 47 patients from PREVENT placebo group used as external comparator

Centers: 36 sites across 11 countries

Follow-up Duration: Median 73.5 weeks (range 11.0–117.7) for ravulizumab; 36.0 weeks (range 1.9–117.7) for PREVENT placebo (capped at 117.7 weeks)

Inclusion Criteria

Age ≥18 years
Diagnosis of AQP4+ NMOSD per 2015 international consensus diagnostic criteria, with serum anti-AQP4 antibody confirmed by cell-based assay at an accredited laboratory
History of ≥1 relapse in the 12 months before screening
EDSS score ≤7
Patients on stable-dose immunosuppressive therapy (IST) for relapse prevention were eligible

Exclusion Criteria

Previous or current treatment with a complement inhibitor
Evidence of active systemic infection
History of Neisseria meningitidis infection
Previous participation in the PREVENT trial
Mitoxantrone or rituximab during the 3 months before screening
Intravenous immunoglobulin during the 3 weeks before screening

Arms

Field	Ravulizumab	Control
Intervention	Ravulizumab IV — weight-based loading dose (2,400–3,000 mg) on day 1, maintenance (3,000–3,600 mg) on day 15, then every 8 weeks	External placebo control from the PREVENT trial (matched patient-level data)
Duration	Open-label treatment period	Matched follow-up (capped at 117.7 weeks)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first adjudicated on-trial relapse in AQP4-IgG-positive NMOSD.	Primary	20/47 patients had adjudicated relapses (during 46.9 patient-years; PREVENT external placebo)	0/58 patients had adjudicated relapses (during 84.0 patient-years; ravulizumab)	HR 0.014 (95% CI 0.000–0.103); relapse risk reduction 98.6% (95% CI 89.7–100.0%)	<0.0001 (log-rank)
	Secondary	Prespecified conservative comparator ARR = 0.25	Adjusted ARR 0.000 (95% upper CL 0.044)	N/A (Poisson regression; ad hoc exact test used given 0 relapses)	<0.0001
	Secondary	11/47 (23.4%)	2/58 (3.4%)	OR 0.155 (logistic regression)	0.0228
	Secondary	−0.043 ± 0.2115	0.005 ± 0.1522	N/A (ANCOVA of ranked change)	0.0567 (not significant; broke hierarchical testing)
	Secondary	0.6 ± 16.4	2.6 ± 14.1	N/A (ANCOVA of ranked change)	N/A (not tested per hierarchical rules)
	Secondary	11/47 (23.4%)	6/58 (10.3%)	OR 0.332 (logistic regression)	0.0588 (nominal; N/A per hierarchical testing after EQ-5D missed)
Any treatment-emergent AE (total)	Adverse		328 TEAEs in 53/58 patients (91.4%) — ravulizumab arm
Treatment-emergent serious adverse events	Adverse		8 TESAEs in 8/58 patients (13.8%) — ravulizumab arm
COVID-19	Adverse		14 (24.1%)
Headache	Adverse	10 (21.3%)	14 (24.1%)
Back pain	Adverse	6 (12.8%)	7 (12.1%)
Arthralgia	Adverse		6 (10.3%)
Urinary tract infection	Adverse	9 (19.1%)	6 (10.3%)
Meningococcal infection	Adverse		2 (3.4%) — both recovered fully with treatment

Subgroup Analysis

Monotherapy subgroup (no concomitant IST, n=30 ravulizumab vs n=13 placebo): HR 0.021 (95% CI 0.000–0.176), p<0.0001; 97.9% relative risk reduction. Prior rituximab in year before screening (n=20 vs n=17): HR 0.063 (95% CI 0.000–0.562), p=0.0078. No prior rituximab (n=38 vs n=30): HR 0.019 (95% CI 0.000–0.142), p<0.0001. Interaction p=0.6774.

Funding

Alexion, AstraZeneca Rare Disease

Based on: CHAMPION-NMOSD (Annals of Neurology, 2023)