PDF: Eculizumab NMO Pilot
(2013)Objective
To investigate the safety and preliminary efficacy of eculizumab—a humanised monoclonal IgG that neutralises complement protein C5—in reducing attack frequency in relapsing AQP4-IgG-positive neuromyelitis optica spectrum disorders
Study Summary
• Median attacks/year decreased from 3 to 0 (p<0.0001); EDSS improved from 4.3 to 3.5 (p=0.0078)
• After discontinuation, 8 attacks in 5 patients within 12 months, supporting active disease suppression rather than sustained remission
Intervention
Eculizumab 600 mg IV weekly x 4 weeks, then 900 mg week 5, then 900 mg IV every 2 weeks for 48 weeks total; meningococcal vaccine 2 weeks before first infusion
Inclusion Criteria
AQP4-IgG seropositive, NMO or NMOSD (2006 criteria), age ≥18 years, ≥2 relapses in prior 6 months or ≥3 in prior 12 months with ≥1 in preceding 6 months, visual acuity ≥20/100 in at least one eye, ambulatory with or without walker
Study Design
Arms: Single arm: Eculizumab IV (n=14); open-label, no control group
Patients per Arm: 14 (all women)
Outcome
• EDSS: Improved from median 4.3 to 3.5 (p=0.0078); no patient worsened
• Hauser ambulation: 5 patients improved (2 by 2 points, 3 by 1 point)
• One meningococcal sepsis (recovered); complement activity suppressed to <1% during treatment
Bottom Line
In this open-label pilot study of 14 patients with highly active AQP4-IgG-positive NMOSD, eculizumab significantly reduced attack frequency (median 3/year to 0/year, p<0.0001) and improved or stabilised disability measures during 12 months of treatment. Twelve patients (86%) were completely relapse-free. The drug was well tolerated except for one case of meningococcal sepsis (which recovered). After eculizumab discontinuation, attacks recurred in 5 patients, suggesting active disease suppression rather than sustained remission. These promising results supported further investigation in randomised controlled trials (which subsequently confirmed efficacy in the PREVENT trial).
Major Points
- First prospective study specifically designed to test complement inhibition in NMOSD based on pathophysiological rationale
- Highly selected population with aggressive disease: median 3 attacks/year pre-enrolment, 6 patients had failed prior immunosuppressants
- 12/14 patients (86%) were completely relapse-free during 12 months of treatment
- Two patients had 'possible' attacks during treatment - both minor and without clear objective findings
- Median EDSS improved from 4.3 to 3.5 (p=0.0078); no patient had worsened disability
- Complete complement inhibition achieved: serum haemolytic activity suppressed from 88.5% to <1% during treatment
- CSF free C5 significantly reduced during treatment (undetectable in 6/11 patients at 3 months)
- AQP4-IgG titres remained unchanged during eculizumab, only decreasing after starting other immunosuppressants at 12 months
- After eculizumab withdrawal, 8 attacks occurred in 5 patients within 12 months (most were major attacks)
- One patient developed meningococcal sepsis despite vaccination - recovered and resumed treatment
- Serum:CSF eculizumab ratio approximately 5000:1, but robust CNS complement inhibition achieved
- This pilot study provided rationale for the subsequent phase 3 PREVENT trial
Study Design
- Study Type
- Open-label, single-arm pilot study (non-randomised)
- Randomization
- No
- Blinding
- None (open-label)
- Sample Size
- 14
- Follow-up
- 12 months treatment + 12 months post-discontinuation follow-up (24 months total)
- Centers
- 2
- Countries
- USA
Primary Outcome
Definition: Co-primary endpoints: (1) Efficacy measured by number of attacks (new worsening of neurological function lasting >24 hours and not attributable to identifiable cause); (2) Safety
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Historical: 39 attacks in year before enrolment (median 3 per patient, range 2-4) | During 12 months eculizumab: 12/14 patients relapse-free; 2 had possible attacks | - | <0.0001 (median attacks/year: 3 pre-treatment vs 0 during treatment) |
Limitations & Criticisms
- Open-label, non-randomised design - cannot control for placebo effect or regression to the mean
- Very small sample size (n=14) limits generalisability and statistical precision
- Highly selected population with aggressive disease - results may not apply to less active NMOSD
- No control group - comparisons with pre-treatment attack rate subject to confounding
- All patients were women - cannot assess efficacy in men
- Single-centre study (two Mayo Clinic sites) - potential selection bias
- Short treatment duration (12 months) - long-term efficacy and safety unknown
- Meningococcal vaccination did not prevent infection in one patient (non-typeable serotype)
- Attacks during eculizumab treatment were 'possible' rather than definite - may overestimate efficacy
- Concomitant steroid use (prednisone) in some patients during follow-up could confound results
- High cost of eculizumab not addressed - important for real-world implementation
- AQP4-IgG titres unchanged during treatment - mechanism may suppress downstream pathology rather than addressing root cause
Citation
Lancet Neurol 2013;12:554-62