N-MOmentum
(2019)Objective
To assess the efficacy and safety of inebilizumab, an anti-CD19 B cell-depleting antibody, in reducing the risk of attacks and disability in neuromyelitis optica spectrum disorder (NMOSD)
Study Summary
• Number needed to treat was 3.73 to prevent one attack over 197 days
• Trial stopped early by data-monitoring committee due to clear efficacy demonstration
Intervention
Inebilizumab 300mg IV on days 1 and 15 (total 600mg) vs placebo
Inclusion Criteria
Adults ≥18 years with NMOSD diagnosis, EDSS ≤8.0, and ≥1 attack requiring rescue therapy in past year or ≥2 attacks in past 2 years
Study Design
Arms: Inebilizumab vs Placebo
Patients per Arm: 174 vs 56
Outcome
• Secondary: Reduced EDSS worsening (OR 0.370), reduced MRI lesions (RR 0.566), reduced hospitalizations (RR 0.286)
• Safety: Similar adverse event rates (72% vs 73%); no deaths during randomized controlled period
Bottom Line
Inebilizumab significantly reduced the risk of NMOSD attacks by 73% compared to placebo (HR 0.272), with benefits also seen in disability worsening, MRI lesion activity, and disease-related hospitalizations. The trial was stopped early due to clear efficacy.
Major Points
- First large randomized controlled trial demonstrating superiority of a B cell-depleting therapy over placebo in NMOSD
- 73% relative risk reduction in NMOSD attacks with inebilizumab (12% vs 39%, p<0.0001)
- Number needed to treat of 3.73 to prevent one attack over 197 days
- Trial stopped early by independent data-monitoring committee due to clear efficacy (conditional power >99%)
- 93% of participants were AQP4-IgG seropositive; similar efficacy in this subgroup (HR 0.227)
- Inebilizumab depleted CD20 B cells to <10% of baseline within 4 weeks
- No significant difference in low-contrast visual acuity despite reduced optic neuritis attacks
- Safety profile similar to placebo during randomized controlled period; two deaths occurred in open-label extension
Study Design
- Study Type
- Phase 2/3 double-blind randomized placebo-controlled trial with open-label extension
- Randomization
- Yes
- Blinding
- Double-blind; participants, investigators, sponsor, adjudication committee, and all clinical staff including EDSS assessors were masked; inebilizumab and placebo were indistinguishable in appearance
- Sample Size
- 230
- Follow-up
- Up to 197 days (randomized controlled period)
- Centers
- 99
- Countries
- Australia, Bulgaria, Canada, Colombia, Czech Republic, Estonia, Germany, Hong Kong, Hungary, Israel, Japan, Mexico, Moldova, New Zealand, Peru, Poland, Russia, Serbia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey, USA
Primary Outcome
Definition: Time (in days) from day 1 to onset of an adjudicated NMOSD attack on or before day 197
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 22/56 (39%) had attack | 21/174 (12%) had attack | 0.272 (0.150-0.496) | <0.0001 |
Limitations & Criticisms
- Did not meet secondary endpoint for low-contrast visual acuity despite reducing optic neuritis attacks, suggesting inebilizumab may not reduce attack severity or facilitate recovery
- Floor effect in placebo group (27% read 0/70 characters on low-contrast chart at baseline) limited ability to detect visual acuity changes
- Only 17 AQP4-IgG seronegative patients enrolled (7%), with only 4 in placebo group - efficacy in seronegative NMOSD could not be determined
- Strict exclusion criteria (comorbidities, lab abnormalities) may limit generalizability to broader NMOSD population
- Relatively small study (230 participants) with short randomized controlled period (6.5 months)
- Study stopped early before reaching target enrollment (252) and target attacks (67)
- One death in open-label phase could not definitively exclude treatment relationship; differential included ADEM, atypical NMOSD attack, and PML
- Long-term safety data beyond 6.5 months not available from randomized controlled period
- 3:1 randomization resulted in small placebo group (n=56) with limited precision
Citation
Lancet 2019; 394: 1352-1363