ASCLEPIOS I & II
(2020)Objective
To compare the efficacy and safety of subcutaneous ofatumumab versus oral teriflunomide in patients with relapsing multiple sclerosis
Study Summary
• Ofatumumab reduced 3-month confirmed disability worsening by 34% (HR 0.66, P=0.002)
• Ofatumumab dramatically reduced Gd+ lesions by 94-97% vs teriflunomide
Intervention
Ofatumumab 20 mg SC every 4 weeks (after loading doses on days 1, 7, 14) vs Teriflunomide 14 mg oral daily
Inclusion Criteria
Age 18-55 years, relapsing-remitting or active secondary progressive MS per 2010 McDonald criteria, EDSS 0-5.5, ≥1 relapse in prior year or ≥2 relapses in prior 2 years or ≥1 Gd+ lesion in prior year, neurologically stable ≥1 month
Study Design
Arms: Ofatumumab 20 mg SC every 4 weeks, Teriflunomide 14 mg oral daily (double-dummy design)
Patients per Arm: 946 ofatumumab, 936 teriflunomide (pooled)
Outcome
• 3-month CDP: 10.9% vs 15.0% (HR 0.66, P=0.002)
• 6-month CDP: 8.1% vs 12.0% (HR 0.68, P=0.01)
• Gd+ lesions: 97% and 94% reduction vs teriflunomide
Bottom Line
In two phase 3 trials, ofatumumab significantly reduced annualized relapse rates by 51-58% compared to teriflunomide, reduced confirmed disability worsening at 3 and 6 months, and dramatically suppressed MRI lesion activity (94-97% fewer Gd+ lesions). Ofatumumab also lowered serum neurofilament light chain levels, though brain volume loss did not differ significantly between treatments.
Major Points
- Ofatumumab reduced ARR by 51% in ASCLEPIOS I (0.11 vs 0.22) and 58% in ASCLEPIOS II (0.10 vs 0.25) compared to teriflunomide
- Pooled analysis: 34% reduction in 3-month confirmed disability worsening (HR 0.66, P=0.002)
- Pooled analysis: 32% reduction in 6-month confirmed disability worsening (HR 0.68, P=0.01)
- No significant difference in 6-month confirmed disability improvement (HR 1.35, P=0.09)
- 97% (trial 1) and 94% (trial 2) fewer Gd-enhancing lesions with ofatumumab
- 82-85% fewer new/enlarging T2 lesions with ofatumumab
- Serum neurofilament light chain was 23-27% lower with ofatumumab at 12-24 months
- No significant difference in brain volume loss between groups
- Injection-related reactions occurred in 20.2% with ofatumumab vs 15.0% with placebo injections
- Serious infections: 2.5% ofatumumab vs 1.8% teriflunomide
- After 4th injection, 74.4% of patients self-administered ofatumumab at home
Study Design
- Study Type
- Two concurrent randomized, double-blind, double-dummy, active-controlled, multicenter phase 3 trials of identical design
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy; patients, centers, investigators, sponsor, and steering committee unaware of treatment assignments; independent data monitoring committee reviewed safety
- Sample Size
- 1882
- Follow-up
- Up to 30 months; median 1.6 years
- Centers
- 385
- Countries
- 37 countries (not individually specified)
Primary Outcome
Definition: Annualized relapse rate (number of confirmed relapses per year)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Active comparator (teriflunomide) is considered a moderate-efficacy DMT; results cannot be extrapolated to comparisons with higher-efficacy therapies
- Median follow-up of only 1.6 years limits assessment of long-term efficacy and safety
- No significant difference in brain volume loss despite marked differences in other outcomes - discrepancy requires further analysis
- Imbalance in appendicitis cases (8 vs 2) unexplained and requires further monitoring
- No head-to-head comparison with other anti-CD20 therapies (ocrelizumab, rituximab)
- Approximately 40% of patients were treatment-naive, limiting generalizability to treatment-experienced populations
- Disability improvement endpoint did not reach significance despite favorable trend
- MRI lesion counts in teriflunomide group higher than previous trials, suggesting possible population or assessment differences
Citation
N Engl J Med 2020;383:546-57