PDF: ULTIMATE I & II
(2022)Objective
To evaluate the efficacy and safety of ublituximab, a glycoengineered anti-CD20 monoclonal antibody, compared with teriflunomide in patients with relapsing multiple sclerosis
Study Summary
• ULTIMATE I: ARR 0.08 vs 0.19 (rate ratio 0.41; 95% CI 0.27–0.62; P<0.001)
• ULTIMATE II: ARR 0.09 vs 0.18 (rate ratio 0.51; 95% CI 0.33–0.78; P=0.002)
• T1 Gd-enhancing lesions dramatically reduced: rate ratio 0.03 (ULTIMATE I) and 0.04 (ULTIMATE II); both P<0.001
• T2 lesion accumulation significantly lower with ublituximab in both trials
• No significant difference in 12-week confirmed disability worsening (pooled: 5.2% vs 5.9%; HR 0.84; P=0.51)
• Infusion-related reactions in 47.7% of ublituximab patients; serious infections 5.0% vs 2.9%
Intervention
Ublituximab IV (150 mg day 1 + 450 mg day 15, then 450 mg at weeks 24, 48, 72) + oral placebo daily vs oral teriflunomide 14 mg daily + IV placebo on ublituximab schedule, for 96 weeks
Inclusion Criteria
• Age 18–55 years
• Relapsing multiple sclerosis (2010 revised McDonald criteria)
• ≥2 relapses in prior 2 years, or ≥1 relapse in prior year, or ≥1 Gd-enhancing lesion in prior year
• EDSS 0–5.5
• Neurologic stability ≥30 days before baseline
Study Design
Arms: Array
Patients per Arm: ULTIMATE I: Ublituximab 274, Teriflunomide 275; ULTIMATE II: Ublituximab 272, Teriflunomide 273
Outcome
• Gd-enhancing T1 lesions: rate ratio 0.03 (ULTIMATE I) and 0.04 (ULTIMATE II); P<0.001
• New/enlarging T2 lesions: rate ratio 0.08 (ULTIMATE I) and 0.10 (ULTIMATE II); P<0.001
• 12-wk confirmed disability worsening (pooled): 5.2% vs 5.9%; HR 0.84; P=0.51
• Infusion-related reactions: 47.7% ublituximab
• Serious infections: 5.0% vs 2.9%
Bottom Line
Ublituximab significantly reduced annualized relapse rates vs teriflunomide in two parallel phase 3 trials (rate ratio 0.41 in ULTIMATE I and 0.51 in ULTIMATE II; both P<0.01). MRI outcomes were dramatically better with ublituximab. However, there was no significant reduction in confirmed disability worsening at 12 weeks (pooled HR 0.84; P=0.51). Ublituximab adds another anti-CD20 option to the MS armamentarium alongside ocrelizumab and ofatumumab, with a unique glycoengineered Fc enhancing NK-cell-mediated cytolysis.
Major Points
- ULTIMATE I and II were two identically designed, phase 3, multicenter, double-blind, double-dummy, active-controlled trials conducted in parallel at 104 sites across 10 countries, enrolling 549 and 545 patients respectively.
- Ublituximab is glycoengineered with low fucose content to enhance binding to FcγRIIIa (CD16A), increasing antibody-dependent cellular cytolysis (ADCC) by NK cells while maintaining complement-mediated lysis, distinguishing it from other anti-CD20 antibodies.
- The primary endpoint (ARR at 96 weeks) was significantly lower with ublituximab in both trials: ULTIMATE I 0.08 vs 0.19 (rate ratio 0.41; P<0.001) and ULTIMATE II 0.09 vs 0.18 (rate ratio 0.51; P=0.002).
- MRI outcomes showed dramatic suppression of disease activity: Gd-enhancing T1 lesions reduced by 97% (ULTIMATE I) and 96% (ULTIMATE II); new/enlarging T2 lesions reduced by 92% (ULTIMATE I) and 90% (ULTIMATE II).
- 12-week confirmed disability worsening was not significantly different (pooled: 5.2% ublituximab vs 5.9% teriflunomide; HR 0.84; P=0.51), a limitation shared with many MS trials powered for relapse rather than disability.
- Infusion-related reactions occurred in 47.7% of ublituximab patients, mostly with the first infusion and generally mild-to-moderate. Pre-medication with antihistamine and corticosteroid was administered.
- Serious infections occurred in 5.0% ublituximab vs 2.9% teriflunomide, consistent with the known immunosuppressive effects of B-cell depletion.
- Ublituximab received FDA approval in December 2022 (Briumvi), providing a third anti-CD20 therapy option for relapsing MS alongside ocrelizumab (Ocrevus) and ofatumumab (Kesimpta).
Study Design
- Study Type
- Two identical, phase 3, multicenter, double-blind, double-dummy, active-controlled, randomized trials conducted in parallel; 1:1 randomization; 96-week treatment period; no stratification factors
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 549
Primary Outcome
Definition: ARR at 96 weeks: ULTIMATE I: 0.08 vs 0.19; rate ratio 0.41 (95% CI 0.27–0.62); P<0.001 | ARR at 96 weeks: ULTIMATE II: 0.09 vs 0.18; rate ratio 0.51 (95% CI 0.33–0.78); P=0.002
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - (0.27-0.62) | P<0.001 |
Citation
N Engl J Med 2022;387:704-14