Table 3.
Summary of clinical and MRI efficacy in phase III clinical trials.
| Rituximab | Rituximab | Ocrelizumab | Ofatumumab | Ublituximab | |||||
|---|---|---|---|---|---|---|---|---|---|
|
Trial
Reference |
OLYMPUS Hawker et al., 2009 |
RIFUND-MS Svenningsson et al., 2022 |
OPERA I Hauser et al., 2017 |
OPERA II Hauser et al., 2017 |
ORATORIO Montalban et al., 2017 |
ASCLEPIOS I Hauser et al., 2020 |
ASCLEPIOS II Hauser et al., 2020 |
ULTIMATE I Steinman et al., 2022 |
ULTIMATE II Steinman et al., 2022 |
| MS form | PPMS | RRMS / CIS | RMS | RMS | PPMS | RMS | RMS | RMS | RMS |
| Trial design | Multicenter, randomized, double-blind, placebo-controlled trial | Multicenter, randomized rater-blinded, active-comparator, | Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group trial | Multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group trial | Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial | Multicenter, randomized, double-blind, double-dummy, active-controlled trial | Multicenter, randomized, double-blind, double-dummy, active-controlled trial | Multicenter, randomized, double-bind, double-dummy, active-controlled trial | Multicenter, randomized, double-bind, double-dummy, active-controlled trial |
| Treatment groups | 2 x 1000 mg intravenous infusions of rituximab in the interval of 2 weeks throughout the whole study Placebo |
Single 1000 mg intravenous infusion of rituximab, followed by 500 mg every 6 months Dimethyl fumarate 240 mg twice daily |
Ocrelizumab 600 mg per 24 weeks Interferon beta-1a 44 µg three times per week |
Ocrelizumab 600 mg per 24 weeks Interferon beta-1a 44 µg three times per week |
Ocrelizumab 600 mg per 24 weeks Placebo |
Ofatumumab at a dose of 20 mg subcutaneously every 4 weeks after 20-mg loading doses at days 1, 7, and 14 and oral teriflunomide at a dose of 14 mg once daily vs placebo | Ofatumumab at a dose of 20 mg subcutaneously every 4 weeks after 20-mg loading doses at days 1, 7, and 14 and oral teriflunomide at a dose of 14 mg once daily vs placebo | Intravenous ublituximab at a dose of 150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72 Teriflunomide at a dose of 14 mg once daily |
Intravenous ublituximab at a dose of 150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72 Teriflunomide at a dose of 14 mg once daily |
| Patients (ratio) | N=439 (2:1) | N=200 (2 :1) | N=821 (1:1) | N=835 (1:1) | N=732 (2:1) | N=927 (1:1) | N=955 (1:1) | N=549 (1:1) | N=545 (1:1) |
| Follow-up | 96 weeks | 24 months | 96 weeks | 96 weeks | 120 weeks | up to 30 months | up to 30 months | 96 weeks | 96 weeks |
| Primary objective | Time to CDP, a prespecified increase in EDSS sustained for 12 weeks | Proportion of patients with at least one relapse |
Annualized relapse rate (ARR) at 96 weeks | Annualized relapse rate (ARR) at 96 weeks | Percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis | Annualized relapse rate (ARR) up to the end of the trial | Annualized relapse rate (ARR) up to the end of the trial | Annualized relapse rate (ARR) by week 96 | Annualized relapse rate (ARR) by week 96 |
| ARR (mean, 90% or 95% CI) | n/a | Relapses had occurred in 3% of patients in the rituximab group and 16% of patients in the dimethyl fumarate group (risk ratio: 0·19 (95% CI 0·06–0·62; p=0·0060) ARR: 0.015 with rituximab and 0.087 with dimethyl fumarate |
ARR: 0.16 with ocrelizumab and 0.29 with interferon beta-1a (rate ratio: 0.54 (0.40 to 0.72); p<0.001) | ARR: 0.16 with ocrelizumab and 0.29 with interferon beta-1a (rate ratio: 0.53 (0.40 to 0.71); p<0.001) | n/a | ARR: 0.11 with ofatumumab and 0.22 with teriflunomide (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; p<0.001) | ARR: 0.10 with ofatumumab and 0.25 with teriflunomide (difference, −0.15; 95% CI, −0.20 to −0.09; p<0.001) | ARR: 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% CI, 0.27 to 0.62; p<0.001) | ARR: 0.09 with ublituximab and 0.18 with teriflunomide (rate ratio, 0.51; 95% CI, 0.33 to 0.78; p = 0.002) |
| Gadolinium-enhancing T1 lesions (mean; SD or 95% CI) | n/a | Rituximab: 0.04 (0.20) Dimethyl fumarate: 0.26 (0.70) p=0·0062 |
Ocrelizumab: 0.02 (0.01-0.03) Placebo: 0.29 (0.20-0.41) Rate ratio: 0.06 (0.03-0.10); p<0.001 |
Ocrelizumab: 0.02 (0.01-0.04) Placebo: 0.42 (0.31-0.56) Rate ratio: 0.05 (0.03-0.09); p<0.001 |
n/a | Ofatumumab: 0.01 (0.01 to 0.02) Teriflunomide: 0.45 (0.36 to 0.58) Rate ratio: 0.03 (0.01 to 0.05); p<0.001 |
Ofatumumab: 0.03 (0.02 to 0.05) Teriflunomide: 0.51 (0.40 to 0.66) Rate ratio: 0.06 (0.04 to 0.10); p<0.001 |
Ublituximab: 0.02 (0.01 to 0.03) Teriflunomide: 0.49 (0.35 to 0.68) Rate ratio: 0.03 (0.02 to 0.06) p<0.001 |
Ublituximab: 0.01 (0.00 to 0.02) Teriflunomide: 0.25 (0.16 to 0.39) Rate ratio: 0.04 (0.02 to 0.06) p<0.001 |
| MRI T2 lesions (mean; SD or 95% CI) | T2 volume change from baseline to week 96 rituximab: 1,507 (3739) placebo: 2,205 (4306) p<0.001 |
Rituximab: 0.3 (0.7) Dimethyl fumarate: 1.5 (4.0) p=0·0047 |
Total number of new or newly enlarged hyperintense lesions on T2-weighted MRI by week 96: Ocrelizumab: 0.32 (0.26-0.41) Placebo: 1.41 (1.12-1.78) Rate ratio: 0.23 (0.17-0.30); p<0.001) |
Total number of new or newly enlarged hyperintense lesions on T2-weighted MRI by week 96: Ocrelizumab: 0.33 (0.26-0.41) Placebo: 1.90 (1.54-2.36) Rate ratio: 0.17 (0.13-0.23); p<0.001 |
Adjusted geometric mean percent change in total volume of lesions on T2-weighted images from baseline to week 120: Ocrelizumab: –3.37 (–4.99 to –1.72) Placebo: 7.43 (4.97 to 9.94) HR: 0.90 (0.88-0.92); p<0.001 |
Mean number of new or enlarging lesions per year: Ofatumumab: 0.72 (0.61 to 0.85) Teriflunomide: 4.00 (3.47 to 4.61) Rate ratio: 0.18 (0.15 to 0.22) p<0.001) |
Mean number of new or enlarging lesions per year: Ofatumumab: 0.64 (0.55 to 0.75) Teriflunomide: 4.15 (3.64 to 4.74) Rate ratio: 0.18 (0.15 to 0.22) p<0.001 |
New or enlarging lesions: 0.21 (0.14 to 0.32) with ublituximab and 2.79 (2.14 to 3.64) with teriflunomide group Rate ratio: 0.08; 95% CI, 0.06 to 0.10; p<0.001) |
New or enlarging lesions: 0.28 (0.20 to 0.40) with ublituximab and 2.83 (2.13 to 3.77) with teriflunomide Rate ratio: 0.10; 95% CI, 0.07 to 0.14; p<0.001 |
| CDP (%; HR; 95% CI) | No evidence of significant difference in time to CDP between the rituximab and placebo groups (p=0.14). Week 96 CDP rates were 38.5% for the placebo and 30.2% for the rituximab group | n/a | Disability progression confirmed at 24 week: Ocrelizumab: 5.9 Placebo: 9.5 HR: 0.57 (0.34-0.95); p=0.03 |
Disability progression confirmed at 24 week: Ocrelizumab: 7.9 Placebo: 11.5 HR: 0.63 (0.40-0.98); p=0.04 |
Confirmed disability progression for ≥12 weeks: Ocrelizumab: 32.9 Placebo: 39.3 HR: 0.76 (0.59-0.98); p=0.03 Confirmed disability progression for ≥24 week: Ocrelizumab: 29.6 Placebo: 35.7 HR: 0.75 (0.58-0.98); p=0.04 |
Disability worsening confirmed at 3 months (pooled analysis): Ofatumumab: 10.9 Teriflunomide: 15.0 HR: 0.66 (0.50 to 0.86) p=0.002 Disability worsening confirmed at 6 months (pooled analysis): Ofatumumab: 8.1 Teriflunomide: 12.0 HR: 0.68 (0.50 to 0.92); p=0.01 |
Worsening of disability confirmed at 12 weeks (pooled analysis): Ublituximab: 5.2 Teriflunomide: 5.9 HR: 0.84 (0.50 to 1.41); p=0.51 |
||
| Mean percent change in brain volume (95% CI) | Brain volume change from baseline to week 96 Placebo: -9.9 (37.0) vs Rituximab: -10.8 (40.3) p=0.62 |
n/a | Brain-volume change from week 24 to 96: Ocrelizumab: -0.57 (-0.66 to -0.49) Placebo: -0.74 (-0.83 to -0.65) Difference (%): 22.8; p=0.004 |
Brain-volume change from week 24 to 96: Ocrelizumab: -0.64 (-0.73 to -0.54) Placebo: -0.75 (-0.85 to -0.65) Difference (%): 14.9; p=0.0 |
Mean percent change in brain volume from week 24 to 120: Ocrelizumab: –0.90 (–1.00 to –0.80) Placebo: –1.09 (–1.24 to –0.95) HR: 17.5 (3.2 to 29.3); p=0.02 |
Annual rate of change: Ofatumumab: −0.28 (−0.34 to −0.22) Teriflunomide: −0.35 (−0.41 to −0.29) HR: 0.07 (−0.02 to 0.15); p=0.12 |
Annual rate of change: Ofatumumab: −0.29 (−0.35 to −0.23) Teriflunomide: −0.35 (−0.42 to −0.29) HR: 0.07 (−0.02 to 0.15); p=0.13 |
Percent change in brain volume from baseline to week 96: Ublituximab: −0.20 (−0.23 to −0.17) Teriflunomide: −0.13 (−0.16 to −0.10) Difference: −0.07 (−0.11 to −0.04) |
Percent change in brain volume from baseline to week 96: Ublituximab: −0.19 (−0.23 to −0.16) Teriflunomide: −0.18 (−0.21 to −0.15) Difference: −0.02 (−0.05 to 0.02) |
n/a, not applicable.