OPERA I & II
Ocrelizumab
The identically designed OPERA I and II trials showed that ocrelizumab outperformed high-dose subcutaneous interferon beta-1a across relapse, disability, and MRI outcomes.
- Phase
- Phase III × 2
- Population
- Relapsing multiple sclerosis (RMS)
- Controlled period
- Aug 31, 2011 — May 12, 2015
What was compared
Ocrelizumab
600 mg intravenously every 24 weeks
Interferon beta-1a
44 μg subcutaneously three times weekly
Primary endpoint
Annualized relapse rate
96 weeks
Primary endpoint results
Annualized relapse rate in each OPERA trial
Relapses per participant-year
46% lower in OPERA I and 47% lower in OPERA II (P<0.001 for both).
Selected secondary outcomes
9.1% versus 13.6% in pooled analysis; HR 0.60 (P<0.001).
94% and 95% lower with ocrelizumab in OPERA I and II.
Who was studied
Key inclusion criteria
- Age 18–55 years
- RMS diagnosis based on McDonald criteria 2010
- Baseline EDSS 0–5.5
- At least 2 relapses in the previous 2 years or at least 1 in the previous year
- MRI lesions consistent with MS
- No neurologic worsening for at least 30 days before screening and baseline
Key exclusion criteria
- PPMS
- MS duration > 10 years with baseline EDSS ≤ 2.0
- Previous B-cell-targeted treatment or other protocol-defined immunosuppressive treatment
Participants at baseline
OPERA I
| Characteristic | OcrelizumabN=410 | IFNβ-1aN=411 |
|---|---|---|
| Age, years — mean ± SD | 37.1 ± 9.3 | 36.9 ± 9.3 |
| Female sex — n (%) | 270 (65.9%) | 272 (66.2%) |
| Time since MS symptom onset, years — mean ± SD | 6.74 ± 6.37 | 6.25 ± 5.98 |
| Time since MS diagnosis, years — mean ± SD | 3.82 ± 4.80 | 3.71 ± 4.63 |
| EDSS — mean ± SD | 2.86 ± 1.24 | 2.75 ± 1.29 |
| Relapses in previous 12 months — mean ± SD | 1.31 ± 0.65 | 1.33 ± 0.64 |
| No DMT in previous 2 years — n/N (%) | 301/408 (73.8%) | 292/409 (71.4%) |
| No gadolinium-enhancing lesions — n/N (%) | 233/405 (57.5%) | 252/407 (61.9%) |
SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy; IFNβ: interferon beta.
Source: Hauser et al., NEJM 2017, Table 1
OPERA II
| Characteristic | OcrelizumabN=417 | IFNβ-1aN=418 |
|---|---|---|
| Age, years — mean ± SD | 37.2 ± 9.1 | 37.4 ± 9.0 |
| Female sex — n (%) | 271 (65.0%) | 280 (67.0%) |
| Time since MS symptom onset, years — mean ± SD | 6.72 ± 6.10 | 6.68 ± 6.13 |
| Time since MS diagnosis, years — mean ± SD | 4.15 ± 4.95 | 4.13 ± 5.07 |
| EDSS — mean ± SD | 2.78 ± 1.30 | 2.84 ± 1.38 |
| Relapses in previous 12 months — mean ± SD | 1.32 ± 0.69 | 1.34 ± 0.73 |
| No DMT in previous 2 years — n/N (%) | 304/417 (72.9%) | 314/417 (75.3%) |
| No gadolinium-enhancing lesions — n/N (%) | 252/413 (61.0%) | 243/415 (58.6%) |
SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy; IFNβ: interferon beta.
Source: Hauser et al., NEJM 2017, Table 1
Safety signal
- Infusion-related reactions occurred in 34.3% with ocrelizumab.
- Serious infection occurred in 1.3% with ocrelizumab and 2.9% with interferon.
- During the 96-week controlled trials, neoplasms occurred in 4 ocrelizumab-treated patients (0.5%) and 2 interferon beta-1a-treated patients (0.2%).
- During the OPERA open-label extension, when all participants received ocrelizumab, 5 additional neoplasms were reported through June 30, 2016: 2 breast cancers, 2 basal-cell skin carcinomas, and 1 malignant melanoma.
- Across all MS studies in the paper’s extended safety analysis—not OPERA alone—the first-neoplasm incidence was 0.40 per 100 patient-years with ocrelizumab versus 0.20 with pooled interferon or placebo comparators. The numerical imbalance warranted continued evaluation; it did not establish causation.
Why it mattered
OPERA I and II independently showed that CD20-positive B-cell depletion reduced relapses, MRI activity, and confirmed disability progression compared with subcutaneous interferon beta-1a. Replication in two trials established B cells as a major therapeutic target in relapsing MS.
Important limitation
The 96-week trials could not define long-term immune, infection, or malignancy risk, and some secondary outcomes rely on prespecified pooled analysis.