What are the results and implications of the OPERA (Ocrelizumab in Relapsing Multiple Sclerosis) trial comparing ocrelizumab (Ocrevus) to interferon beta-1a in patients with relapsing multiple sclerosis (MS)?

OPERA Trial Results: Ocrelizumab vs. Interferon Beta-1a in Relapsing Multiple Sclerosis

Primary Efficacy Outcomes

Ocrelizumab demonstrated superior efficacy to interferon beta-1a across all primary and secondary endpoints in the identical OPERA I and OPERA II trials, reducing annualized relapse rates by approximately 46-47% in patients with relapsing multiple sclerosis over 96 weeks. 1

Relapse Rate Reduction

• The annualized relapse rate was 0.16 with ocrelizumab versus 0.29 with interferon beta-1a in both OPERA I (46% reduction, P<0.001) and OPERA II (47% reduction, P<0.001) 1
• This represents a category 1 level of evidence for ocrelizumab's superiority in reducing disease activity 2

Disability Progression

• Pooled analysis showed 12-week confirmed disability progression occurred in 9.1% of ocrelizumab-treated patients versus 13.6% with interferon beta-1a (hazard ratio 0.60,95% CI 0.45-0.81, P<0.001) 1
• The 24-week confirmed disability progression was 6.9% with ocrelizumab versus 10.5% with interferon beta-1a (hazard ratio 0.60,95% CI 0.43-0.84, P=0.003) 1
• This 40% reduction in disability progression risk represents a clinically meaningful benefit for long-term outcomes 2

MRI Disease Activity

Ocrelizumab achieved near-complete suppression of inflammatory brain lesions compared to interferon beta-1a. 1

• Gadolinium-enhancing T1 lesions were reduced by 94-95%: mean 0.02 lesions with ocrelizumab versus 0.29-0.42 with interferon beta-1a (P<0.001 in both trials) 1
• New or enlarging T2-hyperintense lesions showed 37% reduction (RR 0.63,95% CI 0.57-0.69) 2
• The dramatic reduction in MRI activity suggests more complete control of underlying inflammatory disease processes 3

Safety Profile

Common Adverse Events

• Infusion-related reactions occurred in 34.3% of ocrelizumab-treated patients versus 9.7% with interferon beta-1a, though 92.6% were mild to moderate in severity 4, 1
• The majority of infusion reactions occurred with the first infusion and decreased with subsequent dosing 4
• Overall adverse event rates were similar between groups (RR 1.00,95% CI 0.96-1.04) 2

Serious Adverse Events

• Serious infections occurred in 1.3% of ocrelizumab-treated patients versus 2.9% with interferon beta-1a 1
• Serious adverse events showed no significant difference (RR 0.79,95% CI 0.57-1.11) 2
• Treatment discontinuation due to adverse events was lower with ocrelizumab (RR 0.58,95% CI 0.37-0.91) 2

Important Safety Signals

• Neoplasms occurred in 0.5% of ocrelizumab patients versus 0.2% with interferon beta-1a, requiring ongoing long-term monitoring 1
• Two serious infusion-related reactions occurred across both OPERA studies, including one life-threatening bronchospasm 4
• Premedication with methylprednisolone 100 mg IV plus optional antihistamines significantly reduced infusion reaction rates 4

Clinical Implications

For patients with relapsing multiple sclerosis, ocrelizumab should be considered a high-efficacy first-line or escalation therapy given its superior efficacy across all measured outcomes compared to interferon beta-1a. 3, 2

Dosing and Administration

• Initial dose: Two 300 mg IV infusions separated by 14 days 5
• Maintenance: Single 600 mg IV infusion every 24 weeks 5
• Mandatory premedication: 100 mg IV methylprednisolone before each infusion; optional antihistamines and antipyretics reduce infusion reactions 4

Patient Selection Considerations

• Ocrelizumab demonstrated efficacy even in patients with increased baseline disability (EDSS ≥4.0), showing numerical and sometimes significant reductions in confirmed disability progression 6
• The convenient twice-yearly dosing schedule requires no routine monitoring between infusions, improving treatment adherence 3
• Patients should be screened for active infections and malignancies before initiating therapy given the B-cell depletion mechanism 1

Monitoring Requirements

• Brain MRI should be obtained at baseline and repeated within 3-12 months, then at least annually for stable patients 7
• Be aware of pseudoatrophy effect (excessive brain volume decrease within first 6-12 months due to inflammation resolution) which should not be mistaken for disease progression 8, 7
• Clinical assessments should evaluate relapses, MRI activity, and disability progression to determine treatment response 8

Comparative Context

While the provided evidence focuses primarily on vitamin D supplementation and nutritional interventions in MS (which show no significant benefit for reducing relapses 9), the OPERA trials establish ocrelizumab as a disease-modifying therapy with robust evidence for reducing both clinical and radiological disease activity in relapsing MS 1. The mechanism involves selective CD20+ B-cell depletion, addressing a key pathogenic component of MS distinct from the immunomodulatory effects of interferon beta-1a 8, 1.