The New England Journal of Medicine JANUARY 19, 2017

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Stephen L. Hauser, Amit Bar-Or, Giancarlo Comi, Gavin Giovannoni, Hans-Peter Hartung, Bernhard Hemmer, Fred Lublin, Xavier Montalban, et al.

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Bottom Line

In two phase 3 clinical trials (OPERA I and II), ocrelizumab demonstrated superior efficacy in reducing annualized relapse rates, disability progression, and MRI measures of disease activity compared to interferon beta-1a in patients with relapsing multiple sclerosis.

Key Findings

1. Ocrelizumab significantly reduced the annualized relapse rate compared to interferon beta-1a, with a relative reduction of 46% (0.16 vs. 0.29; P<0.001) in OPERA I and 47% (0.16 vs. 0.29; P<0.001) in OPERA II.

2. Treatment with ocrelizumab was associated with a lower risk of 12-week confirmed disability progression, with a hazard ratio of 0.60 in OPERA I (P=0.01) and 0.57 in OPERA II (P=0.02) compared to interferon beta-1a.

3. Imaging outcomes favored ocrelizumab, showing a 94–95% reduction in the mean number of T1 gadolinium-enhancing lesions per scan and a 77–83% reduction in the number of new or enlarging T2 hyperintense lesions compared to interferon beta-1a (P<0.001 for all).

4. Infusion-related reactions occurred more frequently with ocrelizumab (approximately 34–40%) than with placebo, though the majority were mild to moderate in severity.

Study Design

Design

RCT

Double-Blind

Sample

1,656

Patients

Duration

96 wk

Median

Setting

Multicenter, international

Population Adults aged 18 to 55 years with relapsing forms of multiple sclerosis and an Expanded Disability Status Scale (EDSS) score of 0 to 5.5.

Intervention Ocrelizumab 600 mg administered intravenously every 24 weeks.

Comparator Interferon beta-1a 44 mcg administered subcutaneously three times weekly.

Outcome Annualized relapse rate at 96 weeks.

Study Limitations

• The 96-week follow-up period, while standard for pivotal registration trials, does not capture the long-term safety profile or durability of response beyond two years.

• The study used an active comparator (interferon beta-1a) rather than newer, potentially more potent disease-modifying therapies, which might influence the perceived magnitude of comparative efficacy in contemporary clinical practice.

• The trials primarily enrolled patients with relatively low baseline disability (mean EDSS 2.8), which may limit the generalizability of results to populations with more advanced disease.

Clinical Significance

The OPERA trials established ocrelizumab as a highly effective therapy for relapsing forms of multiple sclerosis, highlighting the critical role of CD20-positive B cells in disease pathogenesis and providing a standard of care that demonstrates superior clinical and radiological efficacy over traditional interferon-based therapies.

Historical Context

The OPERA trials represented a paradigm shift in multiple sclerosis management by validating the therapeutic potential of B-cell depletion, a strategy that emerged following the success of off-label rituximab use and subsequently transformed the treatment landscape for both relapsing and primary progressive multiple sclerosis.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of ocrelizumab, and how does its target cell population contribute to the pathophysiology of Multiple Sclerosis (MS)?

Key Response

Ocrelizumab is a humanized monoclonal antibody that targets CD20+ B cells. By depleting these cells, it reduces B-cell mediated antigen presentation to T cells, decreases the production of proinflammatory cytokines, and limits the formation of ectopic lymphoid structures in the CNS, thereby reducing the inflammatory flares characteristic of relapsing MS.

Resident

Considering the superior efficacy of ocrelizumab over interferon beta-1a in the OPERA trials, what are the critical baseline screenings and long-term monitoring requirements for a patient starting this therapy?

Key Response

Baseline requirements include Hepatitis B screening (due to reactivation risk) and quantitative immunoglobulin levels. Long-term, patients must be monitored for infusion-related reactions, increased risk of upper respiratory and skin infections, and potential for declining IgG/IgM levels, which may necessitate treatment suspension or immunoglobulin replacement.

Fellow

While the OPERA trials demonstrated a reduction in 'confirmed disability progression' (CDP), how does this concept differ from 'progression independent of relapse activity' (PIRA), and which does ocrelizumab impact more effectively based on post-hoc analyses?

Key Response

CDP measures disability worsening that may be relapse-associated or not. Post-hoc analyses of OPERA data suggest that ocrelizumab significantly reduces PIRA, which is thought to represent the underlying neurodegenerative processes in MS. This is a critical distinction for understanding the shift from treating purely inflammatory relapses to protecting against the 'smoldering' disease progression.

Attending

How should the OPERA trial results influence the decision-making process between an 'escalation' strategy versus 'early high-efficacy therapy' in a treatment-naive patient with moderate lesion load?

Key Response

The OPERA trials showed that ocrelizumab provides superior protection against disability and MRI activity compared to traditional first-line therapy (interferon). This supports the 'early high-efficacy' approach, suggesting that preventing early axonal damage is more beneficial than waiting for lower-potency treatments to fail, provided the clinician and patient accept the long-term risk of hypogammaglobulinemia and infection.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The OPERA I and II trials utilized Annualized Relapse Rate (ARR) as the primary endpoint; however, in the era of high-efficacy DMTs, why is ARR becoming a less sensitive measure, and what surrogate biomarkers could be integrated into future trials to better capture neuroaxonal integrity?

Key Response

As MS therapies become more effective, ARR reaches a floor effect, making it difficult to differentiate between potent drugs. Integrating biomarkers like Serum Neurofilament Light chain (sNfL) or measuring 'slowly evolving lesions' (SELs) on MRI provides more sensitive, objective data on subclinical disease activity and neuroprotective effects compared to clinical relapse rates.

Journal Editor

In the OPERA study design, how might the distinct side-effect profile of interferon beta-1a (flu-like symptoms) have compromised the double-blind nature of the trial, and what impact could this have had on the reported secondary endpoints like the Multiple Sclerosis Functional Composite (MSFC)?

Key Response

Interferon's systemic side effects often 'unblind' participants and investigators. In trials with subjective or effort-dependent outcomes like the MSFC or self-reported relapses, this knowledge could lead to an overestimation of the treatment effect of the experimental drug (ocrelizumab), which lacks those specific side effects. Editors look for sensitivity analyses that control for this 'functional unblinding'.

Guideline Committee

Based on the OPERA results, should ocrelizumab be recommended as a first-line agent for RMS, and how does the strength of this evidence compare to current AAN guidelines regarding the 'window of opportunity' for high-efficacy treatments?

Key Response

The OPERA trials provide Level A evidence for ocrelizumab's efficacy in RMS. Current guidelines (AAN 2018) emphasize patient-centered choice but recognize high-potency options early in the disease course. The committee must weigh the magnitude of disability reduction against the cost and safety profile to determine if it should be the 'preferred' first-line agent over older injectables.

Clinical Landscape

Noteworthy Related Trials

2006

AFFIRM Trial

n = 942 · NEJM

Tested

Natalizumab

Population

Relapsing-remitting multiple sclerosis

Comparator

Placebo

Endpoint

Rate of clinical relapse

Key result: Natalizumab monotherapy significantly reduced the rate of clinical relapse and the burden of disease on MRI compared to placebo.

2010

TRANSFORMS Trial

n = 1,292 · NEJM

Tested

Fingolimod

Population

Relapsing-remitting multiple sclerosis

Comparator

Interferon beta-1a

Endpoint

Annualized relapse rate

Key result: Fingolimod was superior to interferon beta-1a in reducing the annualized relapse rate and reducing MRI lesion activity.

2017

ORATORIO Trial

n = 732 · NEJM

Tested

Ocrelizumab

Population

Primary progressive multiple sclerosis

Comparator

Placebo

Endpoint

Confirmed disability progression

Key result: Ocrelizumab significantly reduced the risk of confirmed disability progression compared to placebo in patients with primary progressive MS.

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