Ten years of OPERA: a two-year delay in ocrelizumab left a lasting disability gap

Design

Two phase 3 randomised trials with open-label extension to 10 years (OPERA I and II)

Population

1,656 adults aged 18–55 with relapsing MS, EDSS 0–5.5

Primary outcome

Time to 48-week confirmed disability progression

Effect

HR 0.76 (95% CI 0.61–0.95) continuous vs delayed; EDSS 6.0 HR 0.57 (0.40–0.82)

OPERA I and II randomised 1,656 adults with relapsing multiple sclerosis to ocrelizumab or interferon beta-1a for two years, after which everyone could take ocrelizumab in an open-label extension for up to eight more years. 80% entered the extension and 64% of those completed it.

Over ten years, those started on ocrelizumab had a lower hazard of 48-week confirmed disability progression than those who started two years later (HR 0.76, 95% CI 0.61 to 0.95). The hazard of reaching EDSS 6.0, needing a walking aid, was also lower (HR 0.57, 0.40 to 0.82); for EDSS 4.0 the difference did not reach significance (HR 0.66, 0.43 to 1.03). Annual relapse rate on continuous ocrelizumab fell from 0.139 in year one to 0.016 by year ten. Adverse and serious infection rates did not rise over the extension.

The early gap never closed. That supports the argument for high-efficacy therapy from the start rather than escalation. Long-term extensions lose patients, and those who stay may be doing better, so the absolute rates should be read cautiously; the comparison remains between originally randomised groups.

• Discuss high-efficacy therapy at diagnosis of active relapsing MS rather than planning to escalate later.
• A two-year delay in ocrelizumab was associated with a disability difference still present at ten years.
• Serious infections did not increase with longer exposure in the extension.
• Monitor immunoglobulin levels and infection risk during long-term B-cell depletion.
• Weigh cost and access with the patient, since long-term infusion therapy is a lasting commitment.

Why it matters

It challenges the escalation approach of starting with a modest drug and waiting for breakthrough disease.

Don't overread it

After year two everyone was on open-label ocrelizumab and a third left before completing, so the later years are not a blinded comparison.

The statistics, in plain English

A hazard ratio of 0.76 means about a quarter lower risk of confirmed progression at any point over ten years. The EDSS 4.0 interval (0.43 to 1.03) crosses 1, so that milestone did not show a clear difference.

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