Ocrelizumab May Meaningfully Delay Loss of Ambulation, Independence in PPMS


Extrapolated comparisons from the ORATORIO trial suggest that patients with primary progressive multiple sclerosis can experience major delays in confirmed time to wheelchair requirement and disease progression.

Helmut Butzkueven, PhD, Van Cleef Roet Chair of Neuroscience, and head, department of neuroscience, Central Clinical School, Monash University, and managing director, MSBase Foundation

Helmut Butzkueven, PhD

Based on extrapolation of data from the ORATORIO study (NCT01194570)—which showed that treatment with ocrelizumab (Ocrevus; Genentech) significantly delays the time to 24-week confirmed wheelchair requirement (Expanded Disability Status Scale [EDSS] score ≥7.0)—with the MSBase registry, it appears that the benefits of ocrelizumab may represent a consequential delay in loss of ambulation and independence for patients with primary progressive multiple sclerosis (PPMS).1

Led by Helmut Butzkueven, PhD, Van Cleef Roet Chair of Neuroscience, and head, department of neuroscience, Central Clinical School, Monash University, and managing director, MSBase Foundation, the group assessed the plausibility of making such extrapolations with an independent real‐world cohort.

Post-hoc analysis of the ORATORIO double-blind period and extended controlled period (DBP+ECP; n = 732) showed that ocrelizumab reduced the risk of 24‐week confirmed disability, as measured by EDSS score of 7.0 or more, by 46% compared to placebo (hazard ratio [HR], 0.54 [95% CI, 0.31-0.92]; P =.02).

When extrapolating the median time to 24-week EDSS 7.0 or more in ORATORIO, it was 12.1 years for placebo and 19.2 years for ocrelizumab. Similar to the placebo arm, in patients with primary progressive disease in MSBase (n = 775), the observed median time to 24-week EDSS 7.0 or more was 12.4 years.

By comparing this extrapolated media time in the ORATORIO trial periods for both treatment and placebo arms, the anti-CD20 therapy is predicted to delay 24-week confirmed EDSS 7.0 or more by 7.1 years (95% CI, –4.3 to 18.4). Sensitivity analyses performed without imputation indicated a similar delay of 7.5 years.

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“Real-world data from the MSBase registry show a similar disability trajectory to that extrapolated from placebo-treated patients in ORATORIO, whilst initial data from the ocrelizumab arm of the ORATORIO [open-label extension] period show a similar trajectory to the extrapolation from ocrelizumab-treated patients in the DBP+ECP, supporting the plausibility of these extrapolations,” Butzkueven and colleagues wrote.

Time to wheelchair requirement, they wrote, provides both an effective way to make cross-study and cross-cohort comparisons and offers a clinically meaningful outcome for patients with MS. “High levels of disability are associated with a number of physical, emotional and financial challenges, and an overall reduced quality of life,” Butzkueven et al wrote.

ORATORIO included 732 patients with PPMS, and ocrelizumab significantly reduced the risk of requiring a wheelchair by 46% versus placebo.2

Worth noting is that the patients included in ORATORIO were generally younger (mean age: ocrelizumab, 44.7 years; placebo, 44.4 years) with shorter disease duration (mean time since diagnosis: ocrelizumab, 2.9 years; placebo, 2.8 years) and lower disability levels (mean EDSS score: ocrelizumab, 4.7; placebo, 4.7) than a typical population. This makes the data challenging to generalize to a broad real-world population.

Butzkueven et al did note some limitations to the work, one of which being the lack of direct matching for baseline covariate differences between the ORATORIO and MSBase populations, which they accounted for by restricting patients in the MSBase cohort to those with the same EDSS eligibility criteria. “As a result, the observed disease progression trajectories to EDSS ≥7.0 in MSBase may be affected by potential imbalances in some baseline characteristics between the real-life MSBase cohort and the ORATORIO trial population,” they noted, adding that the populations were comparable for time since MS symptom onset and median baseline EDSS scores (rate of EDSS 6.0-6.5 at baseline: ocrelizumab, 28.3%; placebo, 33.3%; MSBase, 33.3%).

“Additionally, as there are currently no other treatments approved for PPMS, the comparison between the placebo arm and the untreated real-world MSBase cohort remains relevant,” Butzkueven et al wrote.

1. Butzkueven H, Spelman T, Horakova D, et al. Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry. Eur J Neurol. Published online March 16, 2021. doi: 10.1111/ene.14824
2. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376:209-220. doi: 10.1056/NEJMoa1606468
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