Long-term follow-up from the phase 3 ORATORIO extension study (ClinicalTrials.gov Identifier: NCT01194570) provided evidence of a consistent, long-term benefit of early and continuous ocrelizumab treatment on disease progression in primary progressive multiple sclerosis (PPMS), according to study results published in the Lancet Neurology.
Data from the phase 3 ORATORIO trial supported the safety and efficacy of ocrelizumab for patients with PPMS. The objective of this follow-up study was to evaluate the long-term safety and efficacy of maintaining or switching to ocrelizumab therapy in the open-label extension phase of the trial.
ORATORIO was a multi-center, double-blind, phase 3 trial of 732 patients with PPMS. Patients were aged 18-55 years and randomly assigned to receive intravenous ocrelizumab or placebo, every 24 weeks for at least 120 weeks. After the double-blind phase, the participants entered an extended controlled period, followed by an open-label extension phase, during which they continued ocrelizumab or switched from placebo to ocrelizumab.
Time to onset of disability progression was confirmed at 24 weeks months by using 4 measures: increase in Expanded Disability Status Scale score; 20% or more increase in time to complete the 9-Hole Peg Test; 20% or more increase in time to perform the Timed 25-Foot Walk; and composite progression, defined as the first confirmed occurrence of any of these three individual measures.
Of 732 participants, 544 (74%) completed the double-blind period to week 144; 517 of these patients and 10 additional ones (total, 527 [72%]) entered the open-label extension phase. Of the 527 patients, 451 (86%), were ongoing in the open-label extension.
Over a period of 6.5 study years, there was a consistent and sustained treatment-associated benefit in multiple measures of disability progression. The proportion of patients with worsening disability measures was lower in those who initiated ocrelizumab early, compared with those who switched from receiving placebo: Expanded Disability Status Scale (51.7% vs 64.8%, respectively; P =.0018); 9-Hole Peg Test (30.6% vs 43.1%, respectively; P =.0035); Timed 25-Foot Walk (63.2% vs 70.7%, respectively; P =.058), and composite progression (73.2% vs 83.3%, respectively; P =.0023).
Percent changes in T2 lesion volume (0.447% vs 13.002%, respectively; P <.0001) and T1 hypointense lesion volume (36.676% vs 60.925%, respectively; P =.0008) from baseline to the end of the study were lower for patients who were on ocrelizumab from the double-blind phase of the study, compared with those who switched from placebo.
The rate of adverse events and serious adverse events over the entire period in the all-ocrelizumab exposure population were 238.09 (95% CI, 232.71-243.57) per 100 patient-years and 12.63 (95% CI, 11.41-13.94) per 100-patient years, respectively. The most common serious adverse events were serious infections with a rate of 4.13 (95% CI, 3.45-4.91) per 100 patient-years. No new safety signals emerged.
The study had several limitations, including the lack of a control group, open-label treatment, and potential survivor bias.
“Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis,” concluded the study researchers.
Wolinsky JS, Arnold DL, Brochet B, et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. Lancet Neurol. Published online October 29, 2020). doi:10.1016/S1474-4422(20)30342-2