ORATORIO Subgroup Analysis Looks at Baseline Enhancement Activity’s Effect on Outcome

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Jerry S. Wolinsky, MD

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams