Ocrelizumab demonstrates sustained benefit for MS in open-label phase of ORATORIO trial

Patients with primary progressive MS treated continuously with ocrelizumab saw greater benefit in regard to measures of disease progression compared with patients who switched from placebo during an open-label extension of the ORATORIO trial.

Researchers published the findings in The Lancet Neurology.

“The double-blind period of the ORATORIO study established ocrelizumab as the first treatment to show a benefit on disability progression and MRI measures in patients with primary progressive multiple sclerosis (PPMS),” Jerry S. Wolinsky, MD, professor emeritus at McGovern Medical School at the University of Texas Health Science Center at Houston, and colleagues wrote. ”... Following completion of the double-blind period and unblinding of study [centers], patients could enter an open-label extension phase, via an extended control period.”

ORATORIO was a double-blind, randomized, placebo-controlled phase 3 trial conducted at 182 locations in 29 countries. It enrolled adults aged 55 and younger who had Expanded Disability Status Scale (EDSS) scores between 3 and 6.5. At the start of the double-blind period, researchers randomly assigned 488 patients to the treatment group and 244 to the placebo group. Researchers excluded patients previously treated with B-cell-targeted therapies or other immunosuppressive medications, as well as patients with a history of relapsing-remitting, secondary progressive or progressive relapsing disease.

Among all patients randomly assigned to the intention-to-treat group, 544 completed the double-blind period to week 144; 527 began the open-label extension phase and 451 were still participating at the time of publication. Researchers analyzed data from the open-label extension after 6.5 study years; one study year was equal to 48 calendar weeks.

Patients received MRI assessments on day 1 and at weeks 48, 96 and 144 of the open-label extension. Wolinsky and colleagues gathered new baseline data at the start of the extension and used the same measures from the phase 3 trial to assess disease progression, which included EDSS score increase, a 20% or greater increase in 9-Hole Peg Test (9HPT) completion time, a 20% or greater increase in Timed 25-Foot Walk (T25FW) test completion time and composite progression, which researchers defined as the first instance of any of these measures, observed for a period of at least 24 weeks. They also added an outcome measure of time to an EDSS score of 7 or higher, which means that a patient requires a wheelchair, because it is “a key clinical disability milestone for patients with MS.”

Patients who began treatment with ocrelizumab earlier in the trial experienced better outcomes compared with patients who were originally in the placebo group, specifically in regard to most of the measures of 24-week confirmed disability progression: EDSS (51.7% vs. 64.8%; P = .0018), 9HPT (30.6% vs. 43.1%; P = .0035), T25FW (63.2% vs. 70.7%; P = .058), composite progression (73.2% vs. 83.3%; P = .0023) and time to requiring a wheelchair (11.5% vs. 18.9%, P = .0274). The percentage change in lesion volume from baseline to study end was also lower among patients who started ocrelizumab earlier compared with those originally receiving placebo for both T2 lesions (.45% vs. 13%, P < .0001) and T1 hypointense lesions (36.68% vs. 60.93%, P < .0001).

The researchers called the safety profile of ocrelizumab “reassuring” for patients with PPMS, noting that it mirrored similar long-term data in relapsing MS. Among patients who received ocrelizumab in both study phases, the rate of adverse events was 238.09 per 100 patient-years (95% CI, 232.71-243.57) and the rate of serious adverse events was 12.63 (95% CI, 11.41-13.94) per 100-patient years. The most common serious adverse events were serious infections, which occurred at a rate of 4.13 per 100-patient years (95% CI, 3.45-4.91). Wolinsky and colleagues observed no new safety signals compared with the double-blind phase of the trial.

According to the researchers, ORATORIO is the first treatment trial to demonstrate a clinical benefit in regard to disability progression among patients with PPMS, though unmet needs remained for patients with MS.

“Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in MS,” the researchers wrote. “Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods.”