Kristen Krysko, MD, summarizes the results of the phase III ORATORIO trial and discusses the rationale for using ocrelizumab for the treatment of progressive multiple sclerosis.
Bruce Cree, MD: I want to get into ocrelizumab, and I’m going to ask Dr Krysko to discuss the ocrelizumab study. Dr Krysko, could you get into the details of ORATORIO for us?
Kristen Krysko, MD: ORATORIO was the phase 3 trial that led to the approval of the first disease-modifying therapy for primary progressive MS [multiple sclerosis]. It was a study of ocrelizumab, an anti-CD20 monoclonal therapy, which depletes B cells, for primary progressive MS. We didn’t include any patients with secondary progressive MS in this study.
Prior to that, rituximab had been studied for primary progressive MS in the OLYMPUS trial. In that study, they found that, overall, the results were not statistically significant. But interestingly, the younger patients, under the age of 51, and those with gadolinium-enhancing lesions tended to benefit.
That was followed by the ORATORIO study, where they tended to include a younger group and more had some disease activity on MRI at baseline. In the ORATORIO trial, they had a placebo-controlled comparison of 732 patients who were randomized to 600 mg of IV [intravenous] ocrelizumab or placebo every 24 weeks. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks. In that study, the patient population was between the ages of 18 and 55, with a mean study population age of 45 years old, EDSS [Expanded Disability Status Scale] of up to 6.5, and within 10 to 15 years from disease onset, depending on their EDSS at baseline. About 30% of the patients had gadolinium-enhancing lesions at baseline.
The mean study results showed a statistically significant reduction in confirmed disability progression at both the 12-week and the 24-week time points. They had seen disability progression in about 33% of patients on ocrelizumab and 39% on placebo, so the hazard ratio was a 24% reduction in disability progression. That was exciting because it was the first study that showed benefit in primary progressive MS. As discussed before, it was a fairly modest benefit. They also found benefit on brain volume loss metrics in the study.
Many of us are aware of the main adverse events and use ocrelizumab in relapsing MS as well. The same adverse events were described in this study, with infusion reactions and infections being the most common. The infections primarily included upper respiratory tract infections and herpes virus infections, such as reactivation of cold sores. This is the one trial that had a breast cancer signal as well, with 4 cases of breast cancer on ocrelizumab compared to none on placebo. That wasn’t seen in other studies of ocrelizumab.
This trial included a more active group of people with primary progressive MS who were younger and more likely to have gadolinium-enhancing lesions compared to the rituximab study, which led to this demonstration of benefit and the approval of ocrelizumab for primary progressive MS in most countries. It is not approved for secondary progressive MS, though, at least in Canada.
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Transcript Edited for Clarity