Fred Lublin, MD: Let’s move on to ocrelizumab, and Patricia, you lead us off on that.
Patricia K. Coyle, MD: Well, I’d like to talk about ORATORIO, which was the phase 3 primary progressive trial because ocrelizumab is the first DMT [disease-modifying therapy] approved for primary progressive MS [multiple sclerosis]. This trial entered about 732 primary progressive patients. They were randomized 2 to 1 to receive IV [intravenous] ocrelizumab 600 mg every 6 months or placebo. The primary outcome was confirmed disability progression at 12 weeks, and that was met 33% versus 39% in favor of siponimod over placebo. In addition, confirmed disability progression for 24 weeks was met; T2 lesion volume decreased in the ocrelizumab group compared to increasing in the placebo group. You had a positive effect in slowing brain volume loss in favor of ocrelizumab. It was a positive study.
Now, it was interesting: less than 0.1% of this monoclonal penetrates into the CNS [central nervous system]. If you looked at the curves for the primary outcome, they were separating by 6 months. To me, that has to be an anti-inflammatory extraneural impact, which is pretty amazing. We were able to impact progression in primary progressive MS [PPMS] by manipulating the external immune system, and that’s telling us something very important. Now, this phase 3 trial was informed by a negative phase 2 trial with rituximab in primary progressive MS, where in an analysis, for younger PPMS patients who had enhancement of focal inflammatory component, they had a positive treatment effect of the rituximab.
ORATORIO capped the age at 55. They had to be ambulatory. They had to have abnormal spinal fluid as an inflammatory marker. They couldn’t have PPMS longer than 15 years, and indeed, they had about 26% going into the study who had enhancement, and the group that had enhancement had a better response with regard to progression. The question is how much that can be applied to other cohorts. I’ll mention one other very bothersome thing. The FDA asked for an analysis based on sex, and there was no progression effect in women with primary progressive MS. It made the men’s response look better. This is puzzling. I don’t think it’s real, but it is being addressed in post-marketing studies with ocrelizumab.
Fred Lublin, MD: Your initial experience with it? Not so much initial anymore; it’s been around for 3 years.
Patricia K. Coyle, MD: This is a humanized anti-CD20. You have to have reasonable expectations. It’s also approved for relapsing MS, where it’s a stellar treatment. It’s not saying it’s going to stop progression. It slows it compared to placebo or compared to no treatment. The patients need to have accurate concepts of expectations of what it’s going to do. As you get to older groups, nonambulatory groups, or individuals who have a lot of comorbid conditions, if you’re concerned about immunosenescence, it does raise concerns about risk-benefit ratio with this agent.