Ocrelizumab Use in Treating Multiple Sclerosis

Peter L. Salgo, MD: You’ve already established, you have already made it very clear, that early treatment is important. Preventing as much damage as possible is important. And now I know you wanted to get to this, and here it comes. We’ve got newer disease-modifying therapies [DMTs], and this is specifically for SPMS [secondary-progressive multiple sclerosis]. First, I’m going to try this 1. These “mabs” always drive me crazy. Like ocrelizumab, which is what? It’s an anti-CD20 monoclonal antibody?

Patricia K. Coyle, MD, FAAN, FANA: This is a humanized monoclonal antibody against CD20, which is expressed largely on B cells. It’s lytic, so it binds to the CD20 and kills the B cells. You will wipe out B lymphocytes in the circulating blood for 8 to 10 months with it, and it will get some of the B cells in the organs as well. It doesn’t kill all in the body. It’s about 3% to 5% of T cells that have CD20 on it, and it will knock them out. They seem to be very active T cells. So this is a high-efficacy treatment for relapsing MS [multiple sclerosis] that’s given intravenously every 6 months and had dynamite data in their phase 3 trials for relapsing MS.

Peter L. Salgo, MD: That was the ORATORIO trial?

Patricia K. Coyle, MD, FAAN, FANA: This is OPERA I and II for relapsing MS. The ORATORIO was the primary-progressive disease.

Peter L. Salgo, MD: OK.

Patricia K. Coyle, MD, FAAN, FANA: This is the treatment that was also approved for that, but this was a very high-efficacy therapy for relapsing MS and just given half a day twice a year.

Peter L. Salgo, MD: Well, when you say it was very effective, what are the numbers you’re talking about?

Patricia K. Coyle, MD, FAAN, FANA: MRI [magnetic resonance imaging] lesions were wiped out by 95% compared with a high-dose interferon beta. It didn’t go up against placebo. It went up against sub-Q [subcutaneous] interferon beta-1a, 44 mcg. That’s 1 of the high-dose interferon betas.

Peter L. Salgo, MD: Go back, go back.

Patricia K. Coyle, MD, FAAN, FANA: Yes.

Peter L. Salgo, MD: I thought I heard you say 95%.

Patricia K. Coyle, MD, FAAN, FANA: Yes, 95% shut down compared with an interferon beta that shuts down MRI [magnetic resonance imaging] lesions very good. It was amazing. It was amazing.

Peter L. Salgo, MD: Compared with a good drug, if I hear you right, this is an astounding drug.

Patricia K. Coyle, MD, FAAN, FANA: This is way stronger, yes.

Peter L. Salgo, MD: Is it clinically significant? Do these people feel better, act better?

Patricia K. Coyle, MD, FAAN, FANA: It’s clearly statistically significant. With all the high-dose agents, with all the high-efficacy agents, there will be a proportion that actually show confirmed improvement. That’s not an expectation. You never start by telling somebody you’re going to get better. We need the CNS [central nervous system] repair strategies. None of our DMTs are considered repair strategy, so you would never set them up saying, “You’re going to improve.” But that does happen in a subset with the high-efficacy agents.

Peter L. Salgo, MD: If you’ve already got preexisting damage, it would seem to me that preventing damage means you can tell them you’re not going to get much worse if you’re knocking down 95%.

Thomas P. Leist, MD, PhD: The damage that is newly inflammation driven—that damage may be knocked down. There may obviously be legacy costs from previous damage where there is inappropriate aging of neurons or things that will not be affected with that. Anti-CD20s obviously have been known for a period of time. There are other anti-CD20s in development. There was a parent compound that was spearheading much of the development of ocrelizumab. That was rituximab for which there are also phase 2 data available. Certainly, this has also opened discussion on what the role is of the different cell types in the disease process. And it makes a point that B cells—not the B cells that produce antibodies, the plasma cells, but B cells in general—play a significant role in the disease process.

Peter L. Salgo, MD: Now, there was that ORATORIO trial.

Patricia K. Coyle, MD, FAAN, FANA: Yes.

Peter L. Salgo, MD: What was that all about?

Patricia K. Coyle, MD, FAAN, FANA: Well, that was a breakthrough because we had no disease-modifying therapy for primary-progressive MS [PPMS], the unusual form, which by the way shows an equal sex ratio. There’s no female predominance in primary-progressive MS. Ocrelizumab was used in a phase 3 primary-progressive trial—that’s ORATORIO—against placebo, and it was positive. It slowed EDSS [Expanded Disability Status Scale] confirmed progression compared with placebo and got ocrelizumab approved as the first disease-modifying therapy for primary-progressive MS.

Peter L. Salgo, MD: Wow, impressive. What patient factors then do you consider when you’re going to put somebody on this drug? Who do you select?

Patricia K. Coyle, MD, FAAN, FANA: Well, there are a couple of things. As Tom said, this was based on a study, a phase 2 trial of rituximab that failed in primary-progressive MS. But in that earlier study, it worked in younger PPMS patients, 51 years of age or less, and those who had contrast enhancement on their entry MRI scan. In ORATORIO, they capped the age at 55, so they really didn’t study PPMS beyond age 55. They capped the duration of disease at 15. They required abnormal spinal fluid as an inflammatory marker. The real issue is how well does it work in older, long-standing patients, those who have never had a clinical attack or a contrast? And 1 very disturbing thing, the FDA had a post hoc analysis based on sex. Progression was not slowed in women with PPMS, only in men. So they’re addressing that.

Peter L. Salgo, MD: What’s your personal experience with this drug?

Patricia K. Coyle, MD, FAAN, FANA: It’s clearly not as impressive in primary-progressive as in relapsing MS. That’s not surprising. Remember, it’s not saying it’s going to stop progression; it slows it. So that’s clearly been my experience. I think it’s a great drug in relapsing MS. The data are not superimpressive, and my results have been not superimpressive in primary-progressive MS. Tom, what do you think?

Thomas P. Leist, MD, PhD: I agree. Two things. In the patients with very long-term primary-progressive disease, there is really not a lot of difference. It’s the early primary-progressive disease with more significant changes in the exam where it may have an impact.

Peter L. Salgo, MD: Early diagnosis.

Patricia K. Coyle, MD, FAAN, FANA: Yes.

Peter L. Salgo, MD: This is what you were talking about a few minutes ago. Window of opportunity. In the first 6 months, get in there.

Patricia K. Coyle, MD, FAAN, FANA: If possible, absolutely.

Peter L. Salgo, MD: If possible.