Ocrelizumab Shows Range of Benefits for Spectrum of Patients With Multiple Sclerosis

Kathleen Hawker, MD

This is the first of a 2-part interview. For part 2, click here.

A number of data sets examining the efficacy and safety of ocrelizumab (Ocrevus; Genentech) in real-world and long-term populations of patients with multiple sclerosis (MS) were presented at MS Virtual 2020, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020.

All told, the data included findings from a number of studies focused on patients who were exposed to prior disease-modifying therapy (DMT) as well as those who were initially treated with the humanized anti-CD20 monoclonal antibody. Ultimately, the range of posters showed the agent held benefit for those with a prior suboptimal response, and improved symptoms and rates of no evidence of disease activity (NEDA), among other conclusions.^1-4

To find out more about the swath of data presented on the agent at MS Virtual, NeurologyLive spoke with Kathleen Hawker, MD, Medical Director Manager, Neuroscience, Genentech.

NeurologyLive: Could you offer a high-level view of some of the data presented at MS Virtual on ocrelizumab?

Kathleen Hawker, MD: In the newer data, we have 7 years of safety data, and there have been no changes, which is great news. No increase in infections, malignancies, or any other new safety signals. That's been excellent. We have some really interesting data some coming from a rework of the relapsing-remitting MS and also the primary progressive MS data looking at 2 things: thalamic volume, and neurofilament light.

What was really interesting about that is thalamic volume is 1 of the biggest predictors of what a patient's going to do. What it did show is that patients with more thalamic volume loss did worse and that patients treated with Ocrevus did better than patients who have either been on the interferon in 1 and placebo in the other. And again, this is what we've seen over and over again, that when patients start early, they never get caught up, so that atrophy continued in patients who had started on Ocrevus early.

The other one that they looked at was neurofilament light, which was very interesting, too. It's a biomarker that can also predict disability, so you can take a look at it in the beginning and you can say, “This patient is going to do worse than others.” There was a correlation between thalamic volume, and Ocrevus actually brought the NfL levels back down to normal with treatments. That was very exciting to see that we could also alter not only shorter-term MRI data and relapses, but also long-term. And there were correlations with disability data, too. That's really important that we could see differences with the 25-Foot Walk Test and EDSS and also the 9-Hole Peg Test. So that was exciting.

There were a number of presentations on patients who switched to ocrelizumab from other agents, what were your thoughts on those findings?

The transition from natalizumab was also very interesting, and I think the biggest message on that is that we have not seen increases in any PML with the transition from natalizumab. We have seen very few cases, period. None reported—that hasn't been different—and the only cases we've had have been either from fingolimod or from natalizumab. But the numbers are still very, very small, and they haven't been increasing as opposed to some of the other drugs. So that's been very good. The other part of a note is there was no increase in safety issues with that transition, as well. A lot of our patients come from either fingolimod or natalizumab, so that's been good that the safety has persisted.

We had 3 studies: 1 from Europe, 1 from the US, and some substudies from 1 of our global studies, the CHORDS and CASTING studies, looked at patients that had suboptimal responses to other drugs. I think that’s important because these patients typically are more difficult to treat the longer that they've been on other drugs, and across all 3 studies, what we found is that the 24-week confirmed disability was down significantly—89% in one study. Those rates were in the high 80s and all 3 studies showed that the MRI activity went down by over 90%. They looked at what we called NEDA when they re-baselined it after 8 weeks, and the NEDA rate was 75% to over 80% decreased, and there was a slight difference between patients who had been on 1 drug versus more than 1 drug. But there wasn't a big difference. I think that's really exciting news that patients who have failed other drugs and are further along in their course are still doing really, really well on Ocrevus.

They also had long-term efficacy data, looking at both EDSS and relapse rate, and again, the same thing that we've seen before—the patients who had been on interferon or on placebo never caught up, but it was wonderful to see that not only the safety has remained the same, but the relapse rate has actually gone down over a period of 7 years, and also the EDSS has stayed low, too. So again, that long-term persistence on efficacy.

Where there any other data that are worth highlighting?

We have another trial called OBOE, which is still ongoing, and some really exciting data came out of that. There have been changes in B cells, in what they do in the cerebral spinal fluid, which I've never seen, even after 20 years of working in this. We saw some decreases in oligoclonal bands in patients, which is the first time that’s been reported. That was very exciting.

Then we have the 3 new studies, with fenebrutinib which is getting underway and is a BTK inhibitor. That's in PPMS, as well as 2 RMS studies, and we’re just starting up our CHIME study, which is in minorities. It has started to recruit, which is very exciting, and that's going to be 150 patients who are Hispanic and African American. We're going to be looking at some special testing to find out why these 2 minority groups do worse than Caucasians. There's going to be special MRIs as well as a lot of special blood testing to try to find out what we need to do to help these populations. That's underway as well.

How important is it to you, and particularly to physicians, to be aware that this appears to be not only an effective first option but an effective second option as well?

I think it's crucial. It's one of the biggest things we used to struggle with when we were in clinical practice, because, your phase 3 data don't give you that information, obviously, very well because of washouts and things like that. In the real world, we see not only the efficacy—and that's why the CHORDS, CASTING, and the ENSEMBLE data are saying, even after multiple drugs, that the drug is still very, very effective against, relapse, MRI, and disability—but also the safety, too. We always worry about, when people have been on multiple different drugs, what's happened to the immune system, and we haven't seen an uptick in safety signals. We typically know, generally, that when people are a little bit older, safety can change, but we haven't seen that in any age group either. So they're doing better, they're stabilizing, and we're not seeing an uptick in safety concerns, which we've seen with other drugs in some switches.

This is also important, too, because, in our regular studies, there's always a washout. But you don't want to do that in the real world because you want the patient on therapy very quickly. So, I think we've got quite a bit of data from a lot of different drugs that people go on before Ocrevus without a problem in safety at this point, so that was great news.

We saw this in the satralizumab longer-term data too. We haven't seen an uptick in safety, and people who are relapse-free have also stayed very, very low too. That's 2 of the biggest things when you're treating MS. Two years in a clinical study is very different than the real world. We've got 170,000 patients on Ocrevus right now for that period of time, so a lot of powerful data. There was a lot of data about immunoglobulins, and it was the same type of thing—followed for a long period of time and seeing no increase in infections. The good news is we're very boring, and it's exciting that we've seen this across multiple different trials and now in independent studies as well.

How important is it to have that collection of real-world data across the spectrum of disease?

It's a very, very good point. We've been trying to push that boundary of treating very early to prevent, but sometimes you get patients that haven't had that opportunity. So, it is wonderful that you have a drug that can also make a huge difference in their lives from multiple different aspects. And we're still gathering more data. Again, we have trials looking at earlier and earlier patients to see if we can even push that. Can we actually even prevent disease from going on if we start early enough? Those are very big points, and I think, that one of the biggest things people worry about, obviously, is safety. But with this long-term safety, I think this is giving a very good idea that you can use this drug, you can use it for a long time, and you can use it in a variety of patients in a variety of different types of MS very early, before any drug, after one drug, after several drugs, and at different ages, and still maintain that same improvement without making anything worse.

I'm very excited about the data, and we've been presenting it to a lot of neurologists, and they are also very excited that we haven't seen anything new from safety and that the efficacy data is remaining as good as it was in the original trials.

Transcript edited for clarity. For more coverage of MS Virtual 2020, click here.

REFERENCES
1. Weinstock-Guttman B, Bermel R, Cutter G, et al. Ocrelizumab treatment in patients with RRMS who had suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0221.
2. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
3. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
4. Kister I, Cutter G, Buffels R, Clinch S, Kuenzel T, Vermersch P. Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1039.