Ocrelizumab Data Go Against Traditional Conceptions of Wearing Off Effect

Disease Spotlight | <b>Disease Spotlight: Multiple Sclerosis</b>

Ilya Kister, MD, professor of neurology, NYU Grossman School of Medicine, discussed his surprising results from ECTRIMS, which found no evidence of wearing off with ocrelizumab (Ocrevus; Genentech).

For years, there has been ongoing debate as to whether disease-modifying therapies (DMTs) prescribed for patients with multiple sclerosis (MS) have a “wearing-off” effect throughout their infusion cycle. Although this concern has been voiced by the patient community, there is little concrete research to confirm these concerns. The SYMBOLS study (NCT04855617), a prospective, observational, 2-center trial, aims to describe changes in symptom severity in patients with MS treated with ocrelizumab, an FDA approved anti-CD20 antibody therapy administered at 6-month intervals.

Preliminary results presented at the 37th Congress of European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15, did not support the hypothesis that there is a wearing-off phenomenon with ocrelizumab. Among 69 participants who completed the week 4 and week 22 questionnaires, the symptom burden was unchanged from week 4 post-infusion to week 22 post-infusion.

Senior author Ilya Kister, MD, professor of neurology, NYU Grossman School of Medicine, said the results were somewhat shocking, considering that the data goes against traditional qualms from patients in the community. He sat down with NeurologyLive to provide further detail on the realism of this wearing-off effect, ways to prevent it, and the most notable advancements within the field in recent years.

NeurologyLive®: How much of a concern is this possible wearing off effect?

Ilya Kister, MD: This question usually comes around when you’re using the medication at certain intervals. It’s not really an issue for medications that you’re taking daily. But let’s say you have an infusion that you’re giving every few weeks to few months, the question is, does your symptom control stay the same throughout the cycle, or is there this worsening of patients symptomatically towards the end of the cycle. That’s been referred to as wearing-off effect.

This is an area that is wildly discussed informally in the MS community both among patients on social median and with MS healthcare providers. The working assumption we have is that it probably exists because a lot of patients have reported it. Obviously, everyone has their own response to medication, but we’ve heard of it and many other doctors have heard of it from their patients. To my knowledge, it has not been studied in ocrelizumab or rituximab. It has been studied a bit in natalizumab (Tysabri; Biogen), which is usually given every 4 weeks, even though we now think it’s possible to give it every 6 to 8 weeks.

There have been a couple of studies that suggest that towards the end of the cycle, some patients do experience this wearing-off. Part of the difficulty in studying this kind of formula is that you don’t want to bias patients, and you don’t want to imply it to them. Because there definitely is this anticipatory anxiety when you haven’t had your medication for a long time. It’s just human nature.

When we designed our 2-center study, we tried hard not to imply anywhere, not even in the title of the study or in the information, what we set out to test. We basically asked patients that we wanted to record the burden of their symptoms comprehensively at different time points of their infusion cycle without implying that its better or worse at one point or another. To record their symptoms, we used 2 major tools. One is the NeuroQOL, which is an NIH-validated tool widely used that includes a short questionnaire on depression, sleep, cognitive function, dexterity, mobility, etc. The other is a symptom screening tool developed in our center that screens for the 11 different domains affects by MS.

We have preliminary data, but the data we have was surprising enough to us that we wanted to report it and get feedback from the community. At the first cycle of the study, about three-fourth of the patients have completed the questionnaires. The bottom line is that we did not see any difference in the score that people give regarding their symptoms early on versus later. Again, its preliminary data and we’re still analyzing, but these findings are surprising and go against the general feeling about the subject and the community. It will be interesting to see the full results and get the feedback of others. It’s a first step in understanding this.

Are there ways to prevent wearing off?

[NYU Langone] and myself have taken on strategies to deal with it. From face value, one of the obvious strategies is to try to shorten the interval between infusions. Ocrelizumab unfortunately, for better or for worse, is given at a fixed dose. You’re not at liberty to increase it, but there is another drug called rituximab which is just as effective as ocrelizumab in terms of efficacy in MS. There, we’re able to either increase or decrease the frequency of the dose to deal with it.

If the rest of our results are strongly arguing against wearing-off phenomenon, maybe we should address more of the psychological component. Yes, you may feel like you need the drug, but we can test to check and see if that’s true. If your MRI is stable, exam is stable, neurofilament is stable, you can reassure people that nothing is going to happen to them, and that they’re safe.

What has been the biggest advancement for the MS community over the past year?

I think there is a paradigm shift in the world of MS, which has been brewing there for a while. When I started out in this field, there was a debate whether we needed to treat people early and how long we should wait to treat them. This debate is pretty much over. Everybody understands that we save brain and prevent disability in the long-term by starting treatment earlier.

The next part of that debate is, how heavy do we need to go early on? What therapies should we use upfront and what effect is it going to have on the disease? What’s been impressive is that we’ve been generating data towards the induction approach and now it has a lot of support. It’s not the highest-level evidence, it comes mainly from observational studies, but it’s very consistent. It may not seem like its rocket science here; if you use better drugs, you’re going to get better results. In fact, that’s what we’re seeing.

What’s surprising is just how much better we’ve gotten. You never seem to be able to catch up. If you start with the low-efficacy drug, there is still ongoing disease activity. And even if you start harder drugs later, there seems to be a gap that is difficult to overcome. I’m not saying that every patient with MS needs a high efficacy drug, that’s not true. There are a subset of patients with MS who may not even need a drug at all, it depends on the circumstances. An average patient with MS probably needs one of the better drugs. The time of using drugs that have 30% efficacy, the injection drugs, were great state-of-the-art things about 25 years ago. But that was then.

We have moved, our DMTs have moved. They’re much more efficacious and we’re more optimistic that the young patient, the patients who we get to treat early, will use less wheelchairs and experience less disability in the long run. That’s a big message from these studies that has come out. For someone dealing with the chronic disease, that’s good news.

Transcript edited for clarity.