NeuroVoices: Michael Levy, MD, PhD, on Comparing Patient Outcomes of Inebilizumab and Rituximab in NMOSD

Michael Levy, MD, PhD

(Credit: The Sumaira Foundation)

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease that affects the central nervous system, causing recurrent and disabling attacks on the optic nerve, spinal cord, and brainstem. While rituximab, an off-label treatment targeting CD20-positive B-cells, is commonly used for NMOSD, some patients on the treatment have continued to experience relapses or unwanted adverse reactions. Inebilizumab (Uplizna; Amgen), an FDA-approved treatment for adult patients with NMOSD anti-aquaporin-4 antibody positive, targets CD19-positive B-cells with a similar mechanism of action as rituximab.

A recent retrospective chart review published in Frontiers in Neurology examined 14 NMOSD cases from 7 centers who transitioned from rituximab to inebilizumab.¹ The findings from the study revealed inebilizumab had provided significant clinical benefits, effective disease control, and a favorable safety profile. Conducted by senior author Michael Levy, MD, PhD, associate professor of neurology at Harvard Medical School, 71.4% (n = 10) of patients had a combined 17 attacks on rituximab because of breakthrough disease (n = 10) or treatment delays (n =7). The mean duration of rituximab treatment was 38.4 months and the mean duration of inebilizumab treatment was 19.3 months. Authors also reported that after switching to inebilizumab, there were no subsequent attacks observed.

In a new iteration of NeuroVoices, Levy, who also serves as the chairman for the medical advisory board at The Sumaira Foundation, sat down with NeurologyLive^® in an interview to discuss the primary differences in the mechanisms of action between inebilizumab and rituximab. Levy, research director of the Division of Neuroimmunology & Neuroinfectious Disease at Massachusetts General Hospital, also talked about how the real-world data on the effectiveness of inebilizumab compared with the clinical trial results. Furthermore, he spoke about the implications for patients currently on rituximab in terms of switching to inebilizumab.

NeurologyLive: Could you provide an overview of the study including the objective behind it and then dive into the findings?

Michael Levy, MD, PhD: This is a study of inebilizumab, which is a CD19 depleting antibody. In NMO, we've been using the CD20 B cell depleting antibody rituximab for many years. We're all used to it; patients are very fond of the medication that has seemed to work very well for them. It had never been formally trialed in a population with NMO until a recent small one in Japan, but we all had a lot of experience with it. That might have provided some reassurance and comfort to the industry partner who initially did the trial in NMO. They conducted a worldwide phase 3 blinded placebo-controlled study, and it proved to be remarkably effective reducing risk of relapse by 77%.

That's the backstory. The smaller part of that story is that since it's been approved, people have been asking themselves “well, we have rituximab that we use off label and it's cheap now especially the biosimilars. We have inebilizumab, which has scientific evidence to support its use in NMO but it's expensive. Aren't they really the same?” That's what's been bugging people since the approval of inebilizumab. What the inebilizumab folks have done is they said, “well, it's really not the same. If you look at the patient population in the trial, those who were on rituximab, who were then enrolled in the study, had relapses and the drug failed them. Then when they started inebilizumab they did not and here's the proof.”

We looked at the data, we're rubbed our chins we're like, “wow, that could be real. Does that happen in the real world?” This case series was really an attempt to try to reproduce what we saw in the clinical trial in the real world. Several investigators came together and said, “alright, let's take all of our patients on rituximab who were transitioned over time into inebilizumab. Let's just see, are there cases where patients who were on rituximab relapsed and what happened after they switched to inebilizumab?” That was really the question. We didn't try to limit or bias the population. We just took everybody who transitioned from rituximab to inebilizumab, not patients who had a gap in their treatment just those who were just transitioned.

They might have been transitioned for a number of reasons. Maybe it was the patient preference, maybe copay assistance, maybe availability. Whatever the reason was, we just wanted to evaluate all of those cases. There were 14 cases total, 13 of which aquaporin-4 antibody positive and 1 off label aquaporin-4 antibody negative who still met the criteria. What surprised us is that there were quite a few relapses in the rituximab group. Pretty similar to the numbers in the trials. I think out of the 14 patients, there were 6 who had a breakthrough relapse on rituximab. It occurred even during that period of time that we would expect rituximab to be in effect, that they still had some circulating CD19 positive B cells when they were tested.

Maybe it was that the rituximab wasn't fully depleting the B cells, or maybe some of these B cells were internalizing their CD20 and they were still expressing CD19. There's lots of follow-up studies that can be done on this to try to explain why this is true. But then when they were transitioning to inebilizumab, in that year and a half period that they've been followed since the transition, there have been no relapses. This really is similar to what we saw in the trial. There are patients who had rituximab fail them and who responded well to inebilizumab.

What are your thoughts on this type of research, looking at switching therapies in NMOSD?

My first thought is that this really deals with a pressing issue in our NMO patient population. There's still probably the majority that are being treated with off label medications because they were on those medications before these drugs were formally approved. They're still on these drugs: rituximab, mycophenolate, azathioprine and prednisone. Do they stay on it? From the patient's perspective, they seem to be working. So why would you switch? From the scientific perspective, those drugs don't have the support, the proof, that you need to prescribe these drugs to know that they will prevent relapses, or what the risk is and what the safety concerns are. It's always a struggle when I'm face to face with the patient and “I say you're on an older drug. It does seem to work for you. Yes, you haven't relapsed in 4 years. However, we don't have any scientific data to support its use, we have experience.”

Now we have these 4 drugs now. They're all approved. They're all demonstrated to be effective. There's one that works just like rituximab, but maybe even better. Now we have some proof, these are retrospective studies, not Class I evidence. But we have some suggestion that even patients who failed rituximab might respond to inebilizumab. If they say, “well, I had a treatment relapse with rituximab, maybe that mechanism doesn't work for me.” Then I could say, “well, according to studies that have now been published, there are cases where rituximab fails patients, for whatever reason but inebilizumab still seems to work.”

I think it puts back on the table a mechanism of action for patients that had rituximab failed them, who might have thought that this option was not available to them. There are still other options available to them. We have eculizumab (Soliris; Alexion) that was approved and the newer one ravulizumab (Ultomiris; Alexion), totally different mechanism of action but very effective, and satralizumab (Enspryng; Genentech) as well. Very different mechanisms of action, a whole different safety profile and logistics, also a 79% reduction in relapse risk. When I present all of these options to my patients, I have the benefit of being able to say all these drugs are remarkably effective. Here's the efficacy data, here's the safety data. Don't worry about what happened on rituximab, you still have all 4 options.

Is there anything you wanted to share that was not mentioned in the case series?

There were only 2 patients in this series who had infusion reactions. In my experience with rituximab, the risk of infusion reaction is much higher. More of my patients have them than don't. We have to use medications like steroids and Benadryl to suppress that infusion reaction. But with inebilizumab the risk of infusion reaction is much lower, fact in the trial it was equal to the placebo. An equal risk of having an infusion reaction with normal saline. If infusion reactions are a problem for my current patients treated with rituximab, I say “this is an easy decision, same benefit, except scientifically proven plus reduced risk of infusion reactions.” The truth is for a lot of our patients, at least in the US, they will have a copay with rituximab because it's off label. They'll get copay assistance with inebilizumab and it will be cheaper for them.

Transcript edited for clarity. Click here to view more NeuroVoices.

REFERENCES
1. Osborne B, Romanow G, Hemphill JM, et al. Case report: Transition from anti-CD20 therapy to inebilizumab for 14 cases of neuromyelitis optica spectrum disorder. Front Neurol. 2024;15:1352779. Published 2024 Apr 16. doi:10.3389/fneur.2024.1352779