Reviewing Ravulizumab’s Long-Term Profile as New NMOSD Treatment

Sean Pittock, MD

In late March, the FDA approved ravulizumab (Ultomiris; Alexion), a terminal compliment C5 inhibitor, as a new treatment for patients with anti-aquaporin (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). With the decision, the therapy became the fourth approved for this patient population, joining eculizumab (Soliris; Alexion), inebiluzumab (Uplizna; Horizon Therapeutics), and satralizumab (Enspyrng; Genentech). The decision to approve the therapy was based on the phase 3 CHAMPION-NMOSD trial (NCT04201262), a double-blind trial in which ravulizumab-treated patients showed no relapses over a 58 week period.

About a month later, at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, new interim data from the open-label extension (OLE) of the study continued to highlight ravulizumab’s treatment effect. As of June 16, 2023, median follow-up was 138.4 weeks for ravulizumab (n – 58), with 153.9 patient-years. Across both the primary treatment period and OLE, no patients had an adjudicated on-trial relapse during ravulizumab treatment. Furthermore, 91.4% (53 of 58) of patients had stable or improved Hauser Ambulation Index score and 91.4% (53 of 58) of patients had no clinically important worsening in Expanded Disability Status Scale (EDSS) score.

At the meeting, lead investigator Sean Pittock, MD, director for the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, sat down with NeurologyLive^® to discuss the results in detail, outlining the long-term efficacy and safety of the agent. He spoke on how ravulizumab differs from other approved therapies for NMOSD and what it brings to the treatment toolbox for clinicians. In addition, he noted some of the small safety concerns, like meningococcal infections, and how to potentially mitigate them. Furthermore, he provided perspective on the next wave of drug development for NMOSD, considering there are now 4 approved therapies for the disease.

NeurologyLive: Provide a brief overview of the interim results from the open-label extension and how they match up with the double-blind period?

Sean Pittock, MD: it's very exciting times for patients with NMOSD. As you know, the CHAMPION-NMOSD trial was published in the Annals of Neurology just this year, and it was very impressive data. From the efficacy perspective, there were 58 patients that were enrolled in that trial who received ravulizumab for about a median of 73-74 weeks. The main outcome measure that we're interested in is whether patients were having clinical relapses. In NMOSD, we really want to prevent those relapses because we know that they are associated with increased disability.

The CHAMPIONS study was really a great success, we had zero relapses throughout the entire trial. We were very enthused [with that result]. Another thing to point out is that because we had such success with eculizumab, we didn't do a randomized control trial in this situation. As the comparator, we used the external comparator of the placebo group from the PREVENT trial, which was the previous eculizumab trial. So we saw zero attacks, equating to a 98.5% risk reduction, which is essentially as good as you get when it comes to attack prevention in NMOSD.

The interim, open label extension is just essentially watching those patients over an additional 70 patient years. Now, our median follow up was about 138 weeks, and the patients still are doing well. There is no clinical relapses, so we're very happy with that. That's been awesome to see.

With its recent approval, what does ravulizumab bring to the NMOSD treatment landscape?

The benefit of ravulizumab over eculizumab is that ravulizumab is an infusion that you get every eight weeks whereas eculizumab, or Soliris, is an infusion you get every two weeks. It's a big difference for patients, they essentially only have to go into an infusion center to get an infusion just six times per year. The reason that ravulizumab is different is that the backbone of eculizumab has been manipulated so that the drug has a long half-life. But in terms of kinetic and pharmacodynamic effects, it has robust complement inhibition, throughout that longer duration, from one infusion to the other. That's a huge benefit for patients. My suspicion is that if patients decide that they want to pick a complement inhibitor—because there are quite a few drugs now available that are FDA approved for the disease—they want to go for a drug with a better attack preventing role, and they're probably going to go for the longer half-life drugs. Ravulizumab is an option, and we certainly may see patients that are on eculizumab switching to the longer-acting drug.

How do we ensure that ravulizumab is accessible for eligible patients with NMOSD?

That's a really good question. All the clinician, scientists, clinicians, patients, nurses, pharma have worked very hard to get to a point where we have four FDA-approved drugs. It's taken a huge investment of energy and time on the behalf of patients. Now we have all of these medications and yet, many patients are not on them, and there's a combination of reasons for that. In the US, we're very lucky because if you prescribe these medications, these patients will generally get the medications because they're FDA-approved. But in some respects, there's a reluctance in terms of prescribing these medications, and there may be many reasons for that.

For example, for some patients, they may be on a non-approved drug, but have been stable for some time or many years. And maybe patients and physicians are a little reluctant to switch to an FDA-approved drug. Also, sometimes physicians are a little reluctant just to use some of these newer agents because they're not familiar with them. I think it's just important to continue to educate, and to make sure that patients and physicians know that there are a choice of a variety of different medications that all work, they've been FDA approved.

Are there any notable safety aspects clinicians should be aware of with ravulizumab?

The major safety issue with ravulizumab or with any of the complement inhibitors is the potential risks to development in meningococcal infection. In the PREVENT trial, for example, we had no patients with NMOSD who developed meningococcal infection either in the placebo control part of the trial or in the open label extension. In the ravulizumab CHAMPION-NMOSD trial, we had 2 of 58 patients developed meningococcal infection. So that was a concern. Both patients were diagnosed rapidly, because we do watch patients very carefully. And if patients are on a complement inhibitor and they develop fever, headaches, stiff neck, we recommend they go immediately to an emergency room. Both patients were diagnosed very early, both were treated very early, and both made full recoveries.

One patient continued on trial, the other patient pulled out. At the moment, if you're going to use ravulizumab as a therapy, it's very important to follow guidelines very carefully. A few points that I'd make on this. Firstly, if you're going to commence this medication, you need to vaccinate patients against meningococcal infection. And this is for the ACWY and the B serotypes of meningococcal infection. Vaccination has to be the appropriate primary vaccination series for both of those vaccines. Generally, it is reasonable to cover patients with antibiotic therapy to allow the vaccine to kick in. Sometimes we recommend a two week course of penicillin, others other physicians may decide to treat patients for longer with penicillin. That's really important.

We also know that different age groups are more predisposed to developing meningococcal infection, which is something to potentially take into account. With any medication, patients and physicians have to weigh the potential pros—in the case of ravulizumab it has a wonderful efficacy—with the potential risks that go along with this medication. Patients must be informed to watch out for any signs of this infection and to get to emergency room as soon as any of these types of symptoms were developed. That I think is very important. In in other respects, the medication was reasonably well tolerated. In fact, there was very little difference when we compared the frequency of side effects in the treated patients with the external comparator placebo arm treated patients from the prevent trial.

Where do we go now with drug development for NMOSD considering we have a few approved therapies?

It was a great question. It does get difficult, we're dealing with a rare disease. We have 4 FDA-approved drugs. The potential to do placebo arm approaches to therapeutic trials is finished. The CHAMPION-NMOSD study was a nice example where we didn't actually have a placebo arm, we had an external comparator placebo arm. For future studies, there is always the possibility of comparing a drug with an external comparator, or a natural history type of approach. We also need to be cognizant of the fact that these medications are very expensive, and they're lifelong. The potential here is that a patient is diagnosed with NMOSD, starts an FDA-approved drug, and remains on that medication essentially for the rest of their lives. And that's a significant cost. There needs to be some thought and some consideration of additional therapeutic approaches to these types of diseases.

I know that many physicians, scientists, and groups who are focused on NMOSD are thinking a lot about opportunities to potentially cure this disease. Some have suggested the possibility of tolerization approaches to NMOSD and others are also looking at the possibility of using CAR-T therapies. In eculizumab, we have a monoclonal antibody that takes out CD19-positive B cells. We know that those drugs works well, and you get an 85% risk reduction, which is really good. We do know that a lot of CD19 cells can still hang around in the spleen and in the liver. And so some are considering the possibility of using CAR-T therapies to take out CD19-positive B cells. You get a deeper kill, and it'd be very interesting to understand firstly, how does that work? And number two, how long does the benefit of that therapy work? Can you have patients gaining benefit for three, four, or even five years? Maybe you can get some kind of reconstitution of the immune system and patients potentially can avoid having to be on very expensive drugs on every year basis. That's work to do in the future. At the current time, we've got to deal with what we've got. I think we're in a situation where patients have a lot of opportunities to choose medications that are going to be good and prevent them getting disability.

Transcript edited for clarity.