Sean J. Pittock, MD
Mayo Clinic, Rochester, Minnesota

Key Takeaways

  • Discovery of an autoantibody to the aquaporin-4 (AQP-4) water channel protein markedly advanced mechanistic understanding of neuromyelitis optica spectrum disorders (NMOSD).
  • New and emerging drugs that inhibit cleavage of the C5 complement protein have delivered notably improved outcomes in phase 3 clinical trials. One of these, eculizumab, is now approved by the US Food and Drug Administration (FDA) for treatment of NMOSD.
  • In the phase 3 CHAMPION-NMOSD trial, ravulizumab-cwvz — the first long-acting C5 inhibitor drug — has demonstrated efficacy and risk profiles similar to those of eculizumab.
  • Patient access to C5 inhibiting drugs remains a notable challenge to real-world care of NMOSD.

NMOSD consists of demyelinating autoimmune central nervous system (CNS) diseases, affecting particularly the spinal cord, brainstem, and optic nerves. The disorder’s clinical course is notable for highly disabling attacks or relapses. Compared with multiple sclerosis, the functional losses associated with such relapses are more often irreversible. Hence, this group of diseases, while rare, is disproportionately injurious.
Historically, NMOSD has been managed with corticosteroids and immunosuppressive drugs, such as azathioprine, rituximab, and mycophenolate mofetil. More recently, however, a new generation of therapies has emerged, informed by disease-specific knowledge. For example, as much as 88% of patients exhibit an immunoglobulin G (IgG) autoantibody to the AQP-4 water channel protein, which is abundant in the CNS.1 Binding of this antibody triggers the complement cascade, leading to injury of glial tissues. Discovery of this disease mechanism prompted development of a new line of therapy to block this process by inhibiting cleavage of the C5 terminal complement protein.
The phase 3 PREVENT trial ( identifier: NCT01892345) represented a landmark test of this strategy on the C5 cleavage inhibitor eculizumab, and the results were published in 2019.2 In 96 patients with NMOSD who were positive for the AQP-4 antibody, treatment with eculizumab resulted in a dramatic drop in disease relapses, which occurred in 3% of patients in the experimental group vs 43% in the placebo group.
More recently, researchers tested whether treatment with ravulizumab-cwvz, engineered from eculizumab to increase its half-life, would deliver similar results. Ravulizumab is the first long-acting C5 inhibitor; it is delivered by infusion every 8 weeks, whereas eculizumab is administered every 2 weeks in the maintenance phase of treatment. In the phase 3 open-label CHAMPION-NMOSD trial ( identifier: NCT04201262) of this drug, no relapses occurred in 58 patients with AQP-4-positive NMOSD treated for a median duration of 73 weeks.3
Sean J. Pittock, MD, is the director of Mayo Clinic’s Center for Multiple Sclerosis and Autoimmune Neurology, as well as Mayo Clinic’s Neuroimmunology Research Laboratory. His work has been essential to elucidating pathomechanisms in NMOSD. In addition, he is the principal investigator of the multiphase PREVENT and CHAMPION-NMOSD open-label trials of eculizumab and ravulizumab-cwvz. Dr Pittock shared his experiences and perspectives on the past, present, and future of NMOSD therapies.

Can you give an overview of the research and advances that led to C5 protein complement inhibition as therapy for NMOSD?

NMOSD is a serious disorder, characterized by relapsing optic neuritis and inflammation of the spinal cord. If left untreated, about 33% of patients become deceased by 5 years after onset, and 50% of survivors were in a wheelchair and blind after 5 years.4 This is a very severe illness.
The AQP-4 water channel protein autoantibody was discovered in 2004.5,6 This really revolutionized our understanding of neuromyelitis optica. It allowed us to really define the disease entity and to begin understanding the disease mechanism. This is in contrast to, for example, multiple sclerosis. We still do not have a good sense of exactly what is happening in multiple sclerosis because there is no biomarker; we do not know what the pathogenic target is in multiple sclerosis. But in neuromyelitis optica, with the discovery of the water channel antibody, we now suddenly have a target — that is, what the immune system is essentially targeting. That opened up a huge opportunity to understand mechanism.
What we learned through mechanistic studies was that the water channel the antibody binds to actually sits on astrocytes.7 This was surprising because previous work had been focused on the oligodendrocytes, which are the cells that myelinate, and this is a demyelinating disease. However, it turned out that the target — the first-ever target that has been identified for any form of inflammatory CNS-demyelinating disease — actually sits on the astrocytes. When the antibody binds to the water channel on the astrocytes, its major mechanism of injury is activation of the complement system. Activation of the complement causes enzymatic breakdown of the C5 protein into C5b and C5a. C5b action initiates assembly of the membrane attack complex, which injures and potentially kills the astrocyte. C5a is also a strongly inflammatory protein. It is through these 2 proteins, the C5a and C5b, that damage occurs in the context of the clinical attack.
There are many other mechanisms through which injury can occur in the CNS, but the core mechanism, in my opinion, is through the activation of the complement. In 2010, as we began to elucidate the role of the complement in neuromyelitis optica, we reached out to Alexion and conducted an investigator-initiated, open-label trial ( identifier: NCT00904826).8 We treated 14 patients at Mayo Clinic with eculizumab, and we essentially stopped the disease. We had selected very ill patients for that trial, and it was a dramatic result. That open-label trial led to the phase 3 PREVENT trial.2 This trial showed dramatic results; we essentially had a 94% to 95% risk reduction. Essentially, eculizumab was a wonder drug.
By stopping attacks in NMOSD, we believe we can stop the disease in its tracks and stop disability. In NMOSD, the disability accrues through the individual attacks — the relapsing phase of the illness — in contrast to multiple sclerosis, in which the disability accrues through the progressive phase of the illness.
Based on the results of that phase 3 trial, eculizumab became the first FDA-approved drug in North America for the treatment of NMOSD.9 I am not sure what proportion of patients with the disease are using the drug, but there is certainly a growing number of patients being prescribed eculizumab.
Interestingly, around the same time as these data released, data came out from 3 other trials. One of them was the N-MOmentum trial ( identifier: NCT02200770) of inebilizumab, which is a CD19 B-cell depleting drug, conducted by Cree and colleagues.10 That showed promising results, with a roughly 77% risk reduction, so the FDA also approved inebilizumab.11 We also had the SAkuraSky12 ( identifier: NCT02028884) and SAkuraStar13 ( identifier: NCT02073279) studies; these were phase 3 trials of satralizumab, which is an interleukin-6 inhibitor. Both of those studies also showed benefits. We called 2019 “the year of NMOSD” because we went from having essentially no approved treatments for a very rare disease to having 3, so this is good news for patients.

We called 2019 “the year of NMOSD” because we went from having essentially no approved treatments for a very rare disease to having 3, so this is good news for patients.

Even more recently, results from the open-label phase 3 CHAMPION-NMOSD trial of ravulizumab-cwvz illustrated a statistically and clinically significant reduction in the risk of relapse in adults with AQP-4 antibody-positive NMOSD.3 Can you further discuss this study?

One issue regarding eculizumab is that it has a short half-life, and it has to be given as an intravenous infusion every 2 weeks. A patient with some degree of disability having to go to an infusion center, or even receiving at-home infusion, every 2 weeks is problematic. It is also problematic for patients who are busy, functioning well, and are free of attacks while on this drug because they have to take time off work to get the infusion. In ravulizumab, the eculizumab backbone has been manipulated so that it has a longer half-life and, therefore, only has to be given every 8 weeks. It has been FDA-approved for other indications since 2018 and works well for diseases that are responsive to eculizumab.14 Thus, we thought that if we could get ravulizumab to work in place of eculizumab for NMOSD, this would be a great win for patients in terms of the frequency at which they had to get the infusion. That is what led to the CHAMPION-NMOSD study.
The CHAMPION-NMOSD study is quite novel in many respects, though some people may be critical of its design. It represents a seminal approach to drug design in rare diseases, especially when 1 or 2 drugs have been shown to be a benefit. A crucial question was how to have a placebo group. Even when we had no FDA-approved drugs for NMOSD, there was huge resistance to having a placebo group in the N-MOmentum trial. Eventually, the community came around, and the FDA pushed for a placebo group. The N-MOmentum study was well designed, with a placebo group, and demonstrated a good result. However, once eculizumab had been shown to be a dramatic game changer in this disease, we felt that it would be unethical to have a placebo group in the CHAMPION-NMOSD trial. What we did was an open-label trial, studying time to event (ie, time to relapse) but using the placebo group from the PREVENT trial as an external comparator. That may be considered a little novel, but I think it is very important as we move forward in figuring out how to get drugs to patients who have a rare disease and how we are going to design trials, especially if one drug looks like it is going to work well. One thing to realize is even if we had thought about doing an equivalence trial, or an inferiority trial, we would have needed upwards of 7000 to 8000 patients, and that would not be possible. Hence, I feel this study had a very nice design, and it showed incredible results, with 0 attacks in 58 patients over 73.5 weeks.3 By contrast, based on the placebo responses not only in the PREVENT trial but also in the SAkuraSky and SAkuraStar studies, and also based on the predictive mathematical modeling publications that we have,15 we would have expected somewhere around 40% of the 58 patients to have had an attack in that time frame if not treated with ravulizumab.

Administration frequency of ravulizumab-cwvz for NMOSD
Ravulizumab-cwvz was administered every 8 weeks intravenously in phase 3 trials for NMOSD.

Have any real-world differences in efficacy and risks been apparent between eculizumab and ravulizumab?

Generally, no. The sense is that the drugs work in a very similar fashion. For other indications in which eculizumab has been of benefit, such as in paroxysmal nocturnal hemoglobinuria (PNH) and more recently in myasthenia gravis, ravulizumab seems to do what eculizumab does. We were impressed by the risk reduction, which was 98.6% for ravulizumab3 compared to a risk reduction of 94% for eculizumab,2,16 so they are essentially the same.
There is a meningococcal infection risk with any drug that impacts terminal complement. Terminal complement is required for the eradication of certain types of pathogens, so the risk of meningococcal infection is 1000 to 2000 times higher than in the normal population. Overall, if you look at all patients that have been treated with these drugs, the risk is relatively low. Of course, there is always a roll of the dice in any kind of trial; there were 2 patients who had meningococcal infection in the CHAMPION-NMOSD study.3 The big question is whether there is a higher risk of meningococcal infections in patients receiving ravulizumab compared with patients receiving eculizumab. The answer is we do not know. We will need to follow this carefully as we move into the real world with patients on this drug for NMOSD. However, because we did not see any difference in meningococcal infection risk in PNH or in myasthenia gravis with ravulizumab compared with eculizumab, we hope that the infections in those 2 patients are not an indicator of significantly higher infection risk in patients with NMOSD who are receiving ravulizumab. The overall safety profile for ravulizumab in our study was similar to what has been published on use for other indications. Generally, it is a well-tolerated medication. We will have to follow that along and watch these patients very carefully.
The most important thing is to weigh the risks with the benefits. It is also important, in terms of the meningococcal issue, to mitigate the risk as best as possible. Patients should be informed that if they have any symptoms suggestive of a meningococcal infection, they should go to an emergency room immediately. In fact, the management and mitigation of meningococcal infection is quite varied throughout the world. For example, how one mitigates it in the United States is very different from how one mitigates it in France. I actually set up an international consortium of experts from around the world to come up with a consensus and agreement on recommendations for neurologists as they move forward in starting patients on this medication. That way, we can make sure we are all coming at it from the same perspective.

What current challenges and future advances do you see for complement inhibition therapy for NMOSD?

It is a good time to be working in the field of autoimmune neurological diseases. We have a lot of drugs coming down the pipeline that can target a variety of immunological mechanisms. In the trials I have been involved in, we had really good results for inebilizumab, eculizumab, and now ravulizumab. We also know that satralizumab works well.
One challenge is that we need to see patients with NMOSD getting on those drugs in countries where governments and insurance companies will allow them and to support patients in accessing FDA-approved drugs. There has been a reluctance to start patients on these drugs and a tendency to keep them on the old-style, nonapproved drugs. We do have 3 approved drugs — the community has done a lot of work to get these drugs through phase 3 trials. In North America, these drugs are covered; I have not had problems starting patients on these drugs. However, my strong sense is that more than 70% of patients are not on FDA-approved drugs for NMOSD. The first thing we need to do is figure out how to get these patients on the drugs that work.
The second problem is that these drugs are very expensive. They cost hundreds of thousands of dollars per patient per year. These drugs work wonderfully, but many patients cannot get them.
Hopefully, we can figure out some ways of helping individuals in countries without access. We hope the industry will find some ways to assist us in doing that. We also need to think about the possibility of other, smaller companies developing similar drugs that work through similar mechanisms, which potentially could be cheaper — perhaps oral medications that would be more accessible and convenient.
In addition, we need to better understand the disease. Even though we have these 3 drugs that work and have been approved for NMOSD, we still have a lot of questions regarding how they work. For example, with complement inhibition, where is the complement being inhibited? Is it across the blood-brain barrier? We know that only very small amounts of the drug are getting into the CNS, but you really need complete complement inhibition for that class of drug to work. So how and where exactly is it working? Furthermore, we occasionally have patients who have breakthrough episodes. Why are those patients experiencing a breakthrough? Interestingly, there are patients of Asian descent who have genetic mutations in complement-regulatory proteins, and they are not responsive to the medication.17 That is very rare, but we need to consider the subset of patients who are susceptible to relapsing. There is a lot to think about.

This Q&A was edited for clarity and length.


Sean J. Pittock, MD, reported affiliations with Alexion Pharmaceuticals, Inc; Arialys Therapeutics; Astellas Pharma US, Inc; Genentech Inc/Roche Group; Grifols; NovelMed Therapeutics; UCB Pharma Inc; and Viela Bio, Inc/MedImmune, LLC/Horizon Therapeutics plc.


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Reviewed January 2023