Bruce Cree, MD, PhD, on the Historically Fast Progress Made in NMOSD Care

Hoffman,Matt;

News

Article

August 25, 2021

NeurologyLive

November 2021

Volume4

Issue 6

Bruce Cree, MD, PhD, on the Historically Fast Progress Made in NMOSD Care

Author(s):

Matt Hoffman

The clinical research director of the UCSF Multiple Sclerosis Center shared his perspective on the history of clinical care for neuromyelitis optica spectrum disorder in light of 3 recent FDA approvals.

Bruce Cree, MD, PhD, MAS

Despite the medical community’s awareness of the disease since as early as the 1890s, the treatment of neuromyelitis optica spectrum disorder (NMOSD) has only begun to evolve—at an almost unprecedented pace—since the discovery of aquaporin-4 in the early 2000s.^1,2 After just 15 years, the thousands of patients in the US with the rare disorder have been introduced to 3 novel therapies with high rates of efficacy, beginning with the 2019 approval of eculizumab (Soliris; Alexion).³

Very little of the history of NMOSD has been recorded,^2,4 and a similar level of understanding existed about its pathogenesis and distinction from multiple sclerosis (MS) until the late 1990s at the earliest.^5,6 Bruce Cree, MD, PhD, MAS, FAAN, clinical research director, UCSF Multiple Sclerosis Center, and professor of clinical neurology, UCSF Weill Institute for Neurosciences, explained that until the early 2000s, most patients with NMOSD were misdiagnosed with MS, and often were treated with therapies that worsened their condition.

To find out more about the history of the clinical care of NMOSD and the effect that this recent influx of therapeutic options has had on the patient population and those providing care, NeurologyLive inquired further with Cree. He offered his expert insight into work that laid the foundation for these recent advances and perspective on the new therapies.

NeurologyLive: With 3 new therapies being approved in recent years, how would you describe the state of care currently for NMOSD?

Bruce Cree, MD, PhD: The remarkable aspect of this story is that in a relatively short period of time, we've gone from a disease that had no proven therapies to a disease that has 3 proven therapies. Backing it up a little bit, it wasn't even that long ago that there was an ongoing debate as to whether NMO was a distinct disease entity or not. Now it is clearly recognized as being distinct from multiple sclerosis—it shares some clinical features for sure. It is a central nervous system autoimmune disease, just like MS. But we have learned so much about NMO pathogenesis that has been incredibly informative for drug development.

What has that work entailed that’s driven the field to this point?

Some of the earliest work began with work that Claudia F. Lucchinetti, MD, had done at the Mayo Clinic, where she identified the presence of antibodies and complement within pathological lesions and NMO. That led to some of us thinking that perhaps MMO was a B-cell–mediated disorder where antibodies and compliment were involved. That led to the initial treatment with rituximab in a patient with NMO in 2002, where we saw remarkable recovery—almost Lazarus-like treatment response.

Subsequent to that, an antibody that is strongly associated with MMO, the NMO IgG antibody which is directed against aquaporin-4 was identified by Vanda A. Lennon, MD, PhD, and colleagues, also at the Mayo Clinic.⁶ That was around 2006, and it was the start of our real understanding that NMO was a distinct disorder from MS, and that there was a pathogenic antibody involved. Work done by Jeff Bennett, MD, PhD, and others demonstrated clearly that this NMO antibody that recognizes aquaporin-4 was pathogenic and caused very similar lesions histopathologically with astroglial injury in animal models.⁷ Additional work done later again showed the presence of complement within these lesions, and then it became increasingly clear that the aquaporin-4 antibody was capable of fixing complement.

That led to the idea that perhaps by complement inhibition, we would be able to have an impact in NMO. Work by many others has also shown that the inflammatory aspect of NMO, which is much more inflammatory than MS is, at least in part mediated by high levels of expression of interleukin 6. Studies looking at the CSF in patients who had a huge NMO attack showed high levels of interleukin 6, a proinflammatory cytokine that helps recruit additional inflammatory cells to the central nervous system. This led to the idea that perhaps by inhibiting interleukin 6 through, initially tocilizumab, and now through satralizumab, that that might be a strategy for an impact in NMO, as well.

All of this has led to the development of inebilizumab, a B-cell depleting antibody therapy, satralizumab, an interleukin 6 receptor blocker, and eculizumab, a terminal complement inhibitor, to be developed in NMO—and all 3 products work. And not only do they work, but they work incredibly well with respect to therapeutic efficacy, certainly stunningly. All these drugs offer 70% plus effects on attack reduction, and those kinds of effects are uncommon in medicine. A lot of the time we were excited by relatively small changes, but here all 3 of these drugs have a tremendous clinical effect and therapeutic benefit for patients. It's gone from a disease that, when I first started my work in NMOSD 20 years ago, was very difficult to treat. It was often likened to malignancies of the central nervous system in terms of bad outcomes and was a disease that would cause a lot of blindness, paralysis, and even death. And we've gone from that state now to having drugs that work unbelievably well. This is an extraordinarily exciting development for science. It's not that many years of work that has taken us from what was considered by many an incurable, fatal illness to a disease that now has not 1, not 2, but 3, FDA-approved treatments. It's really remarkable. There are many, many people whose work has contributed to these products’ development, as well as the basic science and translational science, that led to the development of these 3 drugs.

What's been the effect on the day-to-day care of patients? Have these therapies been able to make an impact thus far?

That is an evolving story, for sure. You know, part of the challenges with drug development in this disease space is that it is a relatively uncommon illness. So, getting drugs to patients can be quite a challenge. First, identifying the patients who need treatment, then selecting appropriate treatment for that patient, and then getting it authorized through an insurance provider.

Now, as exciting and wonderful as it is to have 3 highly effective drugs available, there are challenges with getting these medications to patients. All 3 drugs are extraordinarily expensive. That is a major barrier to access, not surprisingly. We're seeing a gradual take-up of use of these products, but I think a lot of people who manage MS care are still using empirically derived therapies like mycophenolate mofetil, azathioprine, and rituximab, as well as daily chronic prednisone for the treatment of NMO. For newly diagnosed patients, they think they're going to be offered perhaps, more frequently, the newer treatments, but there are still major barriers of access that have to be overcome.

I personally do think that drugs that have gone through the rigors of clinical trials where you can really explain to a patient what the actual efficacy and safety profile is, in my mind, have a clear advantage over empirically derived off-label therapies where you say, “Well, we think it works, but we don't really know for sure.” I definitely have a bias in that regard, just generally speaking. If there's nothing available, then, hey, there's nothing available. And then of course, you're going to use whatever you can. When you have FDA-approved drugs that have gone through the process, I think you have to, at the very least, discuss those treatments with your patients and not simply rely on older therapies that have been around for a while that you have more comfort and familiarity with.

Two of the products were also launched during the pandemic. I would say that that has been a major inhibitor because normally when a product is launched, there's some fanfare around it, and you get to hear about it at meetings. That element is simply been missing from this entire experience, and I think that is a challenge. Getting the word out, having clinicians become familiar with the use of the drugs, what their ins and outs are—each of them has unique features with respect to the route of administration, frequency of administration, what you need to know about the products to provide them safely. Each of these drugs takes a little bit of effort to get physicians up to speed with them. The fact that all of this occurred during the pandemic has been a real inhibitor on getting that kind of medical education out.

Transcript edited for clarity.