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Three New Treatment Options for Neuromyelitis Optica Spectrum Disorder
‘What A Difference A Few Years Make’

Article In Brief

Three phase 3 trials of drugs with different mechanisms showed promising results for preventing relapses in neuromyelitis optica spectrum disorder.

PHILADELPHIA—The name of the presentation said it all: “Neuromyelitis Optica Spectrum Disorder [NMOSD]: What a Difference a Few Years Makes.”

Stacey Clardy, MD, PhD, was just as emphatic when she gave the year-in-review talk at the closing plenary session at the AAN Annual Meeting here.

“This year has been the most exciting year for NMOSD in the past 200 [years],” Dr. Clardy, assistant professor of neurology at University of Utah, told the audience (The disease features were first recognized more than 200 years ago, and the term, neuromyelitis was coined more than 100 years ago.) She was referring to the fact that three phase 3 clinical trials found three different drugs with different mechanisms of action highly effective at reducing relapse in NMOSD, a rare autoimmune, inflammatory disorder of the central nervous system, for which there are currently no approved treatments. NMOSD causes recurrent optic neuritis and myelitis and can lead to paralysis and blindness as well as death.

At the AAN Annual Meeting, researchers presented data from phase 3 clinical trials—for eculizumab, inebilizumab, and satralizumab—which are all likely to gain Food and Drug Administration (FDA) approval for NMOSD in the months ahead, experts said. The drugs are particularly promising for NMOSD patients with antibodies to aquaporin-4 (AQP4-IgG).

The AAN's Science Committee highlighted the eculizumab study at a press conference as one of three “top science” abstracts that illustrate how breakthroughs in basic science can be translated into better therapies for patients with a rare disease.


“All we can tell you is that we have three drugs when last year we had none,” said Sean J. Pittock, MD, director of Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and of Mayo's Neuroimmunology Research Laboratory in Rochester, MN. Dr. Pittock led the eculizumab study and presented the findings at an “emerging science” session.

Various immunosuppressant drugs, including rituximab, are used off label to prevent recurrent attacks, he said, but about 25 to 60 percent of patients continue to have attacks despite treatment. With the current findings, he said, “it is a very bright day for patients.”

A breakthrough toward drug development came when it was discovered that about two-thirds of patients have antibodies against AQP4, a water channel protein expressed by astrocytes in the central nervous system, Dr. Pittock said.

Research indicates that AQP4-IgG triggers what's known as the complement cascade, which causes inflammation and formation of the membrane attack complex. Eculizumab inhibits the terminal complement protein, interrupting the inflammatory process that leads to an attack.

The findings of the phase 3 trial of eculizumab, known as PREVENT, were also published in the May 3 online edition of The New England Journal of Medicine.

The trial involved 143 NMOSD patients who were all AQP4 antibody-positive. It randomized 96 patients to intravenous eculizumab—at a dose of 900 mg weekly for the first four doses, followed by 1200 mg every two weeks. starting at week four—and 47 to placebo. Patients were allowed to continue on other immunosuppressants except rituximab.

The primary endpoint was the first adjudicated relapse. The study was stopped after 23 of the 24 prespecified adjudicated relapses, after enough relapses occurred to draw conclusions, Dr. Pittock said.

The study found that eculizumab reduced the risk of a recurrent attack by about 94 percent. At 48 weeks, just under 98 percent of those who received eculizumab were relapse-free, compared with about 63 percent of the placebo group. A similar spread continued at 96 weeks.

The study authors reported no differences in measures of disability progression between the two groups but said more research is needed to evaluate the long-term effects of eculizumab.

Upper respiratory tract infections and headaches were more common in the eculizumab group, the researchers reported, and there was one death from pulmonary empyema in that group. Because blockage of the terminal complement protein leaves patients susceptible to meningococcal disease, all patients were vaccinated against it. No such infections occurred, the researchers reported.

The drug is being developed by Alexion and may get FDA approval soon, said Dr. Pittock.

Inebilizumab Results

The second set of results of the phase 3 study, called N-MOmentum, were presented at a plenary session by lead investigator Bruce Cree, MD, PhD, MAS, professor of clinical neurology at University of California, San Francisco. The trial randomized 231 patients to either intravenous inebilizumab or placebo at day one and 15, and then every six months after that. Ninety-one percent of participant tested seropositive for anti-AQP4 antibodies, a biomarker for NMOSD. This study was a monotherapy study and participants were not allowed to continue taking previous immunosuppressant therapies during the trial. The primary outcome was time to first attack.

The study reported that in the AQP4- positive patients inebilizumab resulted in a 86 percent reduction in risk of a recurrent attack compared with 57 percent in the placebo arm during the 28 weeks of the trial; 86 percent of those taking the drug remained relapse-free compared with 57 percent on placebo. For patients overall, there was a 73 percent reduction in attack recurrence for those on the drug compared to placebo.

Recruitment to the randomized controlled trial was stopped early upon recommendation of an independent Data Monitoring Committee due to evidence of efficacy and concern for ongoing exposure to placebo, Dr. Cree said. Study participants were rolled over into an open-label extension trial to give all patients access to the drug.


“To go from nothing proven to three trials, this will be transformative for patients and their families.”


Dr. Cree said inebilizumab also outdid the placebo when it came to other measures including reducing disability (by measure of the Expanded Disability Status Scale, lesions evident on MRI, and disease-related hospitalizations. However, there were two deaths in the open-label portion of the trial, Dr. Cree said, one due to complications from a severe NMOSD attack and the other from ventilator acquired pneumonia after a brain event of unclear etiology.

“Basically at the end of the day you have three (new) treatments that have a very robust effects and reduce the likelihood of a patient having another attack,” said Dr. Cree in a follow-up interview with Neurology Today. “To go from nothing proven to three positive trials, will be transformative for patients and their families.”

He said all three drugs have a “reasonable safety profile.” Dr. Cree, who has no financial ties to the company developing inebilizumab, Viela Bio, said the drug is the only one of the three NMOSD drugs presented at the AAN meeting that demonstrated a statistically significant effect in reducing disability progression and MRI lesions. The drug received both Orphan Drug Designation and Breakthrough Therapy Designation from the FDA, according to a company statement.

Dr. Cree said credit is due to the many scientists and clinical researchers for identifying and testing new approaches to treat NMOSD.

“A lot had to do with better understanding of the pathogenesis of the disease...and companies saying they were willing to take a chance with a relatively rare neurologic disorder,” Dr. Cree told Neurology Today.


The third trial involved satralizumab, which is an anti-IL 6 receptor monoclonal antibody. Takashi Yamamura, MD, PhD, director of the National Institute of Neuroscience in Tokyo, presented data at the AAN meeting showing that the drug achieved an overall 62 percent reduction in relapse compared to placebo and was especially beneficial for AQP4-IgG seropositive patients.

In the study, known as SAkuraSky, 83 NMOSD patients were randomized to satralizumab or placebo as an add-on to their baseline treatment of immunosuppressants and/or corticosteroids. At baseline, 66.3 percent of the patients were AQP4 antibody-positive and 33.7 percent were AQP4 antibody-negative. The patients received a subcutaneous dose of satralizumab at weeks two, four, and every four weeks after that.

The study had an open-label extension period that included patients who experienced a relapse requiring treatment of rescue therapy and/or a protocol defined relapse adjudicated by the Clinical Endpoint Committee, or those who remained in the trial when the 26 protocol defined relapses were accumulated in the trial , Dr. Yamamura said. The primary endpoint was first time to a relapse as defined by the protocol.

Dr. Yamamura reported that the preplanned subgroup analysis found that the drug resulted in a 79 percent reduction in relapse risk compared to placebo for the AQP4-Ab positive group. The proportion of those patients who remained relapse free at 48 and 96 weeks was 91.5 percent compared with 59.9 percent and 53.3 percent for placebo at the same time intervals.

Results were more modest for the AQP4-Ab negative patients, in which satralizumab resulted in a 34 percent reduction in relapse compared to placebo.

Dr. Yamamura reported that the proportion of patients experiencing adverse events and serious adverse events, including serious infections, was no higher among the satralizumab group compared to placebo. No deaths or anaphylactic reactions occurred, he said.

“Although the safety and efficacy of the IL-6 receptor blocking antibody was previously described for rheumatoid arthritis, the results of our study indicate that IL-6 receptor blockade by the new drug satralizumab, a recycling antibody, is very useful and promising for treatment of NMOSD, with regard to the efficacy and safety,” Dr. Yamamura commented to Neurology Today.

Satralizumab, under development by Chugai Pharmaceutical Co. in conjunction with Roche, received a breakthrough therapy designation by the FDA late last year based on the SAkuraSky results.

The drug has also been tested as a monotherapy in a randomized, controlled trial involving 95 patients and reached the desired endpoints, Dr. Yamamura said.

Effects on Clinical Practice

Steven L. Galetta, MD, FAAN, the Philip K. Moskowitz, MD, Professor and chair of neurology at NYU Langone Health, said he shares in the enthusiasm around the three new potential treatments for NMOSD, noting that “it is a devastating disorder” with attacks that can be “difficult and dramatic.”

He said that up to 60 percent of patients may become blind in one or both eyes and at least 50 percent develop ambulatory difficulties in five to 10 years if untreated.

“The disease, unlike MS, is marked more by distinct relapses and not disease progression,” Dr. Galetta said. “If you stop the relapses you stop the disease.”

He said some NMOSD patients already do well on drugs such as rituximab, so it remains to be seen what prescribing patterns will develop if the three new drugs come to market for NMOSD as expected.

“These are powerful options and it's always good to have powerful options when dealing with something like NMO,” he said. He said issues such as the price mode of drug delivery, patient preferences, and side effects will all factor into treatment decisions.

Dr. Clardy, a neurologist specializing in autoimmune diseases at the VA Salt Lake City and the University of Utah, reiterated in a follow-up interview with Neurology Today that the progress with NMOSD has been impressive.


“I don't think we are going to see people change (to them) if they have stable disease for a period of time. ...the good news for patients is that I can give them a Plan A, a Plan B, a Plan C.”


“In the space of 15 years since the Mayo group identified the (AQP4) antibody, there have been three clinical trials completed,” she said. Another antibody known as MOG IgG has also recently been identified in association with some previously seronegative cases of NMOSD, and this will hopefully be a target of future research and trials, she said. Dr. Clardy noted that the Guthy-Jackson Charitable Foundation was integral in organizing and catalyzing many research efforts.

Though she is excited about the new therapies, Dr. Clardy said: “I don't think we are going to see people change (to them) if they have stable disease for a period of time on existing non-FDA approved therapies.”

At the same time, “the good news for patients is that we now have many options—we can outline a plan A, a plan B, a plan C, in the event one medication doesn't work for them.”

“There are three good trials that are prospective, randomized. This is high-quality data. I can have meaningful discussions with patients about what this data means in the context of their condition; our discussions will be less speculative and more evidence-based,” she said.

Having drugs FDA-approved specifically for NMOSD, rather than using drugs off label, may also make life a bit easier for doctors as they deal with insurance companies, she said.

“As neurologists who treat rare disease, we spend a lot of time on the phone with insurance companies trying to plead our patient's case, and essentially begging for coverage of therapy,” Dr. Clardy said. Having data from well-done randomized, controlled trials helps support the argument for why a drug is warranted, she said.

But she said the cost of the new drugs, which has yet to be determined (and could approach $500,000 or more annually for one of the drugs, she said), could in the end be the weightiest determinant of all.

“As neurologists in the modern era, we have an obligation to discuss the potential for personal financial toxicity with our patients. With new treatments comes great opportunities, but also costs, and I don't want my patients to go bankrupt paying for their therapies,” she said.


Dr. Pittock has received an honorarium and travel expenses for speaking and/or serving on the advisory board of Alexion Pharmaceuticals; the compensation for consulting, research and grant support is paid directly to the Mayo Clinic. He also received an honorarium and travel expenses to attend the NMOSD advisory board meeting in March. Dr. Cree has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Abbvie, Akili, Biogen, EMD Serono, GeNeuro, and Novartis. Dr. Yamamura has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Japan Ltd., Takeda Pharmaceutical Co., Ltd, Novartis Pharma K.K., Mitsubishi Tanabe Pharma Corp., Sumitomo Dainippon Pharma Co., Ltd., Daiichi Sankyo Co., Ltd. Medical Review Co. Ltd. Chiome Bioscience Inc., and the Miraca Research Institute. He has received compensation for serving on the board of directors of Mitsubishi Tanabe Pharma, Novartis, Nihon, Santen, Abbott Japan/Eisai, Biogen Japan, Dainippon Sumitomo, Bayer Holding, and Astellas Pharma Inc., and Takeda Pharmaceutical Co., Ltd. Dr. Yamamura also has received research support from Chugai Pharmaceutical Co., Ltd., Biogen Japan Ltd., Novartis Pharma K.K., Chiome Bioscience Inc., and the Miraca Research Institute.

Link Up for More Information

•. Pittock SJ, Berthele A, Fujihara HJ, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder N Engl J Med 2019; Epub 2019 May 3.
    •. Cree B, Bennett J, Kim HJ, et al.AAN Abstract Plen02.001: A double-masked, placebo-controlled study with open-label period to evaluate the efficacy and safety of inebilizumab in adult subjects with neuromyelitis optica spectrum disorders–Top line efficacy
      •. Yamamura T, Kleiter I, Fujihara K, et al.AAN Abstract S43.008: Efficacy of satralizumab (SA237) in subgroups of patients in SAkuraSky: A phase III double-blind, placebo-controlled, add-on study in patients with neuromyelitis optica spectrum disorder (NMOSD) (S43.008).