New treatments for neuromyelitis optica

“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)...

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 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 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.

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...

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.

“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.”... 

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.

https://n.neurology.org/content/92/15_Supplement/Plen02.001

Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, Nakashima I, Terzi M, Totolyan N, Viswanathan S, Wang KC, Pace A, Fujita KP, Armstrong R, Wingerchuk DM. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 May 3. doi: 10.1056/NEJMoa1900866. [Epub ahead of print]

Abstract

BACKGROUND:

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse.

METHODS:

In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death).

RESULTS:

The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group.

CONCLUSIONS:

Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.). 

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 https://n.neurology.org/content/92/15_Supplement/Plen02.001.

Abstract

Objective: To evaluate the safety and efficacy on relapse prevention, of inebilizumab, an anti-CD19, B-cell depleting monoclonal antibody in neuromyelitis optica spectrum disorder (NMOSD).

Background: Currently there are no approved therapies for NMOSD. Empiric experience suggests that depleting B-cells may have therapeutic benefit in attack prevention.

Design/Methods: N-MOmentum is a phase III, double-masked, randomized, placebo-controlled trial of inebilizumab (MEDI-551) in NMOSD. A three-member eligibility committee confirmed entry criteria for AQP4-IgG seronegative subjects. Participants were randomized 3:1 to either treatment with inebilizumab or placebo. Concurrent treatment with other immune suppressants was prohibited. The placebo-controlled period was limited to 6.5 months in duration. The primary outcome measure was time to first adjudicated attack. Clinical criteria for NMOSD attacks were developed and implemented. A three-member committee adjudicated all investigator-reported attacks. Patients who either experienced an adjudicated attack or completed the controlled phase of the study were offered treatment with inebilizumab in an open label extension study. Acute attacks were treated with the investigator’s choice of therapy.

Results: On September 7, 2018, the external data safety monitoring committee (DSMC) concluded that continued enrollment with potential exposure to placebo was no longer ethical due to demonstrated efficacy and safety. The DSMC recommended that all participants in the randomized controlled period be moved to active treatment with inebilizumab and that all study participants continue in the open label extension protocol for ongoing safety assessments. 230 subjects from 24 countries were randomized and dosed (planned sample size: 252). 212 were seropositive and 18 were seronegative for anti-AQP4 antibodies. 42 adjudicated attacks occurred in the controlled period. The study remains masked and data lock will occur in December 2018 after which analysis of the primary and secondary endpoints and safety will occur.

Conclusions: Top-line data on inebilizumab’s efficacy and safety in NMOSD will be presented.

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) https://n.neurology.org/content/92/15_Supplement/S43.008. (S43.008).

Abstract

Objective: To evaluate the efficacy of satralizumab (SA237) in subgroups of the SAkuraSky study (NCT02028884).

Background: Satralizumab, a recycling anti-IL-6 receptor monoclonal antibody, significantly reduced the risk of experiencing a protocol defined relapse (PDR) in NMOSD patients by 62% compared with placebo, in addition to baseline treatment in the overall population of the SAkuraSky study. At baseline, 66.3% of patients were AQP4-antibody (Ab) positive and 33.7% were AQP4-Ab negative.

Design/Methods: SAkuraSky is a randomized, double-blind, phase 3 study of satralizumab compared to placebo as add-on to baseline treatment (immunosuppressants and/or corticosteroids, both at a stable dose). Subjects were randomized to satralizumab (120 mg s.c.) or placebo administered at weeks 0, 2, 4, and Q4W thereafter. The primary endpoint was time to first PDR, adjudicated by a clinical endpoint committee. Pre-specified subgroup analyses included assessing the response to treatment by AQP4-Ab serostatus, baseline treatment, and region. Between-group hazard ratios were based on Cox proportional hazards models.

Results: Satralizumab showed a 79% risk reduction of PDR compared to placebo in the NMO/NMOSD AQP4-Ab positive subgroup (HR, 0.21; 95% CI, 0.06–0.75). The proportion relapse free at weeks 48 and 96 were 91.5% (95% CI, 69.6%–97.8%) and 91.5% (95% CI, 69.6%–97.8%) with satralizumab and 59.9% (95% CI, 36.3%–77.3%) and 53.3% (95% CI, 29.3%–72.4%) with placebo, respectively. For the NMO/NMOSD AQP4-Ab negative subgroup, satralizumab showed a risk reduction of PDR of 34% compared to placebo (HR, 0.66; 95% CI, 0.20–2.23), and the proportion relapse free at weeks 48 and 96 were 84.4% (95% CI, 50.4%–95.9%) and 56.3% (95% CI, 24.2%–79.2%) with satralizumab, and 75.5% (95% CI, 41.6%–91.4%) and 67.1% (95% CI, 34.2%–86.2%) with placebo, respectively.

Conclusions: The subgroup data show that satralizumab is effective in reducing PDR, especially in NMO/NMOSD AQP4-Ab positive patients. Results and conclusions from additional subgroups will be presented at the conference.