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PHILADELPHIA -- Three different drugs in phase III trials demonstrated lower relapse rates in neuromyelitis optica spectrum disorder (NMOSD), especially among people with aquaporin-4 antibodies (AQP4-IgG), researchers reported at the 2019 American Academy of Neurology (AAN) annual meeting.

In the trial, people with NMOSD (also called NMO) and AQP4-IgG experienced a 94% reduction in relapse risk with eculizumab (Soliris) compared with placebo. In , AQP4-IgG positive patients treated with inebilizumab (MEDI-551) had a 77% reduction of relapse risk over placebo. And in , treatment with satralizumab (SA237) led to a 79% risk reduction of relapses vs placebo among the subgroup of patients who were AQP4-IgG positive.

"2019 is the year of NMO," said Natalia Rost, MD, of Massachusetts General Hospital in Boston and chair of the AAN meeting's scientific committee.

"The Holy Grail of science is to be able to identify the basic pathology that underlies disease. That's what happened in the story of NMO," Rost told 名媛直播. "We have known about the disease for a long time: we knew these were patients who looked like they had multiple sclerosis (MS), but it was not quite MS. The breakthrough came with the discovery of aquaporin-4 antibodies; that changed everything."

NMOSD is a relapsing autoimmune inflammatory disorder characterized by recurrent optic neuritis and myelitis. The prevalence is 0.5 to 10 persons per 100,000, predominantly women.

From 65% through 88% of NMOSD patients produce antibodies that target the water-channel protein AQP4. Binding of AQP4-IgG antibodies to central nervous system cells is thought to trigger NMOSD attacks.

"Untreated, this disease is devastating for patients," said Sean Pittock, MD, of the Mayo Clinic in Rochester, Minnesota, who led the PREVENT study presented at the meeting's Emerging Science session. "It can result in blindness or paraplegia in about half of patients within about 5 to 10 years."

Unlike in MS, disability in NMOSD is due to attacks, not disease progression between attacks. Each attack leads to more damage. "If we can stop attacks, we can stop disability in this disease," Pittock told 名媛直播.

No drugs are approved to treat NMOSD. Immunosuppressive therapies including rituximab (Rituxan) are used for relapse prevention off-label, but 25-60% of patients using these medications continue to have recurrent attacks, he noted.

The three drug trials aimed to prevent attacks at different points along the disease pathway. PREVENT targeted complement activation, N-MOmentum used a CD19 B-cell depleting monoclonal antibody, and SAkura-Sky tested an IL-6 inhibitor.

Eculizumab

have indicated that AQP4-IgG triggers the complement cascade, leading to inflammation and the formation of the membrane attack complex. PREVENT studied 143 NMOSD patients with AQP4-IgG, randomized 2:1 to the anti-complement C5 drug eculizumab or placebo.

Stable-dose supportive immunosuppressive therapy except rituximab was permitted. People who had received rituximab in the prior 3 months were excluded because its B-cell depleting mechanism was incompatible with eculizumab.

Eculizumab showed a significant effect on time to first on-trial relapse, the study's primary endpoint, demonstrating a 94.2% reduction in relapse risk compared with placebo. At 48 weeks, 97.9% of eculizumab-treated patients were relapse-free, compared with 63.2% for placebo.

Because it blocks the terminal complement system, eculizumab increases the risk of meningococcal infection. The drug, which is including generalized myasthenia gravis, carries a to that effect.

In PREVENT, all patients received meningococcal vaccination and no cases of meningitis were reported. Higher rates of upper respiratory infection and headache were seen in the eculizumab-treated group, and one patient who had received concomitant azathioprine (Azasan) died from infectious pleural effusion after 108 weeks in the trial. The safety profile was consistent with what occurs when eculizumab is used for other indications, Pittock noted.

Inebilizumab

N-MOmentum tested inebilizumab, an anti-CD19, B-cell depleting monoclonal antibody. "Multiple lines of evidence suggest that NMOSD is a B-cell mediated disorder," said Bruce Cree, MD, PhD, of the University of San Francisco Medical Center, who presented N-MOmentum results at the Clinical Trials Plenary Session. In NMOSD, CD19 is expressed widely throughout B-cell development, more widely than CD20, he added.

The study randomized 230 NMOSD patients 3:1 to inebilizumab or placebo. Concurrent treatment with immune suppressants was prohibited. Most (91%) of the study sample was seropositive, and participants were followed for 28 weeks.

The primary endpoint was the time to an attack among all participants and among people who were AQP4-IgG positive. Relative to placebo, inebilizumab reduced the risk of an attack by 77.3% in AQP4-IgG positive patients and 72.8% in the entire treated population. At the end of the randomized-controlled period, 89% of AQP4-IgG positive patients treated with inebilizumab were attack-free vs 58% in the placebo group.

Inebilizumab and placebo groups showed similar rates of adverse events and serious adverse events. There were no deaths in the randomized-controlled period, but two deaths occurred in the open-label period -- one related to a severe attack, the other to a brain event of unclear etiology.

Satralizumab

SAkuraSky investigated the anti-IL-6 receptor monoclonal antibody, satralizumab, as add-on to baseline treatment with immunosuppressants, corticosteroids, or both.

"IL-6 is thought to impact B-cell mediated features of NMOSD pathogenesis, including AQP4-IgG autoantibody production," said Takashi Yamamura, MD, PhD, of the National Institute of Neuroscience in Tokyo, in an immunotherapy scientific session.

A total of 83 participants in SAkuraSky were randomized 1:1 to satralizumab or placebo. About two-thirds of people in both groups were AQP4-IgG positive.

Compared with placebo, satralizumab showed a 62% relapse risk reduction overall and a 79% relapse risk reduction among AQP4-IgG positive participants. "Treatment benefit was less evident in the small population of AQP4-IgG seronegative patients," Yamamura said.

The number of adverse events and serious adverse events were similar in the satralizumab and placebo groups -- most commonly, infections -- and no deaths occurred.

Full results of the eculizumab PREVENT trial were last week in the New England Journal of Medicine. Of the three drugs, eculizumab is poised to hit the market first: a decision from the FDA is expected by , according to drugmaker Alexion Pharmaceuticals.

Based on the N-MOmentum trial results, the FDA granted Breakthrough Designation last month, making the investigational drug from Viela Bio eligible for expedited regulatory review. Roche and Chugai's also received Breakthrough Designation based on the SAkuraSky phase III results. In addition, satralizumab also met its in a phase III monotherapy trial, .