STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.
Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.
The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.
Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.
“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.
“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”
The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.
Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.
Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.
By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).
“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.
Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.
A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.
The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.
Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”
The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.
Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.
The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.
SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.