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Inebilizumab Beneficial Across Genotypes in NMOSD

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NATIONAL HARBOR, Md. — Treating neuromyelitis optica spectrum disorder (NMOSD) with the recently approved monoclonal antibody inebilizumab (Uplizna, Horizon Therapeutics) is effective across patient genotypes — including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.

The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.

A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.

Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.

“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” co-investigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences, said in a press release.

“The combination of efficacy, safety, and ease of administration with twice yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Cree told Medscape Medical News.

The findings were presented at the Consortium of Multiple Sclerosis Centers (CMSC) 2022 Annual Meeting.

B-Cell Depletion

Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.

The drug’s B cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.

Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers note.

Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.

This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.

With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.

Although inebilizumab joins two other Food and Drug Administration-approved (FDA) treatments for NMOSD — eculizumab and satralizumab — neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.

To evaluate inebilizumab’s effects among patients with the F/F allele, Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.

The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous (IV) inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.

Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.

No Significant Differences

Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.

During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.

The AAR was 0.1 for the V allele group vs 0.3 for the F/F allele group (hazard ratio, .40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs 1.7 (risk ratio, .91; P = .88), respectively.

However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.

“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants compared to F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators report.

“No differences in B cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they add.

Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor.

“These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.

Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation.

That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.

A New Era?

Commenting for Medscape, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital in Boston, said the findings provide valuable insights into risks for key patient subgroups.

“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, that people with this particular genotype do have lower response and are more likely to be refractory,” said Matiello, who was not involved with the research.

He noted that rituximab is the most commonly used medication in the United States for NMOSD.

“It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.

The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.

“I think it’s a new era,” Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”

The study was funded by Horizon Therapeutics. Cree has consulted for Horizon Therapeutics. Matiello reported no relevant financial relationships.

Consortium of Multiple Sclerosis Centers (CMSC) 2022 Annual Meeting. Abstract #NDM01. Presented June 2, 2022.

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