Uplizna Equally Effective in Patients With or Without Genetic Variants

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Uplizna (inebilizumab-cdon) works to treat people with neuromyelitis optica spectrum disorder (NMOSD) regardless of whether such patients carry genetic variants linked to poor responses to other B-cell depleting therapies, new trial data show.

An analysis of N-MOmentum Phase 2/3 data found that the approved therapy was as effective in individuals with such genetic variants as it was for patients who did not carry them.

This is due to the therapy’s unique design, optimized to overcome these challenges, according to researchers.

“Inclusion of genetic biomarkers helps explain the true impact of our therapeutics on patient populations in need of innovative medicines,” Kristina Patterson, MD, PhD, the medical director of neuroimmunology at Horizon Therapeutics, the company marketing Uplizna, said in a press release.

“The results from the pivotal trial for Uplizna demonstrate the effectiveness of Uplizna across patient genotypes [genetic backgrounds] in NMOSD and further reinforce the mechanistic differentiation of its design,” Patterson added.

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These findings are being presented at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, being held in Maryland June 1–4.

NMOSD is an autoimmune disease in which the immune system wrongly produces antibodies that attack cells that support the nervous system, causing inflammation in the optic nerve and spinal cord.

Uplizna is an antibody-based, B-cell-depleting therapy approved in the U.S. and Europe for adults with NMOSD who test positive for antibodies against aquaporin-4, the most common target of NMOSD-related antibodies.

Administered directly into the bloodstream twice a year, the therapy promotes the death of B-cells — the immune cells that make antibodies — by binding to a protein found at their surface. That protein is called CD19.

The therapy’s mechanism of action is similar to that of rituximab (sold as Rituxan and others). That antibody-based, B-cell depleting therapy is commonly used off-label for NMOSD. It instead targets the CD20 protein at the surface of B-cells.

Both treatments are thought to induce B-cell death through an immune response called antibody-dependent cell-mediated cytotoxicity (ADCC), in which immune cells carrying cell surface proteins called Fc gamma receptors recognize and kill antibody-coated cells.

Notably, having a variant, or genetic polymorphism, in FCGR3A, the gene that provides instructions to produce the Fc gamma receptor 3A, has been shown to affect the binding of these receptors to antibodies.

Specifically, the FCGR3A-158F variant is associated with a weaker binding to antibodies and poorer responses to rituximab. Meanwhile, the FCGR3A-158V variant is linked to enhanced response to antibody treatment.

Uplizna was designed not only to strongly bind to CD19 on B-cells’ surface, but also to boost binding to Fc gamma receptors on the surface of immune cells involved in ADCC.

Now, scientists investigated whether these common FCGR3A variants affected the efficacy of Uplizna. The team evaluated data from the pivotal Phase 2/3 N–MOmentum trial (NCT02200770), which had supported the therapy’s approvals.

The study had included 230 adults with NMOSD who were randomly assigned to receive either Uplizna or a placebo on days 1 and 15, and then were followed for about 6.5 months. Results had shown that the B-cell therapy significantly reduced the risk of NMOSD attacks, disability worsening, brain lesions, and NMOSD-related hospitalizations relative to the placebo.

For the study presented at the CMSC meeting, genetic analysis of FCGR3A polymorphism was performed for 142 participants.

No differences were found in disease attacks or disability level regardless of the patients’ FCGR3A genetic profile. That means that having a variant associated with worse treatment efficacy is not linked with inferior benefits with Uplizna.

“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,” said Bruce Cree, MD, PhD, a study author and a professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences.

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