Therapy Areas: Central Nervous System
Horizon Releases Analysis from Phase 3 N-MOmentum Study of Uplizna Among Neuromyelitis Optica Spectrum Disorder Patients with Genetic Variations
31 May 2022 - - Dublin-based biotechnology company Horizon Therapeutics plc (NASDAQ: HZNP) has released data from the Phase 3 pivotal trial of Uplizna in NMOSD illustrating the treatment's effectiveness among patients with different genetic make-ups, including those with certain variations associated with reduced response to conventional monoclonal antibody therapies.

These data are being presented during the Consortium of Multiple Sclerosis Centers annual meeting, June 1-4.

Treatment for NMOSD includes the use of mAbs that bind to and deplete the B cells that drive disease activity. Increasingly, therapeutic research has shown that genetic variations in the immune system can affect the efficacy of these mAb therapies.

Specifically, a variation, or polymorphism, in a gene that encodes the low-affinity Fc gamma receptor IIIa (FCGR3A) has been shown to reduce the effectiveness of certain mAbs, like rituximab, in diseases including NMOSD.

Uplizna is a highly specific CD19 B-cell depleting agent that targets an extended range of B cells, including plasmablasts and plasma cells, which contribute to NMOSD.

Uplizna was purposely engineered to allow for strong binding to the low-affinity Fc gamma receptor IIIa (FCGR3A).

This molecular engineering has been shown to improve efficacy in patients regardless of FCGR3A genotype.

Data from the N-MOmentum pivotal trial of UPLIZNA (NCT02200770) illustrates the potential advantage of the design of UPLIZNA.

As part of the trial, 142 participants underwent genotyping to identify FCGR3A genotype.

The study found no significant differences in disease attacks or disability regardless of FCGR3A genotype, indicating the design of Uplizna was effective even among those whose polymorphism is associated with reduced efficacy of other treatments.

NMOSD is a unifying term for neuromyelitis optica and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.

Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies. AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.

Anti-AQP4 autoantibodies are produced by plasmablasts and plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.

Depletion of these CD19+ B cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage.

Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain. Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.

Each NMOSD attack can lead to further cumulative damage and disability.16,17 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.


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