-- Analysis aims to clarify the relationship between peripheral B-cell subsets in
the blood, AQP4-IgG levels and NMOSD attacks --
Horizon Therapeutics plc (Nasdaq: HZNP) today announced new data from two analyses of the UPLIZNA Phase 3
pivotal trial being presented at the 38th Congress of the European
Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2022), 26-28 October in Amsterdam. UPLIZNA is the first
and only targeted B-cell depleting monotherapy approved by the European
Commission and the U.S. Food and Drug Administration for the treatment of NMOSD
in adults who are anti-aquaporin-4 immunoglobulin G seropositive
(AQP4-IgG+).
Plasmablasts and plasma
cells are responsible for the secretion of pathogenic AQP4 antibodies, leading
to NMOSD.1 These data demonstrate how the mechanism of action of
UPLIZNA effectively and distinctly addressed the underlying causes of the
disease. 2,3 UPLIZNA effectively depleted CD19+ B cells, including
plasmablasts and plasma cells, which is believed to have a profound effect in
controlling attacks in patients living with NMOSD.2,3
Broad reduction of B
cells, specifically plasmablasts, that correlate with NMOSD attacks
Plasmablasts and plasma cells (CD19+ expressing B cells)
are considered a key driver of NMOSD attacks.1 Until recently there has been limited knowledge about
the association between attacks and b-cell subsets. This analysis from
the N-MOmentum trial (NCT02200770) aimed to further clarify the relationship between
peripheral B-cell subsets in the blood, AQP4-IgG levels and NMOSD attacks. To
do so, absolute counts of CD20+ B cells and CD27+ memory B cells in the
peripheral blood, plasma cell gene expression and AQP4-IgG titers were
assessed.4
Increases in plasma cells
were seen in over half (57%, 12/21) of placebo participants at time of attack
relative to baseline compared to 20% (4/20) and 16% (3/19) for total CD20+ B
cells and CD27+ memory B cells respectively.4 Increases in plasma
cells were also observed at the preceding visit relative to baseline (p
< 0.01).4 No significant increases in any B cell subsets at time
of attack were observed in participants treated with UPLIZNA relative to the
preceding visit.4
Unexpectedly, in the
placebo group, significant increases in AQP4+ titer were observed at time of
attack relative to baseline (p = 0.02) but not in those treated with UPLIZNA
(p=0.76); however, changes in
AQP4-IgG titer from baseline to attack were not significantly different between
treatment groups (p = 0.15).4 Moreover, 85% of placebo
participants had AQP4 titer increases and/or increased plasma cells,
representing a potential attack signal.4
UPLIZNA significantly
decreased AQP4+ titer relative to placebo.4 At the end of the
randomised control period, 37% (59/159) of participants treated with UPLIZNA
had a ≥2-fold decrease in AQP4-IgG titers from baseline compared to 18% (9/50)
of those treated with placebo (p=0.014).4 For participants with high
AQP4-IgG titers (>1:20,480), 51% (18/35) of participants treated with
UPLIZNA had a ≥2-fold decrease in AQP4-IgG titers from baseline compared to 8%
(1/12) of placebo participants.4
Previous studies have shown that UPLIZNA targets an extended
range of CD19 B cells,
including plasmablasts and plasma cells, and reduces levels
of plasmablasts as well as memory B cells.
“NMOSD is a devastating rare disease where just one
attack can leave patients with severe, irreversible consequences like loss of
sight or paralysis. This analysis offers a clearer picture of UPLIZNA’s
differentiated mechanism contributing to improved clinical outcomes,” said Karl
Boegl, M.D., executive director, EMEA, regional medical lead, Horizon
Therapeutics. “This is important as it helps healthcare professionals make more
accurate treatment decisions for their NMOSD patients.”
About Neuromyelitis Optica Spectrum Disorder (NMOSD)
NMOSD is a
unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a
rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the
optic nerve, spinal cord, brain and brain stem.5,6 Approximately
80 percent of all patients with NMOSD test positive for anti-AQP4 antibodies.7 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.8
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 CD19.9 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.8,9,10 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.10 Each NMOSD attack can lead to further cumulative damage and disability.12,13 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.14,15
No comments:
Post a Comment