New Analysis of UPLIZNA® (inebilizumab) Phase 3 Trial Data Demonstrates Importance of Reducing Plasmablasts to Help Prevent Neuromyelitis Optica Spectrum Disorder (NMOSD) Attacks

-- Analysis aims to clarify the relationship between peripheral B-cell subsets in the blood, AQP4-IgG levels and NMOSD attacks --

DUBLIN -- Oct. 26, 2022 -- Horizon Therapeutics plc (Nasdaq: HZNP) today announced new data from two analyses of the UPLIZNA Phase 3 pivotal trial being presented at the 38^th 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

“Plasmablasts and plasma cells are thought to play a central role in the underlying physiological process associated with NMOSD, however the relationship between peripheral B-cell subsets in the blood, AQP4-IgG levels and NMOSD has not been widely studied,” said Professor Friedemann Paul, study author and Group Leader of the Clinical Neuroimmunology Department of the NeuroCure Clinical Research Centre at the Charité, Berlin. “These data aim to clarify this relationship and suggest that the critical mechanism of action of UPLIZNA effectively and distinctly treats NMOSD in patients who are AQP4-IgG+. Further studies may help elucidate the therapeutic impact associated with targeting CD19, particularly on plasmablasts and the associated reduction in AQP4-IgG, aimed at reducing attacks.”

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.

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

About UPLIZNA

For information about UPLIZNA for Europe, please view the Summary of Product Characteristics.

About Horizon

Horizon is focused on the discovery, development and commercialisation of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: we apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, visit www.horizontherapeutics.com and follow us on Twitter, LinkedIn, Instagram and Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA. These forward-looking statements are based on management's expectations and assumptions as of the date of this press release and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include, but are not limited to, risks regarding whether future results of clinical trials and data analyses will be consistent with preliminary results or results of prior trials or other data or Horizon’s expectations, the risks associated with clinical development and adoption of novel medicines and risks related to competition or other factors that may change physician treatment strategies. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizon’s filings with the United States Securities and Exchange Commission, including those factors discussed under the caption “Risk Factors” in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law.

References

1. Bennett JL, et al. B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e104.
2. Rensel M, et al. Long-term efficacy and safety of inebilizumab in neuromyelitis optica spectrum disorder: Analysis of aquaporin-4–immunoglobulin G–seropositive participants taking inebilizumab for ⩾4 years in the N-MOmentum trial. Multiple Sclerosis Journal. 2021:135245852110472.
3. Cree BA, Bennett JL et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-Momentum): a double-blind, randomised placebo-controlled phase 2/3 trial. The Lancet. 2019;394:1352-63.
4. Pittock S, et al. Association of B cell subsets and aquaporin-4 antibody titers with disease activity in participants in the N-MOmentum trial receiving inebilizumab treatment. Poster presented at the 38^th Congress of ECTRIMS; 26^th-28^th October; 2022;The Netherlands, Amsterdam.
5. Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103.
6. What is NMO? org. www.guthyjacksonfoundation.org/neuromyelitis-optica-nmo/Accessed April 15, 2021.
7. What We Know About NMO. Sumairafoundation.org. https://www.sumairafoundation.org/what-to-know-about-nmo/Accessed Aug. 2, 2022. 
8. Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021.
9. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706.
10. Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112).
11. Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580.
12. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187.
13. Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther.2015;1(1):9-14.
14. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci.2009;286(1-2):18-23.
15. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol.2016;79(5):775-783.