New Analysis Demonstrates UPLIZNA® (inebilizumab-cdon) Reduces Severity of Attacks Associated with Neuromyelitis Optica Spectrum Disorder (NMOSD)

-- New data links UPLIZNA treatment to fewer severe attacks and reduced levels of key disease-related biomarkers versus placebo --

Horizon Therapeutics plc (Nasdaq: HZNP) today announced results from a new analysis showing treatment with UPLIZNA effectively reduced the severity of attacks in people with NMOSD. These data are being presented at the 48^th Annual Meeting of the North American Neuro-Ophthalmology Society (NANOS 2022), February 12-17 in Austin, Texas. UPLIZNA is the first and only B-cell-depleting agent approved by the U.S. Food and Drug Administration for the treatment of NMOSD in adults who are anti-aquaporin-4 (AQP4) antibody positive.

Treatment of NMOSD aims to reduce acute attacks associated with the disease, which can cause irreversible damage to the optic nerve, spinal cord, brain and brain stem. During the 28-week randomized-controlled period (RCP) of the N-MOmentum Phase 2/3 pivotal trial, 89% of 161 patients in the UPLIZNA treatment group remained attack-free compared to 58% of 52 patients in the placebo group.

A new post hoc analysis of this data was conducted to understand the effect of UPLIZNA on the severity of attacks in the 11% of people in the clinical trial who were not attack-free after being treated with UPLIZNA. Attacks were graded as major or minor based on changes in neurological function according to a modified Opticospinal Impairment Scale (OSIS). The analysis also evaluated the relationship between the severity of these attacks and biomarkers of disease activity, such as serum glial fibrillary acidic protein (sGFAP) and serum neurofilament (sNfL).

“Acute attacks in NMOSD can lead to irreversible consequences and permanent disability in patients, making targeted treatments important to limit disease activity and its severity in patients,” said Jeffrey Bennett, M.D., Ph.D., University of Colorado and study author. “This analysis illustrates the clear clinical impact of UPLIZNA to reduce the debilitating effects of disease while contributing to our understanding of the link between serum biomarkers and severity of attacks.”

Key analysis findings:

• Of the 18 total attacks that occurred in the UPLIZNA treatment group during the RCP, 12 (67%) were minor and six (33%) were major, compared to 12 (55%) minor attacks and 10 (45%) major attacks among the 22 attacks occurring in the placebo group.
• Levels of the sGFAP biomarker were significantly higher during major attacks versus minor attacks overall (p=0.023) and trended higher for optic neuritis (ON) specific attacks (n=20, p=0.06). Concentration levels of the biomarker increased significantly from baseline at the time of attacks in those receiving placebo but not in those treated with UPLIZNA (p=0.31).
• SNfL levels were higher for major versus minor attacks overall (p=0.032), though the levels did not correlate with the severity of ON attacks. In participants that had attacks during the RCP, rates of this marker were higher among placebo versus UPLIZNA-treated participants at Week 26 (p=0.03).

“While the UPLIZNA clinical trial demonstrated that a majority of patients were attack-free after being treated, it also offered an increased understanding of how UPLIZNA impacted the severity of the attacks that occurred,” said Kristina Patterson, M.D., Ph.D., medical director, neuroimmunology, Horizon. “This is an important consideration for physicians as they evaluate treatment options for their patients, as severe attacks can have debilitating consequences.”

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.^1,2 Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies.³ 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.⁴

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 CD19.⁵ 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.^4,6 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.⁷ Each NMOSD attack can lead to further cumulative damage and disability.^8,9 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.^10,11

About UPLIZNA

INDICATION

UPLIZNA (inebilizumab-cdon) is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

IMPORTANT SAFETY INFORMATION

UPLIZNA is contraindicated in patients with:

• A history of life-threatening infusion reaction to UPLIZNA
• Active hepatitis B infection
• Active or untreated latent tuberculosis

WARNINGS AND PRECAUTIONS

Infusion Reactions: UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine and an anti-pyretic.

Infections: The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%) and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

The risk of Hepatitis B Virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.

Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

Reduction in Immunoglobulins: There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.

Fetal Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.

Adverse Reactions: The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

For additional information on UPLIZNA, please see Full Prescribing Information.

About Horizon

Horizon is focused on the discovery, development and commercialization 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 in treating NMOSD. 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 data analyses or clinical evidence will be consistent with the analysis from the Phase 2/3 N-MOmentum clinical trial or Horizon’s expectations. 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. 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.
2. What is NMO? Guthyjacksonfoundation.org. www.guthyjacksonfoundation.org/neuromyelitis-optica-nmo/ Accessed April 15, 2021.
3. Layman’s Guide to NMO. Sumairafoundation.org. https://www.sumairafoundation.org/laymans-guide-to-nmo/ Accessed April 25, 2021.
4. 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.
5. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706.
6. 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).
7. Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580.
8. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187.
9. 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.
10. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci. 2009;286(1-2):18-23.
11. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.

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