New Analysis of MRI Findings Shows UPLIZNA® (inebilizumab-cdon) Reduced the Formation of Subclinical Spinal Cord Lesions in People With Neuromyelitis Optica Spectrum Disorder (NMOSD)

-- Study shows subclinical spinal cord lesions were associated with future NMOSD attacks --

Horizon Therapeutics plc (Nasdaq: HZNP) today announced the presentation of a new analysis of MRI data from the Phase 3 clinical trial of UPLIZNA showing a reduction in the formation of subclinical (asymptomatic) transverse myelitis lesions in people with NMOSD. This analysis is being presented at the 9^th Congress of the European Academy of Neurology (EAN), July 1-4 in Budapest.

UPLIZNA is the first and only targeted CD19+ B-cell-depleting therapy approved by the U.S. Food and Drug Administration, the European Commission and the Brazilian Health Regulatory Agency (ANVISA) for the treatment of NMOSD in adults who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+). The N-MOmentum pivotal trial (NCT02200770) is also the largest Phase 3 clinical trial in NMOSD and the only Phase 3 trial that collected MRI data, which were also incorporated into its attack adjudication criteria. Results from this post-hoc analysis demonstrate that UPLIZNA effectively reduced the formation of subclinical MRI lesions, while also showing an association between subclinical spinal cord lesions and future attacks.

“This analysis offers new insights into the significance of subclinical MRI findings on the spinal cord as a potential signal of future attacks, adding to the growing list of tools available for physicians to better monitor their patients,” said Friedemann Paul, study author and Group Leader of the Clinical Neuroimmunology Department of NeuroCure Clinical Research Centre at the Charité, Berlin. “It is encouraging to see that UPLIZNA reduced the formation of these lesions. Future studies evaluating subclinical findings will help offer additional clarity on their relationship with disease activity.”

During the trial, MRI imaging was conducted on the spinal cord, optic nerve and brain/brainstem to quantify the frequency, prognosis and response to treatment with UPLIZNA of subclinical lesions. This was taken at the time of screening, at the end of the 28-week randomized controlled period (RCP), at the time of any attack and annually during the open-label portion (OLP) of the trial. Of the 134 pivotal trial participants with full neuroaxis MRI and no new NMOSD symptoms at the end of the 28-week RCP, 20 (15%) were found to have asymptomatic MRI lesions on the spinal cord. These lesions were shorter than attack-associated lesions, and importantly were less frequent among those receiving UPLIZNA.

Subsequent MRI findings showed that the formation of these lesions decreased as treatment with UPLIZNA continued. Interestingly, these findings showed that subclinical lesions were associated with domain-specific attacks in the following year.

“Attack prevention is a priority in managing NMOSD, as just one attack can lead to life-altering vision loss and mobility challenges,” said Kristina Patterson, M.D., Ph.D., senior medical director, neuroimmunology medical affairs, Horizon. “We are pleased to see that the long-term Phase 3 pivotal trial data show that UPLIZNA effectively reduced subclinical MRI findings and NMOSD attacks while continuing to offer new learnings that help advance our understanding of the disease and improve patient care.”

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 some 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 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 the Full Prescribing Information at www.UPLIZNA.com.

About Horizon

Horizon is a global biotechnology company 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 and future studies of 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 sub-analysis from the 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

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2. What is NMO? Accessed April 15, 2021. Guthyjacksonfoundation.org.
   
   www.guthyjacksonfoundation.org/neuromyelitis-optica-nmo/
3. What We Know About NMO. Accessed Aug. 2, 2022. Sumairafoundation.org.
   
   https://www.sumairafoundation.org/what-to-know-about-nmo/
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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