UPLIZNA® (inebilizumab-cdon) Pivotal Trial Publication Integrating MRI and Biomarker Evaluation Shows Accuracy and Uniformity of Attack Diagnoses for Neuromyelitis Optica Spectrum Disorder (NMOSD)

-- Findings published in the Multiple Sclerosis Journal provide early validation of a process that could inform new clinical standards to improve attack diagnosis and treatment decision-making --

Horizon Therapeutics plc (Nasdaq: HZNP) today announced the publication of a new analysis from the N-MOmentum clinical trial of UPLIZNA demonstrating the utility of a robust adjudication process that could improve clinical care decision-making in neuromyelitis optica spectrum disorder (NMOSD) through more accurate and consistent assessment of disease-related attacks. These findings are published in the Multiple Sclerosis Journal.

NMOSD is characterized by recurrent disabling attacks, which often lead to permanent disability. Properly defining NMOSD attacks is essential to inform treatment decisions, yet there are no universally accepted criteria for accurate and objective diagnosis of NMOSD attacks.

The N-MOmentum pivotal trial, which demonstrated UPLIZNA reduced the risk of attacks associated with the disease, introduced a new approach for attack analysis. Attacks were evaluated by an adjudication committee (AC, comprised of two neurologists and one neuro-ophthalmologist). The approach was revised based on guidance from the U.S. Food and Drug Administration (FDA). The process evaluated 18 predefined criteria (covering optic neuritis, myelitis and brain/brainstem domains). Domain-specific MRI review was performed in scenarios where the clinical findings were indeterminant. This analysis assessed the accuracy of the attack adjudication criteria against a retrospective review of MRI (for those attacks where MRI was not reviewed) as well as assess the biomarker serum glial fibrillary acidic protein (sGFAP, a structural filament protein that is released following injury of the central nervous system).

“The adjudication process provided an accurate, reliable understanding of the nature of NMOSD attacks, with MRI correlates and biomarker elevations found in the vast majority of adjudicated attacks,” said Brian Weinshenker, M.D., study author and professor of neurology, University of Virginia School of Medicine. “Conversely, events reported as attacks by investigators that were not adjudicated by the AC were usually not accompanied by objective corroboration of attacks by MRI or biomarker elevation. Without accurate criteria, attacks may go undetected or symptoms not indicative of true attacks may be misclassified, leading to potentially erroneous interpretation of study results. The process outlined in this study may serve as a useful benchmark to inform future attack evaluations, while also helping clinicians contextualize the efficacy of UPLIZNA and other NMOSD treatments.”

Of the 230 participants in the trial, 64 participant-reported neurological events occurred; 51 of these (80%) were deemed attacks by the trial investigators and of those, 43 (84%) were independently confirmed by the AC. The use of detailed, predefined criteria enabled reliable and reproducible determinations, as only 16% of investigator-determined attacks were rejected following AC review and no investigator-rejected attack decisions were reversed by the AC.

MRI and sGFAP biomarker findings provided additional specificity in the attack adjudication process. New domain-specific lesions were found in 90% of adjudicated attacks for which MRI data were available, and use of MRI allowed for confirmation of 33% of adjudicated attacks for which clinical findings were inconclusive. Further, increased concentrations of sGFAP (>2-fold mean change from baseline) were observed in more than half (56%) of adjudicated attacks, reinforcing the potential role of sGFAP in NMOSD attacks and supporting the use of sGFAP measurements in clinical care. Importantly, sGFAP elevations were notably less common in UPLIZNA-treated participants than those receiving placebo, consistent with previous findings showing the effectiveness of UPLIZNA in reducing sGFAP levels.

“Together with well-defined review criteria and biomarker analysis, this robust adjudication process could serve as the basis for consistent attack evaluations in future studies and real-world care,” said Kristina Patterson, M.D., Ph.D., senior medical director, neuroimmunology medical affairs, Horizon. “Importantly, the accurate picture of disease-related attack events seen in this analysis further reinforces the efficacy of UPLIZNA in reducing these attacks and improving outcomes for people with NMOSD.”

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 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 and new adjudication processes and Horizon’s research and development plans. 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 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. 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? 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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