-- Month 12 data reinforce durable efficacy of co-treatment approach --

Horizon Therapeutics plc (Nasdaq: HZNP) today announced the publication of the long-term data from the MIRROR randomized controlled clinical trial of KRYSTEXXA^® (pegloticase) injection with methotrexate, a commonly used immunomodulator, in ACR Open Rheumatology [https://doi.org/10.1002/acr2.11578].

“Publication of these 12-month data reinforces key findings shown at Month 6, including the durability of urate-lowering response, reduced infusion reactions and reduced immunogenicity of pegloticase when co-administered with methotrexate,” said Kenneth Saag, M.D., author and Director of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham. “Encouragingly, urate-lowering efficacy with the co-therapy approach was sustained over time with continued treatment in most patients. Further, the number of patients seeing complete resolution of at least one tophus markedly increased between Month 6 and Month 12 of treatment.”

This analysis extends the MIRROR randomized controlled trial body of data through Month 12 of treatment, showing a largely sustained patient response rate and similar safety profile as the Month 6 findings:

• Improvement in the patient response rate remained nearly 30 percentage points higher with methotrexate co-therapy during Month 12 (p<0.001): of patients randomized to receive KRYSTEXXA with methotrexate, 60.0% (60 of 100) achieved a serum urate (SU) level less than 6 mg/dL for at least 80% of the time during Month 12 (Weeks 49-52) versus 30.8% (16 of 52) of those randomized to receive KRYSTEXXA with placebo.
• A 23 percentage-point increase in the complete resolution of at least one tophus at Month 12 (p=0.048): among patients with tophi at baseline, 53.8% (28 of 52) in the KRYSTEXXA with methotrexate group had complete resolution of at least one tophus with no new tophus formation and no single tophus progression at Week 52 (Month 12), compared with 31.0% (9 of 29) in the KRYSTEXXA with placebo group.
• Consistent pharmacokinetic and immunogenicity findings through Month 12: data were consistent with Month 6 findings, indicating higher KRYSTEXXA serum concentrations during treatment that resulted from lower KRYSTEXXA immunogenicity in those who received co-administration with methotrexate.¹
• All Health Assessment Questionnaire (HAQ) measures progressively decreased during treatment in a clinically meaningful way: the least-square mean change from baseline in HAQ Disability Index was −0.35 in patients receiving KRYSTEXXA with methotrexate and -0.31 in patients receiving KRYSTEXXA with placebo at Week 52. The improvement in both groups was clinically meaningful (meaningful clinically important difference [MCID]: −0.22) but was not significantly different between groups (difference: −0.04 [−0.21, 0.13], p=0.6287). HAQ Pain and Health scores also progressively and meaningfully improved during treatment (MCID: 10). At Week 52, the KRYSTEXXA with methotrexate group had greater improvement in both HAQ Pain (least-square mean: −31.03 vs. −22.59; treatment difference: −8.43 [−15.88, −0.97], p=0.0272) and HAQ Health (least-square mean: −28.85 vs. −18.69; treatment difference: −10.16 [−18.84, −1.48], p=0.0222) compared to KRYSTEXXA with placebo.

“Given the damage that uncontrolled gout can cause to bones and joints, as well as its significant impact on a person’s daily life, it is crucial to provide data that demonstrate how a co-treatment approach can quickly lower a patient’s serum urate level and sustain it over time,” said Brian LaMoreaux, M.D., M.S., senior medical director, Horizon. “As clinicians, when we commit ourselves to improving the quality of care provided to people who live with uncontrolled gout, we’re also working to improve their quality of life.”

More information on KRYSTEXXA with methotrexate is available in the Prescribing Information and at KRYSTEXXAhcp.com. Patients with questions can speak to a Gout Nurse Advocate at 833-469-4688.

About MIRROR Randomized Controlled Trial

The co-administration of KRYSTEXXA with an immunomodulator like methotrexate has increasingly been employed for patients with uncontrolled gout (chronic gout refractory to oral therapies) to help reduce the development of antidrug antibodies, which can affect treatment efficacy.^2,3 Following a series of case studies and an open-label study, the MIRROR randomized controlled trial (Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving KRYSTEXXA trial, NCT03994731) was conducted^4-6 and evaluated differences in treatment response for KRYSTEXXA with methotrexate compared to KRYSTEXXA with placebo.

The primary endpoint was the proportion of serum uric acid (sUA) responders defined as sUA less than 6 mg/dL for at least 80% of the time during Month 6 (Weeks 20-24). The study’s secondary endpoints included the proportion of sUA responders during Month 12 (Weeks 48-52), defined as sUA less than 6 mg/dL for at least 80% of the time, and the proportion of participants with complete resolution of at least one tophus with no new tophus and no single tophus showing progression (using digital photography) at Week 52 in subjects with tophi at baseline.⁷

A total of 152 participants were randomized 2:1 to a four-week run-in and treatment period with oral methotrexate (15 mg/week) or placebo, followed by bi-weekly infusions of KRYSTEXXA (8 mg) with either methotrexate or placebo for 52 weeks. The trial demonstrated a 32 percentage-point improvement (p<0.0001) in treatment response rate, with 71% of patients (71 of 100) who were randomized to receive KRYSTEXXA with methotrexate achieving a sustained urate-lowering response during Month 6, compared to 39% (20 of 52) of those randomized to receive KRYSTEXXA with placebo.^2,3

About KRYSTEXXA

INDICATION

KRYSTEXXA^® (pegloticase) is indicated for the treatment of chronic gout in adult patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Limitations of Use: KRYSTEXXA is not recommended for the treatment of asymptomatic hyperuricemia.

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS, G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

• Anaphylaxis and infusion reactions have been reported to occur during and after administration of KRYSTEXXA.
• Anaphylaxis may occur with any infusion, including a first infusion and generally manifests within 2 hours of the infusion. Delayed hypersensitivity reactions have also been reported.
• KRYSTEXXA should be administered in healthcare settings and by healthcare providers prepared to manage anaphylaxis and infusion reactions.
• Patients should be premedicated with antihistamines and corticosteroids and closely monitored for anaphylaxis for an appropriate period after administration of KRYSTEXXA.
• Serum uric acid levels should be monitored prior to each infusion and treatment discontinued if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.
• Patients at risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be screened prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. KRYSTEXXA is contraindicated in patients with G6PD deficiency.

CONTRAINDICATIONS:

• In patients with G6PD deficiency.
• In patients with history of serious hypersensitivity reactions, including anaphylaxis, to KRYSTEXXA or any of its components.

WARNINGS AND PRECAUTIONS

Gout Flares: An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including KRYSTEXXA. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated.

Congestive Heart Failure: KRYSTEXXA has not been formally studied in patients with congestive heart failure, but some patients in the pre-marketing placebo-controlled clinical trials experienced exacerbation. Caution should be exercised in patients who have congestive heart failure and patients should be closely monitored following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions (≥5%) are:

• KRYSTEXXA co-administration with methotrexate trial: gout flares, arthralgia, COVID-19, nausea and fatigue; KRYSTEXXA alone: gout flares, arthralgia, COVID-19, nausea, fatigue, infusion reactions, pain in extremity, hypertension, and vomiting.

• KRYSTEXXA pre-marketing placebo-controlled trials: gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis, and vomiting.

Please see Full Prescribing Information, including Boxed Warning.

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 KRYSTEXXA co-administered with methotrexate for uncontrolled gout . 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 related to the adoption of co-administration of KRYSTEXXA with methotrexate for uncontrolled gout. 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. Botson J, Saag K, Peterson J, et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: 12-mo Findings. ACR Open Rheumatology. Accepted Author Manuscript. doi: 10.1002/acr2.11578.
2. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31:299-316. doi: 10.1007/s40259-017-0231-8.
3. KRYSTEXXA (pegloticase) [prescribing information] Horizon.
4. Botson J, Tesser JHR, Bennett R, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021;48(5):767-774. doi: 10.3899/jrheum.200460.
5. Albert J, Hosey T, LaMoreaux B. Increased Efficacy and Tolerability of Pegloticase in Patients With Uncontrolled Gout Co-Treated With Methotrexate: A Retrospective Study. Rheumatol Ther. 2020;7(3):639-648. doi: 10.1007/s40744-020-00222-7.
6. Botson JK, Peterson J. Pretreatment and Coadministration With Methotrexate Improved Durability of Pegloticase Response: An Observational, Proof-of-Concept Case Series. J Clin Rheumatol. 2022 Jan 1;28(1):e129-e134. doi: 10.1097/RHU.0000000000001639.
7. Botson J, Saag K, Peterson J, et al. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings. Arthritis Rheumatol. 2023 Feb;75(2):293-304. doi: 10.1002/art.42335.

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