-- Horizon expects to file a Supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration in first quarter of 2022 based on significant improvement in response rate --

-- Detailed results to be presented at upcoming medical congress --

Horizon Therapeutics plc (Nasdaq: HZNP) today announced topline results met the primary endpoint, showing a significant increase in efficacy using KRYSTEXXA with the immunomodulator methotrexate as compared to the response rate of KRYSTEXXA with placebo for people with chronic gout refractory to conventional therapies – also known as uncontrolled gout. Results were from the Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving KRYSTEXXA trial [MIRROR randomized controlled trial (RCT)].

“It is rare that you can improve a response rate so substantially for patients; by 30 percentage points in this case based on the results of our trial,” said Elizabeth H.Z. Thompson, Ph.D., executive vice president, research and development, Horizon. “These results reinforce what we have seen from published case series as well as our open-label trial evaluating KRYSTEXXA with methotrexate. Horizon has invested significantly over the last several years to ensure more uncontrolled gout patients are able to benefit from KRYSTEXXA and we continue to develop new approaches that target the underlying cause of gout.”

In the MIRROR randomized controlled trial, 152 adults living with uncontrolled gout were randomized to receive methotrexate or placebo for four weeks and then treatment with KRYSTEXXA and methotrexate or KRYSTEXXA and placebo for 52 weeks. This trial was designed to evaluate the concomitant use of KRYSTEXXA with methotrexate, an immunomodulator commonly prescribed by rheumatologists, to help more patients achieve a complete and durable response to therapy. The primary endpoint was defined as the proportion of serum uric acid (sUA) responders defined as sUA <6 mg/dL at least 80% of the time during Month 6.¹

Results show that 71% (71 of 100) of patients who were randomized to receive KRYSTEXXA with methotrexate compared to 40% (21 of 52) of patients who were randomized to receive KRYSTEXXA with placebo achieved the primary endpoint (p<0.001). No new safety concerns were identified. These results are aligned with published literature and the prior original pivotal clinical trials of KRYSTEXXA monotherapy which showed 42% (36 of 85) of dosed patients had a complete sUA response and met the primary endpoint of maintaining sUA <6 mg/dL at least 80% of the time in Months 3 and 6.^2,3

“The impact of uncontrolled gout cannot be overstated; in addition to its effect on the patient’s quality of life, research underscores the systemic burden and increased risk of morbidity and mortality,” said John K. Botson M.D., R.Ph., C.C.D., president, Alaska Rheumatology Alliance and rheumatologist, Orthopedic Physicians Alaska. “Effectively attenuating the development of anti-drug antibodies often seen in biologics, like KRYSTEXXA, has been central in our approach to reduce the burden of urate and address the long-term consequences of systemic uric acid deposition.”

The MIRROR randomized controlled trial follows the MIRROR open-label trial (NCT03635957), which showed a 79% (11 of 14 patients) response rate (sUA <6 mg/dL) at Month 6 when KRYSTEXXA was used with methotrexate.⁴ Separately, two independent, in-practice case series showed 80⁵ and 100%⁶ of patients (8 of 10 patients and 10 of 10 patients, respectively) were able to receive a full course of treatment with the concomitant use of KRYSTEXXA and methotrexate. No new safety concerns were identified in these studies, but the findings are limited by the small sample sizes.

“These results reinforce trends seen in clinical practice and illustrate that the use of an immunomodulator, such as methotrexate, with KRYSTEXXA can help more uncontrolled gout patients complete a full course of therapy,” said Jeff R. Peterson, M.D., president, Washington Rheumatology Alliance and a director at Northwest Rheumatism Society and Western Washington Medical Group Arthritis Clinic's clinical research department. “Taken together with the open-label trial and published literature, the MIRROR randomized controlled trial results highlight an evolution of care for people living with uncontrolled gout and shift in approach to addressing the underlying burden of disease.”

Data from the trial are expected to be presented at an upcoming medical congress. Horizon plans to submit a Supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2022.

About KRYSTEXXA

INDICATIONS AND USAGE

KRYSTEXXA® (pegloticase injection) is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy.

Gout refractory to conventional therapy occurs in 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.

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

IMPORTANT SAFETY INFORMATION

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS

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. However, delayed-type 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. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Serum uric acid levels should be monitored prior to infusions, and healthcare providers should consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed.

The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response.

Concomitant use of KRYSTEXXA and oral urate-lowering agents may blunt the rise of sUA levels. Patients should discontinue oral urate-lowering agents and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA.

In the event of anaphylaxis or infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

CONTRAINDICATIONS: G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA

Patients should be screened for G6PD deficiency prior to starting KRYSTEXXA. Hemolysis and methemoglobinemia have been reported with KRYSTEXXA in patients with G6PD deficiency. KRYSTEXXA should not be administered to these patients.

GOUT FLARES

An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, including treatment with KRYSTEXXA. If a gout flare occurs during treatment, KRYSTEXXA need not be discontinued. 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 studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Caution should be exercised when using KRYSTEXXA in patients who have congestive heart failure, and patients should be monitored closely following infusion.

ADVERSE REACTIONS

The most commonly reported adverse reactions in clinical trials with KRYSTEXXA were gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting.

Please see Full Prescribing Information and Medication Guide for more 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, please 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 the combination of KRYSTEXXA and methotrexate in treating uncontrolled gout, and Horizon’s plans to submit an sBLA related to the use of KRYSTEXXA with methotrexate. 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 additional data from the MIRROR randomized controlled trial will be consistent with the top-line results or Horizon’s expectations, potential delays in submitting a planned sBLA and whether any sBLA is accepted for filing and approved. 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. National Institutes of Health. Study of KRYSTEXXA^® (pegloticase) Plus Methotrexate in Patients With Uncontrolled Gout (MIRROR RCT). https://www.clinicaltrials.gov/ct2/show/NCT03994731. Accessed Sept 13, 2021.
2. KRYSTEXXA (pegloticase) [prescribing information] Horizon.
3. Sundy JS, Baraf HSB, Yood RA, et al. Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment: Two Randomized Controlled Trials. JAMA. 2011;306(7):711–720. doi:10.1001/jama.2011.1169
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 J, Peterson J. Pretreatment and Coadministration With Methotrexate Improved Durability of Pegloticase Response [published online ahead of print, 2020 Oct 10]. J Clin Rheumatol. 2020;10.1097/rhu.0000000000001639. doi:10.1097/RHU.0000000000001639.

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