Horizon Therapeutics plc (Nasdaq: HZNP) today announced the first subject has been dosed in a Phase 1 randomized, placebo-controlled trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of its development-stage medicine HZN-457, previously known as ARO-XDH. HZN-457 is a small interfering RNA (siRNA) candidate designed to treat gout by silencing liver xanthine dehydrogenase. The development of HZN-457 is part of a global collaboration and license agreement that the Company entered in 2021 with Arrowhead Pharmaceuticals (Nasdaq: ARWR).

Gout is a serious and painful form of inflammatory arthritis that is caused by excess uric acid. In the United States, there are more than 9 million gout patients and approximately a third are treated with oral urate-lowering therapies.^1,2 However, a meaningful portion of those patients do not respond sufficiently and continue to experience painful and debilitating gout symptoms.³ High uric acid levels, if left untreated or undertreated, can lead to acute and persistent inflammatory arthritis,⁴ bone and joint damage, exacerbate comorbidities, and severely impact patients’ lives.⁵ Preclinical studies suggest that HZN-457 has the potential to maintain lower uric acid levels and offer several benefits above standard of care for the treatment of gout.

Up to 56 healthy volunteers are expected to be enrolled sequentially into ascending dose cohorts and administered HZN-457 subcutaneously as a single dose. The primary endpoint is safety and tolerability. Secondary endpoints include the assessment of plasma and urine pharmacokinetic parameters and changes from baseline in uric acid levels.

“As a clinical and commercial leader in gout, Horizon understands the critical need to develop innovative approaches and advance novel treatments to reach more patients who live with this disease,” said Elizabeth H.Z. Thompson, Ph.D., executive vice president, research and development, Horizon. “The HZN-457 Phase 1 clinical trial marks an important milestone for Horizon to advance our research and development in this space, fostered by our partnership with Arrowhead.”

About HZN-457

HZN-457 is a small interfering RNA (siRNA) medicine candidate conjugated to N-acetylgalactosamine (GalNAc) that selectively targets and silences xanthine dehydrogenase expression in the liver, which produces uric acid. The development of HZN-457 is through an exclusive collaboration between Horizon and Arrowhead Pharmaceuticals, Inc.

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, but not limited to, statements related to the potential benefits of HZN-457; the expected scope and endpoints of Horizon’s Phase 1 clinical trial of HZN-457 and other statements that are not historical facts. These forward-looking statements are based on Horizon’s current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to clinical trials, including the fact that prior results may not predict future clinical trial outcomes; impacts of pandemics and geopolitical conflicts and related disruptions to healthcare activities, including potential delays in clinical trials; regulatory obligations and oversight, including any changes in the legal and regulatory environment in which Horizon operates and those risks detailed from time-to-time under the caption "Risk Factors" and elsewhere in Horizon’s filings and reports with the SEC. Horizon undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information.

References

1. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760.
2. Chen-Xu M, Yokose C, Rai SK, et al. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999.
3. Igel TF, Kranokutsky S, Pillinger MH. Recent advances in understanding and managing gout. F1000Res. 2017;6:247.
4. Becker MA, Baraf HS, Yood RA, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72(9):1469-74.
5. Stewart S, Guillen AG, Taylor WJ, et al. The experience of a gout flare: a meta-synthesis of qualitative studies. Semin Arthritis Rheum. 2020;50(4):805-811.

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