Allantoin

● Xanthine Oxidase Inhibition with XRx-008 Blocks Uric Acid Induced Increasein Total Kidney Weight in Polycystic Kidney Disease ● CALGARY, Alberta, Nov. 03, 2022 (GLOBE NEWSWIRE) -- XORTX Therapeutics Inc. ("XORTX" or the “Company”) (NASDAQ: XRTX | TSXV: XRTX | Frankfurt: ANU), a late stage clinical pharmaceutical company focused on developing innovative therapies to treat progressive kidney disease, is pleased to announce the presentation of a peer-reviewed abstract to be presented November 4, 2022 at the American Society of Nephrology (“ASN”) Annual Conference – Kidney Week. The abstract presents new discoveries in two species – mouse and rat models of polycystic kidney disease (“PKD”) and reports original work showing the harmful consequence of chronically increased uric acid on both structure and function of kidneys. The Abstract “Raising Serum Uric Acid with a Uricase Inhibitor Worsens PKD in Rat and Mouse models” will be presented during the Session Title: Genetic Diseases of the Kidneys, by Dr. Charles Edelstein of the University of Colorado and Dr. Allen Davidoff, CEO of XORTX.  This presentation will report for the first time, that XORTX's XRx-008 formulation of Xanthine Oxidase inhibitor can substantially and significantly block the increase in kidney size associated with high circulating uric acid in a rodent model of polycystic kidney disease. The abstract presents the findings of studies conducted at the University of Colorado, by Dr. Charles Edelstein and the PKD research team. Results of this study, in two models of PKD, show similar results and reach similar conclusions, confirming that increasing uric acid by inhibiting uricase enzyme metabolism of uric acid to allantoin, results in substantially and statistically significant increases in:  Total kidney / body weight ratio – indicating the possibility of accelerated formation or growth of cysts and represents a measure analogous to total kidney volume measures in humans with PKD;Creatinine, supporting the concept of a decrease in filtering capacity of kidneys;Cyst index is increased, suggesting uric acid may act to specifically accelerate disease progression in PKD; andXanthine oxidase inhibition with XRx-008 decreases total kidney weight in a model of polycystic kidney disease. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid (“OXO”) results in an increase in kidney weight, and decreased kidney function in rodent models of PKD. Xanthine oxidase inhibition with XRx-008 blocks this mechanism of injury in Rodent PKD. Dr. Allen Davidoff, CEO of XORTX, stated, “We are pleased to present these important new findings during the ASN Kidney Week 2022. The results of this study show that increased serum uric acid can accelerate injury in two separate models of PKD and importantly reports fundamental findings in support of the Company’s XRx-008 program. With these results presented today, XORTX now has the information required to prepare and pursue Orphan Drug Designation for XRx-008.” About this Study  Unlike most forms of life, humans lack an active uricase enzyme that converts uric acid to allantoin.  In rodents, uricase converts uric acid to allantoin and uricase inhibition raises serum uric acid. The aim of this study was to determine whether raising serum uric acid with OXO was associated with worse PKD. About the American Society of Nephrology – Kidney Week ASN represents more than 21,000 kidney health professionals working to help people with kidney diseases and their families. Source: https://www.asn-online.org/. The Kidney Week Conference is attended by approximately 10,000 kidney professionals from across the globe at Kidney Week 2022 in Orlando, Florida. The world's premier nephrology meeting, Kidney Week provides participants exciting and challenging opportunities to exchange knowledge, learn the latest scientific and medical advances, and listen to engaging and provocative discussions with leading experts in the field. Source: https://www.asn-online.org/education/kidneyweek/. American Society of Nephrology – Program and Abstracts The Kidney Week program and abstracts are available on the ASN website. About ADPKD ADPKD is a rare disease that affects more that 10 million individuals worldwide.1,2 ADPKD is typically diagnosed based upon expansion of fluid-filled cysts in the kidneys. Over time, the increasing number and size of cysts can contribute to structural and functional changes to kidneys and is frequently accompanied by chronic pain which is a common problem for patients with ADPKD.3 Expansion of cysts is thought to compress healthy functioning tissue surrounding the cysts and contribute to further loss of kidney function, fibrosis, impaired nutrient exchange and impaired kidney function, accompanied later by end-stage renal disease.1 Health consequences of high uric acid have been reported to be increased in ADPKD individuals, including increased incidence of kidney stones5 and gout.6,7 For individuals with progressing ADPKD, treatment recommendations include anti-hypertensive treatment, dietary restrictions, and, for a limited percentage of suitable patients, pharmacotherapy.4 New, more broadly applicable therapies to effectively slow decline of kidney function in ADPKD are needed. About XORTX Therapeutics Inc. XORTX is a pharmaceutical company with two clinically advanced products in development: 1) our lead, XRx-008 program for ADPKD; and 2) our secondary program in XRx-101 for acute kidney and other acute organ injury associated with Coronavirus / COVID-19 infection. In addition, XRx-225 is a pre-clinical stage program for Type 2 Diabetic Nephropathy. XORTX is working to advance its clinical development stage products that target aberrant purine metabolism and xanthine oxidase to decrease or inhibit production of uric acid. At XORTX, we are dedicated to developing medications to improve the quality of life and future health of patients. Additional information on XORTX is available at www.xortx.com. For further information, please contact: Allen Davidoff, CEOadavidoff@xortx.com or +1 403 455 7727Nick Rigopulos, Director of Communicationsnick@alpineequityadv.com or +1 617 901 0785 Media Inquiries, David Melamed, Ph.D.david.melamed@russopartnersllc.com or +1 212 845 4225 Neither the TSX Venture Exchange nor Nasdaq has approved or disapproved the contents of this news release. No stock exchange, securities commission or other regulatory authority has approved or disapproved the information contained herein. References: Wiley C., Kamat S., Stelhorn R., Blais J., Analysis of nationwide date to determine the incidence and diagnosis of autosomal dominant polycystic kidney disease in the USA, Kidney Disease, 5(2): 107-117, 2019 Bergmann C., Guay-Woodford L.M., Harris P.C., Horie S., Peters D.J., Torres V.E., Polycystic Kidney Disease, Nat Rev Dis Primers. 4(1): 50, 2018 https://pkdcure.org/living-with-pkd/chronic-pain-management Gimpel C., Bermann C., Bockenhauer D., et al., International consensus statement of the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people, Nat Rev Nephrol 15(11):713-726, 2019 Torres VE, et al, The Association of Nephrolithiasis and Autosomal Dominant Polycystic Kidney Disease, Am J Kidney Dis, 1988, vol 11, 318-325 Newcombe, DS. Letter Gouty Arthritis and polycystic kidney disease, Ann Intern Med, 1973 vol 79, pg 605 Rivera JV Martinez, et al, Association of hyperuricemia and polycystic kidney disease, Bol Asoc Med P R, 1965 vol 7 251-263 Forward Looking Statements This press release contains express or implied forward-looking statements pursuant to U.S. Federal securities laws. These forward-looking statements and their implications are based on the current expectations of the management of XORTX only, and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as otherwise required by law, XORTX undertakes no obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. More detailed information about the risks and uncertainties affecting XORTX is contained under the heading “Risk Factors” in XORTX’s Registration Statement on Form F-1 filed with the SEC, which is available on the SEC's website, www.sec.gov (including any documents forming a part thereof or incorporated by reference therein), as well as in our reports, public disclosure documents and other filings with the securities commissions and other regulatory bodies in Canada, which are available on www.sedar.com.

Third-Quarter 2022 Results: -- Net Sales of $925.4 Million -- -- GAAP Net Income of $135.8 Million; Adjusted EBITDA of $335.3 Million, Which Includes $19.0 Million of Acquired IPR&D and Milestones Expenses -- -- TEPEZZA® (teprotumumab-trbw) Net Sales of $490.9 Million -- -- KRYSTEXXA® (pegloticase injection) Net Sales of $191.6 Million -- -- Cash Position of $2.13 Billion as of Sept. 30, 2022 -- Full-Year 2022 Guidance and Peak Annual Net Sales Expectations: -- Increasing Full-Year 2022 Net Sales Guidance to $3.59 Billion to $3.61 Billion -- -- Increasing Full-Year 2022 Adjusted EBITDA Guidance to $1.32 Billion to $1.34 Billion, Which Includes $52.5 Million of Acquired IPR&D and Milestones Expenses -- -- Continue to Expect Full-Year 2022 TEPEZZA Net Sales Percentage Growth in the High Teens -- -- Increasing Full-Year 2022 KRYSTEXXA Net Sales Growth Expectations to Approximately 25% -- -- Increasing TEPEZZA Ex-U.S. Peak Annual Net Sales Expectations to Greater than $1 Billion, Bringing Global Peak Annual Net Sales Expectations to Greater than $4 Billion -- -- Increasing KRYSTEXXA U.S. Peak Annual Net Sales Expectations to Greater than $1.5 Billion -- Recent Company Highlights: -- Completed Enrollment in TEPEZZA Chronic/Low Clinical Activity Score (CAS) Thyroid Eye Disease (TED) Trial; Topline Results Expected in the Second Quarter of 2023 -- -- Announced Positive Topline Data from Phase 2 Dazodalibep Sjögren’s Syndrome Trial; Planning to Initiate a Phase 3 Clinical Program in 2023 -- -- First Patient Enrolled in ADX-914 Phase 2 Trial in Collaboration with Q32 Bio -- DUBLIN--(BUSINESS WIRE)-- Horizon Therapeutics plc (Nasdaq: HZNP) today announced third-quarter 2022 financial results and increased its full-year 2022 net sales and adjusted EBITDA guidance. “Our third-quarter focus on clinical, commercial and operational execution drove continued progress across our portfolio,” said Tim Walbert, chairman, president and chief executive officer, Horizon. “We advanced our pipeline, achieving several important R&D milestones, including completing enrollment in our TEPEZZA trial for chronic/low CAS thyroid eye disease and announcing positive Phase 2 topline results from our dazodalibep trial in Sjögren’s syndrome. These achievements reflect our commitment to bring innovative medicines to more patients in need.” “Our successful launch of the KRYSTEXXA expanded label has driven increased use of KRYSTEXXA with immunomodulation. Encouraged by the momentum we are seeing, we increased our KRYSTEXXA U.S. peak annual net sales expectations to greater than $1.5 billion. We also see a significantly greater opportunity for TEPEZZA in various international markets and are increasing our ex-U.S. peak annual net sales expectations for TEPEZZA to greater than $1 billion.” Financial Highlights (in millions except for per share amounts and percentages) Q3 22 Q3 21 % Change YTD 22 YTD 21 % Change Net sales $ 925.4 $ 1,037.0 (11 ) $ 2,687.0 $ 2,211.9 21 Net income 135.8 326.5 (58 ) 401.1 361.3 11 Non-GAAP net income 293.3 410.3 (29 ) 862.9 755.7 14 Adjusted EBITDA(1) 335.3 505.0 (34 ) 1,013.1 868.3 17 Earnings per share - diluted 0.58 1.38 (58 ) 1.70 1.54 10 Non-GAAP earnings per share - diluted 1.25 1.74 (28 ) 3.66 3.21 14 (1) Third-quarter 2022 and 2021 adjusted EBITDA includes $19.0 million and $4.0 million, respectively, in acquired IPR&D and milestones expenses. Year-to-date 2022 and 2021 adjusted EBITDA includes $19.0 million and $47.0 million, respectively, in acquired IPR&D and milestones expenses. Third Quarter and Recent Company Highlights Increasing TEPEZZA Ex-U.S. Peak Annual Net Sales Expectations to Greater than $1 Billion: Today, the Company announced it is increasing its ex-U.S. peak annual net sales expectations for TEPEZZA to greater than $1 billion from the previous estimate of greater than $500 million, following further assessment of the ex-U.S. TED market opportunity and now also incorporating plans to launch TEPEZZA in Europe. The Company continues to expect U.S. peak annual net sales of greater than $3 billion, bringing global peak annual net sales expectations to greater than $4 billion. Increasing KRYSTEXXA U.S. Peak Annual Net Sales Expectations to Greater than $1.5 Billion: Today, the Company announced it is increasing its U.S. peak annual net sales expectations for KRYSTEXXA to greater than $1.5 billion from the previous estimate of greater than $1 billion. This increase follows strong momentum across rheumatology and nephrology, with the use of KRYSTEXXA with immunomodulation now exceeding 60% of new patient starts and increased clinical conviction among physicians. Given the strong performance of KRYSTEXXA through the third quarter, the Company is also increasing its guidance for full-year 2022 net sales growth to approximately 25% from more than 20%. Completed Enrollment in TEPEZZA Chronic/Low CAS TED Clinical Trial: In September, the Company completed enrollment in the Phase 4 clinical trial evaluating TEPEZZA for the treatment of TED in patients with a low CAS. Topline results are expected in the second quarter of 2023. Announced Positive Topline Data from Dazodalibep Sjögren’s Syndrome Trial: In September, the Company announced positive topline data from the Phase 2 trial evaluating dazodalibep in Sjögren’s syndrome patients with moderate-to-severe systemic disease activity as defined by the European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥ 5. The results met the primary endpoint, showing a 6.3-point reduction in the ESSDAI score at Week 24 in patients treated with dazodalibep, and achieving a statistically significant least squares mean difference of 2.2 points compared to placebo (p=0.017). Other numerical improvements observed in key secondary, exploratory and post-hoc analyses suggest that dazodalibep may also impact other important symptoms for patients living with Sjögren’s syndrome, such as the number of tender and swollen joints, fatigue and dryness. The Company plans to work with global regulatory bodies to design a Phase 3 program which is expected to initiate in 2023. The Phase 2 trial in a second population of Sjögren’s syndrome patients with moderate-to-severe localized symptoms as defined by the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score of ≥ 5, is fully enrolled and continues to progress. Entered into Agreement with Q32 Bio for Pipeline Candidate in Development for the Treatment of Autoimmune Diseases: In August, the Company entered into a collaboration and option agreement with Q32 Bio to develop its pipeline candidate ADX-914 for the treatment of autoimmune diseases. ADX-914, a fully human anti-IL-7Rα antibody targeting the IL-7 and TSLP pathways, demonstrated pharmacological effect on T-cells in a Phase 1 study in healthy volunteers. A Phase 2 trial in atopic dermatitis initiated in October and a Phase 2 trial in a second autoimmune disease is planned to initiate next year. Announced Planned Expansion of Manufacturing Facility in Waterford, Ireland: In August, the Company announced plans to expand its facility in Waterford, Ireland to add new drug substance biologics development and manufacturing capabilities. The project would expand the footprint of the Company’s current drug product (fill-finish) biologics facility, which it purchased in July 2021. The Company continues to invest in its development and manufacturing capabilities to supplement its current network of contract manufacturing organizations and provide flexibility over production and supply. FDA Approved Expanded Label for KRYSTEXXA to Include Co-Administration with Methotrexate: In July, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) expanding the KRYSTEXXA label to include co-administration with methotrexate. The approval was based on 6-month and 12-month results from the MIRROR randomized controlled trial (RCT), which demonstrated significant improvements in response rate and sustained patient response of KRYSTEXXA with methotrexate compared to KRYSTEXXA with placebo, as well as a significant reduction in infusion reactions. Presenting Results from the KRYSTEXXA MIRROR RCT and Dazodalibep Rheumatoid Arthritis (RA) Trial at Key Upcoming Medical Meeting: Multiple data will be presented at the American College of Rheumatology (ACR) Convergence 2022 which will take place on Nov. 10-14, 2022, including 12-month results from the MIRROR RCT. In addition, data from the Phase 2 trial of dazodalibep in patients with RA will be presented. The study met the primary endpoint across all doses, achieving a statistically significant change from baseline in DAS28-CRP, a standardized measure of disease activity in RA trials, at Day 113. Presented New TEPEZZA Data at Key Medical Meetings: In October, new data were presented at the American Academy of Ophthalmology (AAO) Annual Meeting 2022 showing that insulin-like growth factor-1 (IGF-1) and its related pathways are extensively upregulated throughout all stages of TED, including in both high and low CAS patients. Additionally, in October, new data from a real-world analysis of TEPEZZA were presented at the American Thyroid Association (ATA) Annual Meeting 2022 showing only 4.9% of patients analyzed were prescribed an additional course of TEPEZZA, with 1.9% of analyzed patients going on to initiate treatment. Presented New UPLIZNA® (inebilizumab-cdon) Data at Key Medical Meeting: In October, multiple new data from the UPLIZNA Phase 3 trial were presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), including data showing that UPLIZNA effectively depletes CD19+ B-cells, including plasmablasts and plasma cells, which have been found to play a crucial role during a neuromyelitis optica spectrum disorder (NMOSD) attack. A separate analysis highlighted the efficacy of UPLIZNA among patients with genetic variations typically associated with reduced response to other types of monoclonal antibody therapies. Advancing the Company’s Global Expansion for UPLIZNA and TEPEZZA: In August, the Company launched UPLIZNA in Germany, and in France under an early access program, followed by the launch in Austria in September. In October, the Company announced that it submitted a regulatory filing to the Brazil National Health Surveillance Agency (ANVISA) for teprotumumab, in addition to inebilizumab, which was filed earlier this year. Announced Share Repurchase Program: In September, the Company’s Board of Directors authorized a share repurchase program of up to $500 million of the Company’s ordinary shares. To date, the Company has repurchased $250.0 million of its ordinary shares under the program. The Company’s strong balance sheet and cash generation provides the flexibility to opportunistically repurchase shares while preserving capital to continue prioritizing business development. Environmental, Social and Governance (ESG) Highlights: In August, the Company published its inaugural Sustainability Accounting Standards Board (SASB) Index as part of its updated 2021 ESG Overview. In addition, the Company continues to receive recognition for its high employee engagement, receiving multiple workplace awards, including Fortune’s “Best Workplaces in Biopharma 2022 List” for the sixth consecutive year and ranked first overall for the third time, Seramount’s “Inclusion Index”, Seramount's “100 Best Companies”, Seramount's “Best Companies for Dad”, Newsweek’s “2022 Top 100 Most Loved Workplaces®”, PEOPLE’s “100 Companies That Care® and was recognized in the PatientView global survey of patient groups, ranking third overall in corporate reputation. Key Clinical Development Programs Daxdilimab, an anti-ILT7 human monoclonal antibody that depletes certain dendritic cells. Depleting these cells may interrupt the cycle of inflammation that causes tissue damage in diseases such as lupus, and a variety of other autoimmune conditions. Systemic Lupus Erythematosus (SLE) Trial: Phase 2 randomized placebo-controlled trial underway to evaluate daxdilimab in patients with SLE, a disease in which the body's immune system attacks its own tissues and organs. Trial enrollment was completed in the second quarter of 2022. Alopecia Areata Trial: Phase 2 open-label trial underway to evaluate daxdilimab in patients with alopecia areata, an autoimmune disorder characterized by nonscarring hair loss. Discoid Lupus Erythematosus (DLE) Trial: Planned Phase 2 randomized placebo-controlled trial to evaluate daxdilimab in patients with DLE, a rare, chronic, inflammatory skin condition characterized by lesions that result in scarring. Lupus Nephritis Trial: Planned Phase 2 trial to evaluate daxdilimab in patients with lupus nephritis, a rare, autoimmune and inflammatory condition of the kidney. Dermatomyositis Trial: Planned Phase 2 trial to evaluate daxdilimab in patients with dermatomyositis, a rare autoimmune disorder characterized by rashes, debilitating muscle weakness and interstitial lung disease. Dazodalibep, a CD40 ligand antagonist that blocks T-cell interaction with CD40-expressing B-cells, disrupting the overactivation of the CD40 ligand co-stimulatory pathway. Several autoimmune diseases are associated with the overactivation of this pathway. Sjögren's Syndrome Trial: Phase 2 randomized placebo-controlled trial underway to evaluate dazodalibep in patients with Sjögren's syndrome, a chronic, systemic autoimmune condition that impacts exocrine glands, including the salivary and tear glands. Topline data in Sjögren’s syndrome patients with moderate-to-severe systemic disease activity, as defined by an ESSDAI score of ≥ 5, were announced in September. The trial met the primary endpoint and showed numerical improvements in key secondary and exploratory endpoints. The Phase 2 trial in a second population of Sjögren’s syndrome patients with moderate-to-severe localized symptoms, as defined by an ESSPRI score of ≥ 5, is fully enrolled and continues to progress. Rheumatoid Arthritis Trial: Phase 2 randomized placebo-controlled trial to evaluate dazodalibep in patients with RA. Topline results were announced in May 2022. The trial met the primary endpoint and dazodalibep was well tolerated. The trial results may inform the dosing regimen for other studies with dazodalibep. Data from the trial will be presented at an upcoming medical meeting. Kidney Transplant Rejection Trial: Phase 2 open-label trial underway to evaluate dazodalibep in kidney transplant rejection patients. Focal Segmental Glomerulosclerosis (FSGS) Trial: Planned Phase 2 trial to evaluate dazodalibep in patients with FSGS, a rare kidney disorder characterized by scarring of glomeruli. HZN-825, an oral lysophosphatidic acid receptor 1 (LPAR1) antagonist designed to prevent gene activation. Diffuse Cutaneous Systemic Sclerosis Trial: Pivotal Phase 2b trial underway to evaluate HZN-825 in diffuse cutaneous systemic sclerosis. Idiopathic Pulmonary Fibrosis Trial: Pivotal Phase 2b trial underway to evaluate HZN-825 in idiopathic pulmonary fibrosis, the most common form of interstitial lung disease. UPLIZNA, an anti-CD19 humanized monoclonal antibody that depletes B-cells, including the pathogenic cells that produce autoantibodies. Myasthenia Gravis Trial: Phase 3 randomized placebo-controlled trial underway to evaluate UPLIZNA in patients with myasthenia gravis, a chronic, rare, autoimmune neuromuscular disease that affects voluntary muscles, especially those that control the eyes, mouth, throat and limbs. IgG4-Related Disease Trial: Phase 3 randomized placebo-controlled trial underway to evaluate UPLIZNA in patients with IgG4-related disease, which is a group of disorders marked by tumor-like swelling and fibrosis of affected organs, such as the pancreas, salivary glands and kidneys. TEPEZZA, an insulin-like growth factor type 1 receptor (IGF-1R) antagonist monoclonal antibody. Chronic/Low CAS TED Trial: Phase 4 randomized placebo-controlled trial underway to evaluate TEPEZZA in chronic/low CAS TED. The trial completed enrollment in September 2022. TED in Japan (OPTIC-J) Trial: Phase 3 randomized placebo-controlled trial in Japan underway to evaluate TEPEZZA in patients with moderate-to-severe active TED. Subcutaneous (SC) Administration Trial: Phase 1b trial initiated in July 2022 to explore the pharmacokinetics, safety, tolerability, efficacy and immunogenicity of subcutaneous administration of TEPEZZA in patients with TED. Diffuse Cutaneous Systemic Sclerosis Exploratory Trial: Phase 1 exploratory trial underway to evaluate TEPEZZA in diffuse cutaneous systemic sclerosis. ADX-914 (collaboration with Q32 Bio), a fully human anti-IL-7Rα antibody that re-regulates adaptive immune function by blocking signaling mediated by both IL-7 and TSLP. The Company has an option to acquire ADX-914 on pre-negotiated terms with Q32 Bio. Atopic Dermatitis Trial: Phase 2 trial initiated in October 2022 to evaluate ADX-914 in atopic dermatitis, a chronic, autoimmune disorder that causes inflammation, redness and irritation of the skin. Autoimmune Disease Trial: Planned Phase 2 trial to evaluate ADX-914 in a second autoimmune disease. KRYSTEXXA, a recombinant uricase enzyme that converts urate into a water-soluble liquid, allantoin, that can be easily excreted from the body. Shorter Infusion Duration Trial: Phase 4 open-label trial underway to evaluate the impact of administering KRYSTEXXA with methotrexate over a shorter infusion duration in patients with uncontrolled gout. Monthly Dosing Trial: Phase 4 open-label trial underway to evaluate monthly dosing of KRYSTEXXA with methotrexate in patients with uncontrolled gout. HZN-1116, a fully human monoclonal antibody designed to bind and neutralize the function of the FLT3-ligand, thereby reducing both conventional and plasmacytoid dendritic cells. Autoimmune Disease Trial: Phase 1 trial underway to evaluate HZN-1116 in patients with autoimmune diseases. Third-Quarter Financial Results Note: For additional detail and reconciliation of non-GAAP financial measures to the most directly comparable GAAP financial measures, please refer to the tables at the end of this release. Beginning with the third quarter of 2022, the Company is separately presenting upfront, milestone, and similar payments pursuant to collaborations, licenses of third-party technologies, and asset acquisitions as “Acquired in-process research and development and milestones” expenses in the condensed consolidated statement of comprehensive income. Amounts recorded in this line item for the three and nine months ended September 30, 2022, would have historically been recorded to research and development (“R&D”) expenses. The Company believes the new classification assists users of the financial statements in better understanding the payments incurred to acquire in-process research and development (“IPR&D”). Prior period condensed consolidated statements of comprehensive income have been reclassified to conform with the new classification. Net Sales: Third-quarter 2022 net sales were $925.4 million. Third-quarter 2021 net sales were $1.037 billion. Gross Profit: Under U.S. GAAP, the third-quarter 2022 gross profit ratio was 74.7% compared to 75.7% in the third quarter of 2021. The non-GAAP gross profit ratio in the third quarter of 2022 was 87.2% compared to 85.4% in the third quarter of 2021. Operating Expenses: Under U.S. GAAP, third-quarter 2022 R&D expenses were 12.3% of net sales and non-GAAP R&D expenses were 11.7% of net sales. Third-quarter 2022 acquired IPR&D and milestones expenses were 2.1% of net sales. Under U.S. GAAP, third-quarter 2022 SG&A expenses were 43.0% of net sales and non-GAAP SG&A expenses were 37.0% of net sales. Income Tax (Benefit) Expense: On a GAAP basis in the third quarter of 2022, income tax benefit was $0.8 million. Third-quarter non-GAAP income tax expense was $21.8 million. Net Income: In the third quarter of 2022, net income on a GAAP and non-GAAP basis was $135.8 million and $293.3 million, respectively. Adjusted EBITDA: Third-quarter 2022 adjusted EBITDA was $335.3 million and includes $19.0 million of acquired IPR&D and milestones expenses. Earnings per Share: On a GAAP basis, diluted earnings per share in the third quarter of 2022 and 2021 were $0.58 and $1.38, respectively. Non-GAAP diluted earnings per share in the third quarter of 2022 and 2021 were $1.25 and $1.74, respectively. Weighted average shares outstanding used for calculating GAAP and non-GAAP diluted earnings per share in the third quarter of 2022 were 235.4 million. These reported results for the third quarter of 2022 and 2021 include an unfavorable impact of $0.08 and $0.02, respectively, to both GAAP diluted earnings per share and non-GAAP diluted earnings per share, related to acquired IPR&D and milestones expenses. Third-Quarter Segment Results Management uses net sales and segment operating income to evaluate the performance of the Company’s two segments, the orphan segment and the inflammation segment. While segment operating income contains certain adjustments to the directly comparable GAAP figures in the Company’s consolidated financial results, such as the exclusion of acquired IPR&D and milestones expenses, it is considered to be prepared in accordance with GAAP for purposes of presenting the Company’s segment operating results. Orphan Segment (in millions except for percentages) Q3 22 Q3 21 % Change YTD 22 YTD 21 % Change TEPEZZA®(1) $ 490.9 $ 616.4 (20 ) $ 1,472.2 $ 1,071.7 37 KRYSTEXXA® 191.6 158.1 21 500.1 395.2 27 RAVICTI® 84.3 76.2 10 238.1 217.6 9 PROCYSBI®(2) 57.8 49.3 17 155.1 142.5 9 UPLIZNA®(3) 43.8 18.7 134 112.9 35.0 222 ACTIMMUNE® 34.4 30.1 15 95.8 86.6 11 BUPHENYL® 1.7 1.9 (8 ) 5.3 5.8 (9 ) QUINSAIRTM 0.2 0.3 (26 ) 0.9 0.7 16 Orphan Net Sales $ 904.7 $ 951.0 (5 ) $ 2,580.4 $ 1,955.1 32 Orphan Segment Operating Income $ 366.9 $ 476.2 (23 ) $ 1,033.5 $ 798.5 29 (1) TEPEZZA net sales in the third quarter of 2021 accounted for a larger share of full-year 2021 net sales due to a supply disruption caused by the U.S. government-mandated COVID-19 vaccine orders. (2) PROCYSBI net sales in the third quarter of 2022 benefitted from a $7.5 million partial release in the pricing review liability recorded during the three months ended September 30, 2022, as a result of a decision made by the Patented Medicines Prices Review Board (PMPRB) in September relating to PROCYSBI pricing in Canada. (3) Third-quarter and year-to-date 2022 UPLIZNA net sales included $3.2 million and $17.0 million, respectively, in international net sales, related primarily to revenue and milestone payments from the Company’s international partners. Third-quarter 2022 net sales of the orphan segment, the Company’s strategic growth segment, were $904.7 million, with strong contributions from TEPEZZA, KRYSTEXXA, UPLIZNA, RAVICTI, PROCYSBI and ACTIMMUNE. Third-quarter 2022 orphan segment operating income was $366.9 million. TEPEZZA third-quarter 2022 net sales were $490.9 million. TEPEZZA third-quarter 2021 net sales were $616.4 million and accounted for a larger share of full-year 2021 net sales due to a supply disruption caused by the U.S. government-mandated COVID-19 vaccine orders. KRYSTEXXA third-quarter 2022 net sales increased 21% year-over-year driven by higher adoption of KRYSTEXXA with immunomodulation, which now exceeds 60% of new patient starts. In addition, the Company continues to see strong uptake of KRYSTEXXA from both rheumatologists and nephrologists. Inflammation Segment (in millions except for percentages) Q3 22 Q3 21 % Change YTD 22 YTD 21 % Change RAYOS® $ 10.6 $ 14.9 (29 ) $ 35.1 $ 43.6 (19 ) PENNSAID 2%®(1) 7.6 48.0 (84 ) 66.6 142.7 (53 ) DUEXIS®(2) 2.0 20.9 (90 ) 3.2 62.5 (95 ) VIMOVO® 0.5 2.2 (78 ) 1.7 8.1 (79 ) Inflammation Net Sales $ 20.7 $ 86.0 (76 ) $ 106.6 $ 256.9 (59 ) Inflammation Segment Operating (Loss) Income $ (10.8 ) $ 34.1 NM $ (2.0 ) $ 123.6 NM (1) On May 6, 2022, Apotex Inc. initiated an at-risk launch of generic PENNSAID 2% in the United States. (2) On Aug. 4, 2021, Alkem Laboratories, Inc. initiated an at-risk launch of generic DUEXIS in the United States. Third-quarter 2022 net sales of the inflammation segment were $20.7 million and segment operating loss was $10.8 million. The Company expects the wind down of the inflammation segment to be substantially complete in the fourth quarter of 2022. Cash Flow Statement and Balance Sheet Highlights Third-quarter 2022 operating cash flow on a GAAP and non-GAAP basis was $366.5 million and $368.4 million, respectively. As of Sept. 30, 2022, the Company had cash and cash equivalents of $2.13 billion. As of Sept. 30, 2022, the total principal amount of debt outstanding was $2.59 billion. Revised 2022 Guidance The Company increased its full-year 2022 net sales guidance to range between $3.59 billion and $3.61 billion, compared to the previous guidance range of $3.53 billion to $3.60 billion. The Company continues to expect TEPEZZA full-year 2022 net sales percentage growth in the high teens and is increasing KRYSTEXXA full-year 2022 net sales growth to approximately 25% compared to the previous guidance of more than 20%. The Company increased its full-year 2022 adjusted EBITDA guidance to range between $1.32 billion to $1.34 billion, compared to the previous guidance range of $1.268 billion to $1.318 billion, which includes $52.5 million of expected full-year 2022 acquired IPR&D and milestones expenses. Webcast At 8 a.m. EDT / 12 p.m. GMT today, the Company will host a live webcast to review its financial and operating results and provide a general business update. The live webcast and a replay may be accessed at . Please connect to the Company's website at least 15 minutes prior to the live webcast to ensure adequate time for any software download that may be needed to access the webcast. A replay of the webcast will be available approximately two hours after the live webcast. 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 and follow us on Twitter, LinkedIn, Instagram and Facebook. Note Regarding Use of Non-GAAP Financial Measures Horizon provides certain non-GAAP financial measures, including EBITDA, or earnings before interest, taxes, depreciation and amortization, adjusted EBITDA, non-GAAP net income, non-GAAP diluted earnings per share, non-GAAP gross profit and gross profit ratio, non-GAAP operating expenses, non-GAAP operating income, non-GAAP tax benefit (expense) and tax rate, non-GAAP operating cash flow and certain other non-GAAP income statement line items, each of which include adjustments to GAAP figures. These non-GAAP measures are intended to provide additional information on Horizon’s performance, operations, expenses, profitability and cash flows. Adjustments to Horizon’s GAAP figures exclude, as applicable, acquisition and/or divestiture-related costs, manufacturing facility start-up costs, restructuring and realignment costs, as well as non-cash items such as share-based compensation, inventory step-up expense, depreciation and amortization, non-cash interest expense, goodwill and long-lived assets impairment charges, gain (loss) on equity security investments and sales of assets, and other non-cash adjustments. Certain other special items or substantive events may also be included in the non-GAAP adjustments periodically when their magnitude is significant within the periods incurred. Horizon maintains an established non-GAAP cost policy that guides the determination of what costs will be excluded in non-GAAP measures. Horizon believes that these non-GAAP financial measures, when considered together with the GAAP figures, can enhance an overall understanding of Horizon’s financial and operating performance. The non-GAAP financial measures are included with the intent of providing investors with a more complete understanding of the Company’s historical and expected financial results and trends and to facilitate comparisons between periods and with respect to projected information. In addition, these non-GAAP financial measures are among the indicators Horizon’s management uses for planning and forecasting purposes and measuring the Company's performance. These non-GAAP financial measures should be considered in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The non-GAAP financial measures used by the Company may be calculated differently from, and therefore may not be comparable to, non-GAAP financial measures used by other companies. Horizon has not provided a reconciliation of its full-year 2022 adjusted EBITDA guidance to expected GAAP net income (loss) guidance because certain items such as acquisition/divestiture-related expenses and share-based compensation that are components of net income (loss) cannot be reasonably projected due to the significant impact of changes in Horizon’s share price, the variability associated with the size and/or timing of acquisitions/divestitures, and other factors. These components of net income (loss) could significantly impact Horizon’s GAAP net income (loss). Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to Horizon’s full-year 2022 net sales and adjusted EBITDA guidance; expected financial performance and operating results in future periods, including projected growth in net sales of certain of Horizon’s medicines; estimates of peak annual net sales; development, manufacturing and commercialization plans; expected timing of clinical trials and, availability of clinical data; expected future milestones, pipeline expansions and regulatory approvals; potential market opportunities for, and benefits of, Horizon’s medicines and medicine candidates and business 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 that Horizon’s actual future financial and operating results may differ from its expectations or goals; Horizon’s ability to grow net sales from existing medicines; impacts of the COVID-19 pandemic and actions taken to slow its spread, including impacts on supplies and net sales of Horizon’s medicines and potential delays in clinical trials; impacts of the on-going war between Russia and Ukraine; changes in inflation, interest rates and general economic conditions; acquisitions, such as the risk that acquired businesses or products will not be integrated successfully, that such integration may be more difficult, time-consuming or costly than expected or that the expected benefits of the related transactions will not occur; the availability of coverage and adequate reimbursement and pricing from government and third-party payers; Horizon’s ability to successfully implement its business strategies, including the risks that its TEPEZZA growth and global expansion initiatives and strategies may not be successful and that new challenges to TEPEZZA growth may arise in the future; risks inherent in developing novel medicine candidates and existing medicines for new indications; risks associated with regulatory approvals; risks in the ability to recruit, train and retain qualified personnel; competition, including generic competition; the ability to protect intellectual property and defend patents; 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. Horizon Therapeutics plc Condensed Consolidated Statements of Operations (Unaudited) (in thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 Net sales $ 925,359 $ 1,036,992 $ 2,687,015 $ 2,211,946 Cost of goods sold 234,132 251,640 679,410 553,003 Gross profit 691,227 785,352 2,007,605 1,658,943 OPERATING EXPENSES: Research and development (1) 114,058 89,549 320,436 244,076 Acquired in-process research and development and milestones (1) 19,000 4,000 19,000 47,000 Selling, general and administrative 397,563 360,260 1,168,518 1,047,456 Impairment of goodwill - - 56,171 - Impairment of long-lived asset - - - 12,371 Gain on sale of asset - - - (2,000 ) Total operating expenses 530,621 453,809 1,564,125 1,348,903 Operating income 160,606 331,543 443,480 310,040 OTHER EXPENSE, NET: Interest expense, net (22,480 ) (22,977 ) (65,145 ) (59,018 ) Foreign exchange loss (768 ) (476 ) (320 ) (1,363 ) Other (expense) income, net (2,277 ) (849 ) (5,408 ) 2,113 Total other expense, net (25,525 ) (24,302 ) (70,873 ) (58,268 ) Income before benefit for income taxes 135,081 307,241 372,607 251,772 Benefit for income taxes (758 ) (19,302 ) (28,467 ) (109,537 ) Net income $ 135,839 $ 326,543 $ 401,074 $ 361,309 Net income per ordinary share - basic $ 0.59 $ 1.44 $ 1.75 $ 1.61 Weighted average ordinary shares outstanding - basic 230,333,287 226,096,747 229,820,406 225,053,704 Net income per ordinary share - diluted $ 0.58 $ 1.38 $ 1.70 $ 1.54 Weighted average ordinary shares outstanding - diluted 235,385,570 236,198,789 235,923,030 235,256,424 (1) Beginning with the third quarter of 2022, the Company is separately presenting upfront, milestone, and similar payments pursuant to collaborations, licenses of third-party technologies, and asset acquisitions as “Acquired in-process research and development and milestones” expenses in the condensed consolidated statement of comprehensive income. Amounts recorded in this line item for the three and nine months ended September 30, 2022, would have historically been recorded to research and development (“R&D”) expenses. The Company believes the new classification assists users of the financial statements in better understanding the payments incurred to acquire in-process research and development (“IPR&D”). Prior period condensed consolidated statements of comprehensive income have been reclassified to conform with the new classification. Horizon Therapeutics plc Condensed Consolidated Balance Sheets (Unaudited) (in thousands, except share data) As of September 30, 2022 December 31, 2021 ASSETS CURRENT ASSETS: Cash and cash equivalents $ 2,130,527 $ 1,580,317 Restricted cash 4,743 3,839 Accounts receivable, net 646,386 632,775 Inventories, net 190,258 225,730 Prepaid expenses and other current assets 440,095 357,106 Total current assets 3,412,009 2,799,767 Property, plant and equipment, net 317,692 292,298 Developed technology and other intangible assets, net 2,757,694 2,960,118 In-process research and development 810,000 880,000 Goodwill 1,010,538 1,066,709 Deferred tax assets, net 516,317 538,098 Other long-term assets 203,612 140,738 Total assets $ 9,027,862 $ 8,677,728 LIABILITIES AND SHAREHOLDERS' EQUITY CURRENT LIABILITIES: Accounts payable $ 32,113 $ 30,125 Accrued expenses and other current liabilities 457,288 523,015 Accrued trade discounts and rebates 355,213 317,431 Long-term debt—current portion 16,000 16,000 Total current liabilities 860,614 886,571 LONG-TERM LIABILITIES: Long-term debt, net 2,549,140 2,555,233 Deferred tax liabilities, net 385,121 390,455 Other long-term liabilities 199,300 173,076 Total long-term liabilities 3,133,561 3,118,764 COMMITMENTS AND CONTINGENCIES SHAREHOLDERS' EQUITY: Ordinary shares, $0.0001 nominal value; 600,000,000 shares authorized at September 30, 2022 and December 31, 2021; 229,076,182 and 227,760,936 shares issued at September 30, 2022 and December 31, 2021, respectively; and 228,691,816 and 227,376,570 shares outstanding at September 30, 2022 and December 31, 2021, respectively 23 23 Treasury stock, 384,366 ordinary shares at September 30, 2022 and December 31, 2021 (4,585 ) (4,585 ) Additional paid-in capital 4,424,509 4,373,337 Accumulated other comprehensive income (loss) 7,460 (14,987 ) Retained earnings 606,280 318,605 Total shareholders' equity 5,033,687 4,672,393 Total liabilities and shareholders' equity $ 9,027,862 $ 8,677,728 Horizon Therapeutics plc Condensed Consolidated Statements of Cash Flows (Unaudited) (in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 CASH FLOWS FROM OPERATING ACTIVITIES: Net income $ 135,839 $ 326,543 $ 401,074 $ 361,309 Adjustments to reconcile net income to net cash provided by operating activities: Depreciation and amortization expense 99,081 94,480 291,619 257,216 Equity-settled share-based compensation 45,066 54,804 137,515 170,394 Acquired IPR&D and milestones 15,000 - 15,000 40,000 Impairment of goodwill - - 56,171 - Impairment of long-lived asset - - - 12,371 Amortization of debt discount and deferred financing costs 2,232 1,500 6,136 3,740 Gain on sale of asset - - - (2,000 ) Deferred income taxes 11,686 (129,819 ) 8,654 (147,934 ) Foreign exchange and other adjustments (2,870 ) 1,958 7,696 5,006 Changes in operating assets and liabilities: Accounts receivable 26,832 (39,762 ) (13,681 ) (107,776 ) Inventories 13,376 21,219 35,409 (10,494 ) Prepaid expenses and other current assets (3,079 ) 34,333 (74,657 ) (60,790 ) Accounts payable 11,125 (2,666 ) (855 ) 7,640 Accrued trade discounts and rebates 18,057 (2,825 ) 38,289 (50,838 ) Accrued expenses and other current liabilities 11,913 59,021 (64,988 ) 34,380 Other non-current assets and liabilities (17,794 ) (7,746 ) (11,931 ) (15,510 ) Net cash provided by operating activities 366,464 411,040 831,451 496,714 CASH FLOWS FROM INVESTING ACTIVITIES: Payments for acquisitions, net of cash acquired - (67,945 ) (3,122 ) (2,843,275 ) Purchases of property, plant and equipment (14,816 ) (27,440 ) (39,168 ) (59,695 ) Payments for long-term investments (2,209 ) (2,219 ) (7,056 ) (13,385 ) Receipts from long-term investments - - 4,416 3,588 Proceeds from sale of asset - 2,000 - 2,000 Payments related to license and collaboration agreements (15,000 ) (46,500 ) (40,000 ) (46,500 ) Net cash used in investing activities (32,025 ) (142,104 ) (84,930 ) (2,957,267 ) CASH FLOWS FROM FINANCING ACTIVITIES: Net proceeds from term loans - - - 1,574,993 Repayment of term loans (4,000 ) (4,000 ) (12,000 ) (8,000 ) Proceeds from the issuance of ordinary shares in conjunction with ESPP program - - 13,884 11,482 Proceeds from the issuance of ordinary shares in connection with stock option exercises 1,258 12,174 23,280 40,013 Payment of employee withholding taxes relating to share-based awards (3,420 ) (16,429 ) (123,947 ) (158,077 ) Repurchase of ordinary shares (88,209 ) - (88,209 ) - Net cash (used in) provided by financing activities (94,371 ) (8,255 ) (186,992 ) 1,460,411 Effect of foreign exchange rate changes on cash, cash equivalents and restricted cash (2,098 ) (4,452 ) (8,415 ) (10,951 ) Net increase (decrease) in cash, cash equivalents and restricted cash 237,970 256,229 551,114 (1,011,093 ) Cash, cash equivalents and restricted cash, beginning of the period(1) 1,897,300 816,157 1,584,156 2,083,479 Cash, cash equivalents and restricted cash, end of the period(1) $ 2,135,270 $ 1,072,386 $ 2,135,270 $ 1,072,386 (1) Amounts include restricted cash balance in accordance with ASU No. 2016-18. Cash and cash equivalents excluding restricted cash are shown on the balance sheet. Horizon Therapeutics plc GAAP to Non-GAAP Reconciliations Net Income and Earnings Per Share (Unaudited) (in thousands, except share and per share data) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 GAAP net income $ 135,839 $ 326,543 $ 401,074 $ 361,309 Non-GAAP adjustments: Acquisition/divestiture-related costs 825 9,228 3,437 88,166 Loss on equity security investments 1,247 - 6,331 - Restructuring and realignment costs 7,731 680 9,521 7,703 Manufacturing facility start-up costs 2,024 1,712 4,413 1,712 Amortization and step-up: Intangible amortization expense 92,951 90,368 273,546 245,260 Inventory step-up expense 21,779 8,912 66,342 16,914 Amortization of debt discount and deferred financing costs 2,232 1,500 6,136 3,740 Impairment of long-lived asset - - - 12,371 Impairment of goodwill - - 56,171 - Gain on sale of asset - - - (2,000 ) Share-based compensation 45,066 54,804 137,515 170,394 Depreciation 6,130 4,112 18,073 11,956 Litigation settlement - 5,000 - 5,000 Total of pre-tax non-GAAP adjustments 179,985 176,316 581,485 561,216 Income tax effect of pre-tax non-GAAP adjustments (24,623 ) (36,602 ) (121,754 ) (141,665 ) Other non-GAAP income tax adjustments 2,079 (56,007 ) 2,079 (25,126 ) Total of non-GAAP adjustments 157,441 83,707 461,810 394,425 Non-GAAP net income $ 293,280 $ 410,250 $ 862,884 $ 755,734 Non-GAAP Earnings Per Share: Weighted average ordinary shares - Basic 230,333,287 226,096,747 229,820,406 225,053,704 Non-GAAP Earnings Per Share - Basic: GAAP earnings per share - Basic $ 0.59 $ 1.44 $ 1.75 $ 1.61 Non-GAAP adjustments 0.68 0.37 2.00 1.75 Non-GAAP earnings per share - Basic $ 1.27 $ 1.81 $ 3.75 $ 3.36 Weighted average ordinary shares - Diluted Weighted average ordinary shares - Basic 230,333,287 226,096,747 229,820,406 225,053,704 Ordinary share equivalents 5,052,283 10,102,042 6,102,624 10,202,720 Weighted average ordinary shares - Diluted 235,385,570 236,198,789 235,923,030 235,256,424 Non-GAAP Earnings Per Share - Diluted GAAP earnings per share - Diluted $ 0.58 $ 1.38 $ 1.70 $ 1.54 Non-GAAP adjustments 0.67 0.36 1.96 1.67 Non-GAAP earnings per share - Diluted $ 1.25 $ 1.74 $ 3.66 $ 3.21 Horizon Therapeutics plc GAAP to Non-GAAP Reconciliations EBITDA and Adjusted EBITDA (Unaudited) (in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 GAAP net income $ 135,839 $ 326,543 $ 401,074 $ 361,309 Depreciation 6,130 4,112 18,073 11,956 Amortization and step-up: Intangible amortization expense 92,951 90,368 273,546 245,260 Inventory step-up expense 21,779 8,912 66,342 16,914 Interest expense, net (including amortization of debt discount and deferred financing costs) 22,480 22,977 65,145 59,018 Benefit for income taxes (758 ) (19,302 ) (28,467 ) (109,537 ) EBITDA $ 278,421 $ 433,610 $ 795,713 $ 584,920 Other non-GAAP adjustments: Share-based compensation 45,066 54,804 137,515 170,394 Loss on equity security investments 1,247 - 6,331 - Acquisition/divestiture-related costs 825 9,228 3,437 88,166 Manufacturing facility start-up costs 2,024 1,712 4,413 1,712 Restructuring and realignment costs 7,731 680 9,521 7,703 Impairment of goodwill - - 56,171 - Impairment of long-lived asset - - - 12,371 Gain on sale of asset - - - (2,000 ) Litigation settlement - 5,000 - 5,000 Total of other non-GAAP adjustments 56,893 71,424 217,388 283,346 Adjusted EBITDA $ 335,314 $ 505,034 $ 1,013,101 $ 868,266 Horizon Therapeutics plc GAAP to Non-GAAP Reconciliations Operating Income (Unaudited) (in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 GAAP operating income $ 160,606 $ 331,543 $ 443,480 $ 310,040 Non-GAAP adjustments: Acquisition/divestiture-related costs 825 9,224 3,437 89,241 Restructuring and realignment costs 7,731 680 9,521 7,703 Manufacturing facility start-up costs 2,024 1,712 4,413 1,712 Amortization and step-up: Intangible amortization expense 92,951 90,368 273,546 245,260 Inventory step-up expense 21,779 8,912 66,342 16,914 Impairment of long-lived asset - - - 12,371 Impairment of goodwill - - 56,171 - Gain on sale of asset - - - (2,000 ) Share-based compensation 45,066 54,804 137,515 170,394 Depreciation 6,130 4,111 18,073 11,955 Litigation settlement - 5,000 - 5,000 Total of non-GAAP adjustments 176,506 174,811 569,018 558,550 Non-GAAP operating income $ 337,112 $ 506,354 $ 1,012,498 $ 868,590 Foreign exchange loss (768 ) (476 ) (320 ) (1,363 ) Other (expense) income, net (1,030 ) (844 ) 923 1,039 Adjusted EBITDA $ 335,314 $ 505,034 $ 1,013,101 $ 868,266 Horizon Therapeutics plc GAAP to Non-GAAP Reconciliations Gross Profit and Operating Cash Flow (Unaudited) (in thousands, except percentages) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 Non-GAAP Gross Profit: GAAP gross profit $ 691,227 $ 785,352 $ 2,007,605 $ 1,658,943 Non-GAAP gross profit adjustments: Acquisition/divestiture-related costs 273 (204 ) (1,150 ) (75 ) Intangible amortization expense 91,868 89,892 271,032 244,382 Inventory step-up expense 21,779 8,912 66,342 16,914 Share-based compensation 2,167 1,795 6,638 6,875 Depreciation 56 55 167 227 Total of Non-GAAP adjustments 116,143 100,450 343,029 268,323 Non-GAAP gross profit $ 807,370 $ 885,802 $ 2,350,634 $ 1,927,266 GAAP gross profit % 74.7 % 75.7 % 74.7 % 75.0 % Non-GAAP gross profit % 87.2 % 85.4 % 87.5 % 87.1 % GAAP cash provided by operating activities $ 366,464 $ 411,040 $ 831,451 $ 496,714 Cash payments for acquisition/divestiture-related costs 167 15,839 5,363 136,073 Cash payments for restructuring and realignment costs 1,635 583 2,779 1,803 Cash payments for manufacturing facility start-up costs 114 869 2,777 869 Non-GAAP operating cash flow $ 368,380 $ 428,331 $ 842,370 $ 635,459 Horizon Therapeutics plc GAAP to Non-GAAP Tax Rate Reconciliation (Unaudited) (in millions, except percentages and per share amounts) Q3 2022 Pre-tax Net Income Income Tax (Benefit) Expense Tax Rate Net Income Diluted Earnings Per Share As reported - GAAP $ 135.1 $ (0.8 ) (0.6 )% $ 135.8 $ 0.58 Non-GAAP adjustments 180.0 22.5 157.4 Non-GAAP $ 315.1 $ 21.8 6.9 % $ 293.3 $ 1.25 Q3 2021 Pre-tax Net Income Income Tax (Benefit) Expense Tax Rate Net Income Diluted Earnings Per Share As reported - GAAP $ 307.2 $ (19.3 ) (6.3 )% $ 326.5 $ 1.38 Non-GAAP adjustments 176.3 92.6 83.7 Non-GAAP $ 483.6 $ 73.3 15.2 % $ 410.3 $ 1.74 YTD 2022 Pre-tax Net Income Income Tax (Benefit) Expense Tax Rate Net Income Diluted Earnings Per Share As reported - GAAP $ 372.6 $ (28.5 ) (7.6 )% $ 401.1 $ 1.70 Non-GAAP adjustments 581.5 119.7 461.8 Non-GAAP $ 954.1 $ 91.2 9.6 % $ 862.9 $ 3.66 YTD 2021 Pre-tax Net Income Income Tax (Benefit) Expense Tax Rate Net Income Diluted Earnings Per Share As reported - GAAP $ 251.8 $ (109.5 ) (43.5 )% $ 361.3 $ 1.54 Non-GAAP adjustments 561.2 166.8 394.4 Non-GAAP $ 813.0 $ 57.3 7.0 % $ 755.7 $ 3.21 Horizon Therapeutics plc Certain Income Statement Line Items - Non-GAAP Adjusted For the Three Months Ended September 30, 2022 (Unaudited) (in thousands) Income Tax Research & Acquired IPR&D Selling, General Interest Other Income Benefit COGS Development (16) and milestones (16) & Administrative Expense (Expense), net (Expense) GAAP as reported $ (234,132 ) $ (114,058 ) $ (19,000 ) $ (397,563 ) $ (22,480 ) $ (2,277 ) $ 758 Non-GAAP Adjustments: Acquisition/divestiture-related costs(1) 273 (803 ) - 1,355 - - - Loss on equity security investments(2) - - - - - 1,247 - Restructuring and realignment costs(3) - 538 - 7,193 - - - Manufacturing facility start-up costs(4) - - - 2,024 - - - Amortization and step-up: Intangible amortization expense(5) 91,868 - - 1,083 - - - Inventory step-up expense(6) 21,779 - - - - - - Amortization of debt discount and deferred financing costs(7) - - - - 2,232 - - Share-based compensation(8) 2,167 5,590 - 37,309 - - - Depreciation(9) 56 309 - 5,765 - - - Income tax effect on pre-tax non-GAAP adjustments(10) - - - - - - (24,623 ) Other non-GAAP income tax adjustments(11) - - - - - - 2,079 Total of non-GAAP adjustments (17) 116,143 5,634 - 54,729 2,232 1,247 (22,544 ) Non-GAAP (17) $ (117,989 ) $ (108,424 ) $ (19,000 ) $ (342,834 ) $ (20,248 ) $ (1,030 ) $ (21,786 ) Horizon Therapeutics plc Certain Income Statement Line Items - Non-GAAP Adjusted For the Three Months Ended September 30, 2021 (Unaudited) (in thousands) Income Tax Research & Acquired IPR&D Selling, General Interest Other Income Benefit COGS Development (16) and milestones (16) & Administrative Expense (Expense), net (Expense) GAAP as reported $ (251,640 ) $ (89,549 ) $ (4,000 ) $ (360,260 ) $ (22,977 ) $ (849 ) $ 19,302 Non-GAAP Adjustments: Acquisition/divestiture-related costs(1) (204 ) 15 - 9,415 - 2 - Restructuring and realignment costs(3) - - - 680 - - - Manufacturing facility start-up costs(4) - - - 1,712 - - - Amortization and step-up: Intangible amortization expense(5) 89,892 - - 476 - - - Inventory step-up expense(6) 8,912 - - - - - - Amortization of debt discount and deferred financing costs(7) - - - - 1,500 - - Share-based compensation(8) 1,795 15,075 - 37,934 - - - Depreciation(9) 55 125 - 3,932 - - - Litigation settlement(12) - - - 5,000 - - - Income tax effect on pre-tax non-GAAP adjustments(10) - - - - - - (36,602 ) Other non-GAAP income tax adjustments(11) - - - - - - (56,007 ) Total of non-GAAP adjustments (17) 100,450 15,215 - 59,149 1,500 2 (92,609 ) Non-GAAP (17) $ (151,190 ) $ (74,334 ) $ (4,000 ) $ (301,111 ) $ (21,477 ) $ (847 ) $ (73,307 ) - Horizon Therapeutics plc Certain Income Statement Line Items - Non-GAAP Adjusted For the Nine Months Ended September 30, 2022 (Unaudited) (in thousands) Income Tax Research & Acquired IPR&D Selling, General Impairment of Interest Other Income Benefit COGS Development (16) and milestones (16) & Administrative goodwill Expense (Expense), net (Expense) GAAP as reported $ (679,410 ) $ (320,436 ) $ (19,000 ) $ (1,168,518 ) $ (56,171 ) $ (65,145 ) $ (5,408 ) $ 28,467 Non-GAAP Adjustments: Acquisition/divestiture-related costs(1) (1,150 ) 2,000 - 2,587 - - - - Loss on equity security investments(2) - - - - - - 6,331 - Restructuring and realignment costs(3) - 538 - 8,983 - - - - Manufacturing facility start-up costs(4) - - - 4,413 - - - - Amortization and step-up: Intangible amortization expense(5) 271,032 - - 2,514 - - - - Inventory step-up expense(6) 66,342 - - - - - - - Amortization of debt discount and deferred financing costs(7) - - - - - 6,136 - - Share-based compensation(8) 6,638 21,308 - 109,569 - - - - Depreciation(9) 167 802 - 17,104 - - - - Impairment of goodwill(13) - - - - 56,171 - - - Income tax effect on pre-tax non-GAAP adjustments(10) - - - - - - - (121,754 ) Other non-GAAP income tax adjustments(11) - - - - - - - 2,079 Total of non-GAAP adjustments (17) 343,029 24,648 - 145,170 56,171 6,136 6,331 (119,675 ) Non-GAAP (17) $ (336,381 ) $ (295,788 ) $ (19,000 ) $ (1,023,348 ) $ - $ (59,009 ) $ 923 $ (91,208 ) Horizon Therapeutics plc Certain Income Statement Line Items - Non-GAAP Adjusted For the Nine Months Ended September 30, 2021 (Unaudited) (in thousands) Income Tax Research & Acquired IPR&D Selling, General Impairment of Gain on Interest Other Income Benefit COGS Development (16) and milestones (16) & Administrative Long-lived asset Sale of Asset Expense (Expense), net (Expense) GAAP as reported $ (553,003 ) $ (244,076 ) $ (47,000 ) $ (1,047,456 ) $ (12,371 ) $ 2,000 $ (59,018 ) 2,113 $ 109,537 Non-GAAP Adjustments: Acquisition/divestiture-related costs(1) (75 ) 18 - 89,300 - - - (1,077 ) - Restructuring and realignment costs(3) - - - 7,703 - - - - - Manufacturing facility start-up costs(4) - - - 1,712 - - - - - Amortization and step-up: - Intangible amortization expense(5) 244,382 - - 878 - - - - - Inventory step-up expense(6) 16,914 - - - - - - - - Amortization of debt discount and deferred financing costs(7) - - - - - - 3,740 - - Impairment of long lived asset(14) - - - - 12,371 - - - - Gain on sale of asset(15) - - - - - (2,000 ) - - - Share-based compensation(8) 6,875 32,851 - 130,668 - - - - - Depreciation(9) 227 291 - 11,438 - - - - - Litigation settlement(12) - - - 5,000 - - - - - Income tax effect on pre-tax non-GAAP adjustments(10) - - - - - - - - (141,665 ) Other non-GAAP income tax adjustments(11) - - - - - - - - (25,126 ) Total of non-GAAP adjustments (17) 268,323 33,160 - 246,699 12,371 (2,000 ) 3,740 (1,077 ) (166,791 ) Non-GAAP (17) $ (284,680 ) $ (210,916 ) $ (47,000 ) $ (800,757 ) $ - $ - $ (55,278 ) $ 1,036 $ (57,254 ) NOTES FOR CERTAIN INCOME STATEMENT LINE ITEMS - NON-GAAP 1. Primarily represents transaction and integration costs, including, advisory, legal, consulting and certain employee-related costs, incurred in connection with our acquisitions and divestitures. Costs recovered from subleases of acquired facilities and reimbursed expenses incurred under transition arrangements for divestitures are also reflected in this line item. 2. We held investments in equity securities with readily determinable fair values of $6.9 million as of September 30, 2022, which are included in other long-term assets in the condensed consolidated balance sheet. For the three and nine months ended September 30, 2022, we recognized a net unrealized loss of $1.2 million and $6.3 million, respectively, due to the change in fair value of these securities. 3. Primarily represents severance and consulting costs related to the winding down of our inflammation segment in the third quarter of 2022 and rent and maintenance charges as a result of vacating the leased Lake Forest office in the first quarter of 2021. 4. During the three and nine months ended September 30, 2022, we recorded $2.0 million and $4.4 million, respectively, of manufacturing facility start-up costs related to our drug product biologics manufacturing facility in Waterford, Ireland. During the three and nine months ended September 30, 2021, we recorded $1.7 million of manufacturing facility start-up costs related to the purchase of our drug product biologics manufacturing facility in Waterford, Ireland from EirGen in July 2021. 5. Intangible amortization expenses are primarily associated with our developed technology related to TEPEZZA, KRYSTEXXA, RAVICTI, PROCYSBI, UPLIZNA, ACTIMMUNE, BUPHENYL and RAYOS. 6. During the three and nine months ended September 30, 2022, we recognized in cost of goods sold $21.8 million and $66.3 million, respectively, for inventory step-up expense related to UPLIZNA inventory revalued in connection with the Viela acquisition. We recorded $8.9 million and $16.9 million, respectively, of UPLIZNA inventory step-up expense in cost of goods sold during the three and nine months ended September 30, 2021. Because inventory step-up expense is related to an acquisition, will not continue indefinitely and has a significant effect on our gross profit, gross margin percentage and net income for all affected periods, we exclude inventory step-up expense from our non-GAAP financial measures. 7. Represents amortization of debt discount and deferred financing costs associated with our debt. 8. Represents share-based compensation expense associated with our stock option, restricted stock unit and performance stock unit grants to our employees and non-employee directors, and our employee share purchase plan. 9. Represents depreciation expense related to our property, plant, equipment, software and leasehold improvements. 10. Income tax adjustments on pre-tax non-GAAP adjustments represent the estimated income tax impact of each pre-tax non-GAAP adjustment based on the statutory income tax rate of the applicable jurisdictions for each non-GAAP adjustment. 11. During the three and nine months ended September 30, 2022, we recognized tax expense attributable to state tax legislation enacted during the period, resulting in a non-GAAP tax adjustment of $2.1 million. During the three and nine months ended September 30, 2021, other non-GAAP income tax adjustments resulted primarily from the recognition of a reduction in the state tax rate expected to apply to the reversal of temporary differences between the book values and tax bases of certain assets acquired through the Viela acquisition. The reduction in state tax rate resulted in a reduction in the deferred tax liability relating to these assets and a non-GAAP tax adjustment of $51.3 million. In addition, during the nine months ended September 30, 2021, we recognized a U.S. federal and state tax liability on U.S. taxable income generated from an intercompany transfer and license of intellectual property from a U.S. subsidiary to an Irish subsidiary which was partially offset by the recognition of a deferred tax asset in the Irish subsidiary, resulting in a non-GAAP tax adjustment of $26.2 million. 12. We recorded $5.0 million of expense during the three and nine months ended September 30, 2021 for litigation settlements. 13. Our interim goodwill impairment test in the second quarter of 2022 indicated an impairment which represented the difference between the estimated fair value of the inflammation reporting unit and its carrying value. As a result, we recognized an impairment charge of $56.2 million in June 2022 representing the full amount of goodwill for the inflammation reporting unit. 14. During the nine months ended September 30, 2021, we recorded a right-of-use asset impairment charge of $12.4 million as a result of vacating the leased Lake Forest office. 15. During the nine months ended September 30, 2021, gain on sale of asset represents a $2.0 million contingent consideration payment related to the sale of MIGERGOT in 2019. The contingent consideration was triggered during the second quarter of 2021 and it was received in July 2021. 16. Beginning with the third quarter of 2022, the Company is separately presenting upfront, milestone, and similar payments pursuant to collaborations, licenses of third-party technologies, and asset acquisitions as “Acquired in-process research and development and milestones” expenses in the condensed consolidated statement of comprehensive income. Amounts recorded in this line item for the three and nine months ended September 30, 2022, would have historically been recorded to research and development (“R&D”) expenses. The Company believes the new classification assists users of the financial statements in better understanding the payments incurred to acquire in-process research and development (“IPR&D”). Prior period condensed consolidated statements of comprehensive income have been reclassified to conform with the new classification. No non-GAAP adjustments to IPR&D and milestones expenses for the three and nine months ended September 30, 2022, and September 30, 2021. 17. Following consultation with the staff of the Division of Corporation Finance of the U.S. Securities and Exchange Commission, we no longer exclude acquired IPR&D and milestones expenses from our non-GAAP financial measures and its line item components. Adjusted EBITDA and non-GAAP net income for the three and nine months ended September 30, 2021, includes $4.0 million and $47.0 million, respectively, of acquired IPR&D and milestones expenses. These amounts continue to be excluded from our segment operating income (loss) and from certain measures contained in our credit agreement that are relevant to, among other things, the calculation of the interest rate.