Metastatic HER2 positive gastroesophageal junction cancer

Focus on commercial execution drove 1Q23 total revenues of $892.8 million Continued adoption of Xywav®; net product sales increased 49% 1Q23 compared to 1Q22 Confident in blockbuster potential of Epidiolex®; net product sales increased 20% 1Q23 compared to 1Q22 Strong Rylaze® demand drove 58% increase in net product sales 1Q23 compared to 1Q22 Enhanced pipeline positioned to deliver at least three late-stage data readouts by the end of 2024 DUBLIN, May 10, 2023 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced financial results for the first quarter of 2023, affirmed 2023 financial guidance and provided business updates. "This quarter, we once again delivered strong commercial results, advanced our efforts to unlock the tremendous potential of our pipeline and built on our record of driving operational excellence. On the commercial front, key products launched over the past several years are demonstrating impressive and durable performance with Xywav annualizing at more than $1 billion and our oncology therapeutic area approaching $1 billion in annual revenue, driven by Rylaze and Zepzelca®. Adoption of low-sodium Xywav continues to grow across both narcolepsy and idiopathic hypersomnia (IH), and we expect Xywav to remain the oxybate of choice in 2023. We remain confident in the blockbuster potential of Epidiolex/Epidyolex® and its significant additional growth opportunities, and we look forward to continued strong in-person engagement with customers globally," said Bruce Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals. "Our strong execution and robust pipeline position us well to achieve Vision 2025 and create meaningful value for our shareholders." "Our enhanced pipeline is positioned to deliver at least three late-stage data readouts by the end of 2024, including JZP150 in post-traumatic stress disorder (PTSD), suvecaltamide in essential tremor (ET) and zanidatamab in first-line gastroesophageal adenocarcinoma (1L GEA)," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "These late-stage trials are exploring new therapies with the potential to transform the lives of patients affected by diseases where substantial unmet medical need remains." Key Highlights Continued confidence that low-sodium Xywav will remain the oxybate of choice in 2023; already annualizing at more than $1 billion. Epidiolex/Epidyolex continues to grow year-over-year with an expanding global prescriber base. Strong Rylaze demand drove net product sales of $85.9 million in 1Q23. Pipeline positioned to deliver at least three late-stage data readouts by the end of 2024, including JZP150 in PTSD, suvecaltamide in ET and zanidatamab in 1L GEA. The Company will host a KOL investor webcast to review the HERIZON-BTC-01 trial data, which will be presented at the 2023 ASCO Annual Meeting. 1Q23 total revenues increased 10% to $892.8 million compared to 1Q22. On track to achieve full year revenue expectations; full year financial guidance affirmed. Business Updates Key Commercial Products Oxybate (Xywav and Xyrem®): Total revenues for the combined oxybate business, including royalties from a high-sodium oxybate authorized generic (AG) in 1Q23, increased 6% to $458.0 million in 1Q23 compared to the same period in 2022. Average active Jazz oxybate patients on therapy was approximately 17,400 in 1Q23, an increase of 5% compared to the same period in 2022. Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution: Xywav net product sales increased 49% to $277.8 million in 1Q23 compared to the same period in 2022. Xywav is the Company's largest product by net product sales, annualizing at more than $1 billion, as a result of continued adoption in both narcolepsy and IH. There were approximately 11,050 active Xywav patients exiting 1Q23. Xywav for Narcolepsy: There were approximately 9,050 narcolepsy patients taking Xywav exiting 1Q23. The benefits of reducing sodium intake resonate with patients and prescribers as the large majority of new-to-oxybate narcolepsy patients continue to be prescribed Xywav. FDA continues to recognize seven years of Orphan Drug Exclusivity (ODE), through July 2027, for Xywav in narcolepsy. FDA published its summary of clinical superiority findings stating that "Xywav is clinically superior to Xyrem by means of greater safety because Xywav provides a greatly reduced chronic sodium burden compared to Xyrem." Further, FDA stated that "the differences in the sodium content of the two products at the recommended doses will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated." For clarity, the authorized generics of Xyrem contain the exact same drug product as branded Xyrem. FDA has also recognized that the difference in sodium content between Xywav and Lumryz is likely to be clinically meaningful in all patients with narcolepsy and that Xywav is safer than Lumryz in all such patients. Lumryz is a branded, fixed-dose, high-sodium oxybate that has the same sodium content as Xyrem. Xywav is the only approved oxybate therapy that does not carry a warning and precaution related to high sodium intake. Xywav for Idiopathic Hypersomnia (IH): There were approximately 2,000 IH patients taking Xywav exiting 1Q23. Recent Jazz survey of sleep specialists indicates 70% anticipate increasing their prescribing of Xywav for IH over the next six months. Xywav is the first and only treatment approved by FDA to treat the full condition of IH. FDA recognized ODE for IH extending regulatory exclusivity to August 2028. Xyrem (sodium oxybate) oral solution: Xyrem net product sales decreased 28% to $178.1 million in 1Q23 compared to the same period in 2022, reflecting the continued adoption of Xywav by patients with narcolepsy and the launch of a high-sodium oxybate AG in January 2023. Royalties from high-sodium oxybate AG were $2.1 million in 1Q23. Due to the royalty structures within the AG agreements, we expect the royalties from AG to be significantly higher in the second half of 2023 relative to the first half. Epidiolex/ Epidyolex (cannabidiol): Epidiolex/Epidyolex net product sales increased 20% to $188.9 million in 1Q23 compared to the same period in 2022. A pivotal Phase 3 trial of Epidyolex for Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex in Japan is enrolling patients. Epidiolex/Epidyolex global prescriber base is increasing with multiple launches expected outside of the U.S. this year. Additional Epidiolex growth opportunities underscored by BECOME survey's caregiver reported outcomes beyond seizure control, and compelling data for use of Epidiolex in combination with clobazam. Epidyolex is launched and reimbursed in all five key European markets: United Kingdom, Germany, Italy, Spain and France. Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn): Rylaze net product sales increased 58% to $85.9 million in 1Q23 compared to the same period in 2022. Continued strong demand for Rylaze reflects the significant unmet patient need for a high-quality, reliable supply of Erwinia asparaginase for patients with acute lymphoblastic leukemia. In May 2022, the Company completed the Marketing Authorization Application submission to European Medicines Agency for a Monday/Wednesday/Friday dosing schedule and intramuscular and intravenous administration for JZP458 (approved as Rylaze in the U.S.) with potential for approval in 2023. The Company is also continuing to evaluate patient need in other geographies. Zepzelca (lurbinectedin): Zepzelca net product sales increased 13% to $67.2 million in 1Q23 compared to the same period in 2022. Zepzelca is the treatment of choice in second-line (2L) small cell lung cancer (SCLC) setting. Zepzelca development program highlights: The EMERGE-201 Phase 2 basket trial evaluating Zepzelca as monotherapy in select relapsed/refractory solid tumors is ongoing. Phase 3 trial in partnership with F. Hoffmann-La Roche Ltd (Roche) to evaluate 1L use of Zepzelca in combination with Tecentriq® (atezolizumab), compared to Tecentriq alone, as maintenance therapy in patients with extensive-stage SCLC after induction chemotherapy is ongoing. The Company expects complete enrollment in the trial by the end of 2023. The Company's partner, PharmaMar, is conducting the Phase 3 confirmatory trial, LAGOON, in 2L SCLC. If positive, this trial could confirm the benefit of Zepzelca in the treatment of SCLC when patients progress following 1L treatment with a platinum-based regimen. Key Pipeline Highlights Zanidatamab: Zanidatamab is a bispecific antibody that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Initial focus is in biliary tract cancers (BTC) and GEA with potential to transform the current standard of care in multiple HER2-expressing cancers. Positive top-line data from the pivotal HERIZON-BTC-01 clinical trial has the potential to support regulatory submissions for zanidatamab as a monotherapy in patients with previously treated HER2-amplifed and expressing BTC. Data from the HERIZON-BTC-01 clinical trial will be presented at the 2023 ASCO Annual Meeting on Friday, June 2, 2023; the Company will host an investor webcast with Dr. Shubham Pant, M.D., MBBS, Professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of the Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, to review the BTC data. In January 2023, the Company and Zymeworks announced the first overall survival data of 84% at 18 months from a Phase 2 trial of zanidatamab in combination with chemotherapy in 1L patients with HER2-expressing metastatic GEA. The pivotal trial, HERIZON-GEA-01, evaluating zanidatamab in 1L GEA is ongoing and top-line data are expected in 2024. JZP150: JZP150, a selective fatty acid amide hydrolase, or FAAH, inhibitor, is in clinical development for the potential treatment of PTSD. Patient enrollment is ongoing in a Phase 2 trial and top-line data readout is anticipated in late 2023. The Company received Fast Track Designation for JZP150 development in PTSD from FDA, underscoring the significant unmet medical needs of patients. Suvecaltamide (JZP385): Suvecaltamide, a highly selective and state dependent modulator of T-type calcium channels, is in clinical development for the treatment of ET and Parkinson's disease tremor. Patient enrollment is ongoing in the Phase 2b ET trial and top-line data readout is anticipated in 1H24. A Phase 2 trial in patients with Parkinson's disease tremor is ongoing. JZP441: JZP441, is a potent, highly selective oral orexin-2 receptor agonist designed to activate orexin signaling with the potential to be applicable in the treatment of narcolepsy, IH and other sleep disorders. A Phase 1 development program to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of JZP441 in sleep-deprived healthy volunteers is ongoing. The Company expects initial proof of concept in healthy volunteers in 2023. JZP815: A Phase 1 trial evaluating JZP815 in patients with advanced or metastatic solid tumors with MAPK pathway alterations is ongoing. The pan-RAF inhibitor program is part of a novel class of next-generation precision oncology therapies that has the potential to benefit cancer patients with high unmet needs in multiple different solid tumors. JZP898: JZP898 is an engineered IFNα cytokine pro-drug that is activated specifically within the tumor microenvironment where it can stimulate IFNα receptors on cancer-fighting immune effector cells. The Company expects to file an Investigational New Drug (IND) application for JZP898 in the U.S. this year. Financial Highlights GAAP net income for 1Q23 was $69.4 million, or $1.04 per diluted share, compared to $1.6 million, or $0.03 per diluted share, for 1Q22. Non-GAAP adjusted net income for 1Q23 was $285.3 million, or $3.95 per diluted share, compared to $261.9 million, or $3.73 per diluted share, for 1Q22. Reconciliations of applicable GAAP reported to non-GAAP adjusted information are included at the end of this press release. Total Revenues Total revenues increased 10% in 1Q23 compared to the same period in 2022. Total neuroscience revenue, including high-sodium oxybate AG royalty revenue, was $654.0 million in 1Q23 compared to $612.1 million in 1Q22. Neuroscience net product sales in 1Q23 increased 7% to $651.9 million compared to the same period in 2022 primarily driven by increased Xywav and Epidiolex/Epidyolex net product sales, partially offset by the decline in Xyrem revenues, reflecting the continued strong adoption of Xywav by patients with narcolepsy and the launch of a high-sodium oxybate AG in January 2023. High-sodium oxybate AG royalty revenue relates to royalty revenue received from Hikma Pharmaceuticals plc on net sales of a high-sodium oxybate AG product. Oncology net product sales in 1Q23 increased 16% to $228.9 million compared to the same period in 2022 primarily driven by the continued growth in Rylaze product sales, which increased 58% to $86.0 million. Operating Expenses and Effective Tax Rate Changes in operating expenses in 1Q23 over the prior year period are primarily due to the following: Cost of product sales increased in 1Q23 compared to the same period in 2022, on a GAAP and on a non-GAAP adjusted basis, primarily due to changes in product mix. Selling, general and administrative (SG&A) expenses, on a GAAP basis, decreased in 1Q23 compared to the same period in 2022 primarily due to transaction and integration expenses related to the acquisition of GW Pharmaceuticals plc (GW) and Sunosi® (solriamfetol) related spend incurred in 1Q22, partially offset by increased investment in our priority programs. SG&A expenses, on a non-GAAP adjusted basis, were in line with the same period in 2022. Research and development (R&D) expenses increased in 1Q23 compared to the same period in 2022, on a GAAP and on a non-GAAP adjusted basis, primarily due to the inclusion of costs related to clinical programs for zanidatamab, as well as JZP815, JZP898 and JZP441, offset by a decrease in costs related to JZP458. Cash Flow and Balance Sheet As of March 31, 2023, cash and cash equivalents were $1.2 billion, and the outstanding principal balance of the Company's long-term debt was $5.8 billion. In addition, the Company had undrawn borrowing capacity under a revolving credit facility of $500 million. For the three months ended March 31, 2023, the Company generated $320.7 million of cash from operations which is an increase of $111.7 million as compared to the same period in 2022, reflecting strong business performance and continued financial discipline. 2023 Financial Guidance The Company is affirming its full year 2023 financial guidance as follows: Conference Call Details Jazz Pharmaceuticals will host an investor conference call and live audio webcast today at 4:30 p.m. ET (9:30 p.m. IST) to provide a business and financial update and discuss its 2023 first quarter results. Interested parties may register for the call in advance here or via the Investors section of the Jazz Pharmaceuticals website at . To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. A replay of the webcast will be available via the Investors section of the Jazz Pharmaceuticals website at . About Jazz Pharmaceuticals Jazz Pharmaceuticals plc (NASDAQ: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases - often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. Please visit for more information. Non-GAAP Financial Measures To supplement Jazz Pharmaceuticals' financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP (also referred to as adjusted or non-GAAP adjusted) financial measures in this press release and the accompanying tables. In particular, the Company presents non-GAAP adjusted net income (and the related per share measure) and its line item components, as well as certain non-GAAP adjusted financial measures derived therefrom, including non-GAAP adjusted gross margin percentage and non-GAAP adjusted effective tax rate. Non-GAAP adjusted net income (and the related per share measure) and its line item components exclude from GAAP reported net income (and the related per share measure) and its line item components certain items, as detailed in the reconciliation tables that follow, and in the case of non-GAAP adjusted net income (and the related per share measure), adjust for the income tax effect of the non-GAAP adjustments. In this regard, the components of non-GAAP adjusted net income, including non-GAAP adjusted cost of product sales, SG&A expenses and R&D expenses, are income statement line items prepared on the same basis as, and therefore components of, the overall non-GAAP adjusted net income measure. The Company believes that each of these non-GAAP financial measures provides useful supplementary information to, and facilitates additional analysis by, investors and analysts and that each of these non-GAAP financial measures, when considered together with the Company's financial information prepared in accordance with GAAP, can enhance investors' and analysts' ability to meaningfully compare the Company's results from period to period, to its forward-looking guidance, and to identify operating trends in the Company's business. In addition, these non-GAAP financial measures are regularly used by investors and analysts to model and track the Company's financial performance. Jazz Pharmaceuticals' management also regularly uses these non-GAAP financial measures internally to understand, manage and evaluate the Company's business and to make operating decisions, and compensation of executives is based in part on certain of these non-GAAP financial measures. Because these non-GAAP financial measures are important internal measurements for Jazz Pharmaceuticals' management, the Company also believes that these non-GAAP financial measures are useful to investors and analysts since these measures allow for greater transparency with respect to key financial metrics the Company uses in assessing its own operating performance and making operating decisions. These non-GAAP financial measures are not meant to be considered in isolation or as a substitute for comparable GAAP measures; should be read in conjunction with the Company's consolidated financial statements prepared in accordance with GAAP; have no standardized meaning prescribed by GAAP; and are not prepared under any comprehensive set of accounting rules or principles in the reconciliation tables that follow. In addition, from time to time in the future there may be other items that the Company may exclude for purposes of its non-GAAP financial measures; and the Company has ceased, and may in the future cease, to exclude items that it has historically excluded for purposes of its non-GAAP financial measures. Likewise, the Company may determine to modify the nature of its adjustments to arrive at its non-GAAP financial measures. Because of the non-standardized definitions of non-GAAP financial measures, the non-GAAP financial measures as used by Jazz Pharmaceuticals in this press release and the accompanying tables have limits in their usefulness to investors and may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by other companies. Caution Concerning Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to: the Company's growth prospects and future financial and operating results, including the Company's 2023 financial guidance and the Company's expectations related thereto and anticipated catalysts; the Company's expectations for total revenue growth in 2023 and anticipated product sales; expectations of continued growth in net sales of Xywav, Epidiolex/Epidyolex and the oncology portfolio; the blockbuster potential of Epidiolex/Epidyolex and its significant additional growth opportunities; the Company's expectations to executing multiple Epidyolex ex-U.S. launches this year; expectations that the royalties from AG will be higher in the second half of 2023 relative to the first half; the Company's ability to achieve Vision 2025 and the Company's progress related thereto; the Company's development, regulatory and commercialization strategy; the Company's advancement of pipeline programs and the timing of development activities, regulatory activities and submissions related thereto, including the ability to deliver at least three late-stage data readouts by the end of 2024, expectations to file an IND application for JZP898 in the U.S. this year and proof of concept of JZP441 in 2023; the Company's expectations with respect to its products and product candidates and the potential of the Company's products and product candidates, including the potential of zanidatamab to transform the current standard of care in multiple HER2-expressing cancers; expectations that Xywav will remain the oxybate of choice in 2023; the Company's capital allocation and corporate development strategy; the potential successful future development, manufacturing, regulatory and commercialization activities; the Company's expectation of meaningful growth as part of its Vision 2025; growing and diversifying the Company's revenue, investing in its pipeline of novel therapies, and delivering innovative therapies for patients and the potential benefits of such therapies; the Company's ability to realize the commercial potential of its products; the Company's net product sales and goals for net product sales from new and acquired products; the Company's views and expectations relating to its patent portfolio, including with respect to expected patent protection, as well as expectations with respect to exclusivity; planned or anticipated clinical trial events, including with respect to initiations, enrollment and data read-outs, and the anticipated timing thereof; the Company's clinical trials confirming clinical benefit or enabling regulatory submissions; planned or anticipated regulatory submissions and filings, and the anticipated timing thereof; potential regulatory approvals, including for Rylaze; and other statements that are not historical facts. These forward-looking statements are based on the Company's current plans, objectives, estimates, expectations and intentions 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 and uncertainties associated with: maintaining or increasing sales of and revenue from the Company's oxybate products, Zepzelca and other key marketed products; effectively launching and commercializing the Company's other products and product candidates; the successful completion of development and regulatory activities with respect to the Company's product candidates, obtaining and maintaining adequate coverage and reimbursement for the Company's products; the time-consuming and uncertain regulatory approval process, including the risk that the Company's current and/or planned regulatory submissions may not be submitted, accepted or approved by applicable regulatory authorities in a timely manner or at all; the costly and time-consuming pharmaceutical product development and the uncertainty of clinical success, including risks related to failure or delays in successfully initiating or completing clinical trials and assessing patients; the Company's failure to realize the expected benefits of its acquisition of GW, including the failure to realize the blockbuster potential of Epidiolex; global economic, financial, and healthcare system disruptions and the current and potential future negative impacts to the Company's business operations and financial results; geopolitical events, including the conflict between Russia and Ukraine and related sanctions; macroeconomic conditions, including global financial markets, rising interest rates and inflation; regulatory initiatives and changes in tax laws; market volatility; protecting and enhancing the Company's intellectual property rights and the Company's commercial success being dependent upon the Company obtaining, maintaining and defending intellectual property protection for its products and product candidates; delays or problems in the supply or manufacture of the Company's products and product candidates; complying with applicable U.S. and non-U.S. regulatory requirements, including those governing the research, development, manufacturing and distribution of controlled substances; government investigations, legal proceedings and other actions; identifying and consummating corporate development transactions, financing these transactions and successfully integrating acquired product candidates, products and businesses; the Company's ability to realize the anticipated benefits of its collaborations and license agreements with third parties; the sufficiency of the Company's cash flows and capital resources; the Company's ability to achieve targeted or expected future financial performance and results and the uncertainty of future tax, accounting and other provisions and estimates; the Company's ability to meet its projected long-term goals and objectives, including as part of Vision 2025, in the time periods that the Company anticipates, or at all, and the inherent uncertainty and significant judgments and assumptions underlying the Company's long-term goals and objectives; and other risks and uncertainties affecting the Company, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals' Securities and Exchange Commission filings and reports, including the Company's Annual Report on Form 10-K for the year ended December 31, 2022, as supplemented by our Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, and future filings and reports by the Company. Other risks and uncertainties of which the Company is not currently aware may also affect the Company's forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. Contacts: Investors: Andrea N. Flynn, Ph.D. Vice President, Head, Investor Relations Jazz Pharmaceuticals plc [email protected] Ireland +353 1 634 3211 U.S. +1 650 496 2717 Media: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc [email protected] Ireland +353 1 637 2141 U.S. +1 215 867 4948 SOURCE Jazz Pharmaceuticals plc

Strong Execution Drove Record Revenues in 2022 of $3.7 billion, an increase of 18% over 2021 Positioned for Total Revenue and Net Income Growth in 2023 Xywav Enters 2023 as the Oxybate Therapy of Choice and Company's Largest Product by Net Sales Enhanced Investment in R&D to Advance Pipeline towards Key Value Inflection Points in 2023 and 2024 Company is Well-Positioned to Achieve Vision 2025 DUBLIN, March 1, 2023 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced financial results for the full year and fourth quarter of 2022 and provided financial guidance for 2023. "2022 was a year of significant execution across our business that exemplified our purpose to innovate to transform the lives of patients and their families and advanced Jazz towards achieving Vision 2025. Our substantial top-line growth was led by the strength of our commercial franchises, including the continued adoption of Xywav® across both narcolepsy and idiopathic hypersomnia (IH), meaningful Epidiolex® growth, and robust demand for Rylaze®, driven by critical unmet patient need," said Bruce Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals. "In addition to achieving considerable revenue growth in 2022, we generated $1.3 billion in cash from operations and significantly improved our operational efficiency in line with our objectives for Vision 2025. Our strong financial performance, alongside a more disciplined approach to capital allocation, allowed us to delever our balance sheet six months ahead of our stated target, while investing in multiple strategic transactions that have the potential to create meaningful long-term value for patients and shareholders. We are proud of our 2022 accomplishments, which position us in 2023 to grow our top-line revenues through continued commercial execution, enhance our pipeline investments in innovation, and demonstrate continued progress towards achieving Vision 2025." "Building on several transformative years for R&D at Jazz, we have enhanced the breadth and depth of our pipeline, as well as our capabilities. In 2022, we added three promising candidates to our pipeline: zanidatamab, a late-stage novel HER2-targeted bispecific antibody with biparatopic binding, JZP441, an orexin-2 receptor agonist, and JZP898, a differentiated, conditionally-activated interferon alpha (IFNα) INDUKINE™ molecule. We're very encouraged by the positive top-line results from the pivotal trial of zanidatamab in biliary tract cancers (BTC) and the first overall survival data for zanidatamab from the Phase 2 first-line (1L) metastatic gastroesophageal adenocarcinoma (GEA) trial that was announced at ASCO GI," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "With the initiation of multiple clinical trials in 2022, we continue to expand our pipeline into disease areas with significant unmet patient need and market potential, including difficult-to-treat cancers and Parkinson's disease tremor, and we've rapidly progressed JZP441 since bringing it in-house to enable initial proof-of-concept in healthy volunteers in 2023. We enter 2023 with meaningfully increased investment in R&D, which coupled with our upcoming catalysts and expanded capabilities, gives us confidence in delivering sustainable long-term value." Key Highlights Business and Execution Xywav became the Company's largest product by net sales in 4Q22, annualizing at more than $1 billion as a result of continued adoption in both narcolepsy and IH. Achieved a significant milestone exiting October 2022, with more narcolepsy patients taking Xywav than Xyrem®. Expect Xywav to remain the oxybate of choice in 2023. Epidyolex® delivered compelling growth in 4Q22 and is now launched and reimbursed in all five key European markets: United Kingdom, Germany, Italy, Spain and France. Received U.S. Food and Drug Administration (FDA) approval of Rylaze supplemental Biologics Licensing Application (sBLA) for Monday/Wednesday/Friday (MWF) intramuscular (IM) dosing. Strategic corporate development further expanded R&D pipeline with the addition of zanidatamab, a novel late-stage oncology asset. Positive top-line results from the pivotal trial of zanidatamab in BTC in December 2022 and the first overall survival data for zanidatamab from a Phase 2 trial in 1L HER2-expressing metastatic GEA in January 2023. Enrolled the first patient in a Phase 2 trial for suvecaltamide (JZP385) in Parkinson's disease tremor in 4Q22. Financial Growing and durable commercial franchises drove 2022 total revenues of $3.7 billion; 18% increase compared to 2021. Successfully delevered balance sheet in 2022; exiting the year at 2.9x adjusted net leverage ratio1. Focus on disciplined capital allocation and operational excellence drove: Significantly increased cash from operations of $1.3 billion for the year ended December 31, 2022 compared to $779 million in 2021. Improved leverage of selling, general and administrative (SG&A) expenses, which as a percentage of sales decreased significantly in 4Q22 and FY22 relative to the same periods in 2021. Ability to invest nearly $450 million in strategic transactions in 2022, while still achieving net leverage target. 2023 total revenue guidance of $3,675 to $3,875 million, 3% growth at the mid-point. Total revenue guidance is underpinned by expectations of continued growth in net sales of Xywav, Epidiolex/Epidyolex and the oncology portfolio, a continued decline in net sales of Xyrem and royalties on net sales of Authorized Generics of Xyrem. Business Updates Key Commercial Products Oxybate (Xywav and Xyrem): Net product sales for the combined oxybate business increased 10% to $1,978.9 million in 2022 and increased 12% to $528.9 million in 4Q22 compared to the same periods in 2021. Average active oxybate patients on therapy was approximately 18,000 in 4Q22, an increase of 11% compared to the same period in 2021. Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution: Xywav net product sales increased 79% to $958.4 million in 2022 and increased 54% to $281.4 million in 4Q22 compared to the same periods in 2021. Xywav became the Company's largest product by net product sales in 4Q22, annualizing at more than $1 billion as a result of continued adoption in both narcolepsy and IH. There were approximately 10,300 active Xywav patients exiting 4Q22. Xywav for Narcolepsy: There were approximately 8,550 narcolepsy patients taking Xywav exiting 4Q22. Achieved another significant milestone exiting October 2022, with more narcolepsy patients taking Xywav than Xyrem. The benefits of lowering sodium intake continue to resonate with patients and prescribers. In June 2021, FDA recognized seven years of Orphan Drug Exclusivity (ODE), through July 2027, for Xywav and published its summary of clinical superiority findings. Xywav for Idiopathic Hypersomnia (IH): There were approximately 1,750 IH patients taking Xywav exiting 4Q22. The Company has achieved its goal of obtaining similar payer coverage to narcolepsy, with coverage now at approximately 90% of commercial lives for IH. The Company launched Xywav, the first and only treatment approved by FDA for IH, in November 2021. Initial launch efforts have focused on the approximately 37,000 currently diagnosed patients in the U.S. who are actively seeking healthcare. Healthcare providers are excited to have a treatment option with positive and compelling clinical trial results that addresses IH and not just its symptoms. FDA recognized ODE for IH in January 2022, extending regulatory exclusivity to August 2028. Xyrem (sodium oxybate) oral solution: Xyrem net product sales decreased 19% to $1,020.5 million in 2022 and decreased 14% to $247.5 million in 4Q22 compared to the same periods in 2021, reflecting the continued adoption of Xywav by patients with narcolepsy. Epidiolex/ Epidyolex (cannabidiol): Epidiolex/Epidyolex net product sales increased 12%, on a proforma basis, to $736.4 million in 2022 and increased 7% to $207.0 million in 4Q22 compared to the same periods in 2021. The Company successfully completed the pricing and reimbursement process and the commercial launch of Epidyolex in France in 4Q22. Epidyolex is now launched in all five key European markets: United Kingdom, Germany, Italy, Spain and France. In 4Q22, the Company enrolled the first patient in a pivotal Phase 3 trial of Epidyolex for Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis in Japan. Zepzelca ® (lurbinectedin): Zepzelca net product sales increased 9% to $269.9 million in 2022 and increased 11% to $72.0 million in 4Q22 compared to the same periods in 2021. The Company is pleased Zepzelca continues to be the treatment of choice in the second-line (2L) small cell lung cancer (SCLC) setting. Zepzelca development program highlights: The EMERGE-201 Phase 2 basket trial evaluating Zepzelca as monotherapy in select relapsed/refractory solid tumors is ongoing. Phase 3 trial in partnership with F. Hoffmann-La Roche Ltd (Roche) to evaluate 1L use of Zepzelca in combination with Tecentriq® (atezolizumab), compared to Tecentriq alone, as maintenance therapy in patients with extensive-stage SCLC after induction chemotherapy is ongoing. The Company expects complete enrollment in the trial by the end of 2023. The Company's partner, PharmaMar, is conducting the Phase 3 confirmatory trial, LAGOON, in 2L SCLC. If positive, this trial could confirm the benefit of Zepzelca in the treatment of SCLC when patients progress following 1L treatment with a platinum-based regimen. Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn): Rylaze net product sales were $281.7 million in 2022 compared to $85.6 million in 2021, following commercial launch in July 2021, and increased 25% to $81.0 million in 4Q22 compared to the same period in 2021. Strong demand for Rylaze in the first year of launch reflects the significant unmet patient need for a high-quality, reliable supply of Erwinia asparaginase for patients with acute lymphoblastic leukemia. In November 2022, the Company received FDA approval for a MWF IM dosing schedule for Rylaze. In May 2022, the Company completed the Marketing Authorization Application submission to European Medicines Agency for a MWF dosing schedule and IM and intravenous (IV) administration for JZP458 (approved as Rylaze in the U.S.) with potential for approval in 2023. The Company is also advancing the program for potential submission, approval and launch in Japan. In April 2022, the Company submitted an sBLA for IV administration. In February 2023, the Company received a complete response letter from FDA requesting additional clinical data on the IV administration of Rylaze. There is no impact on the approved product labeling for Rylaze IM administration. Corporate Development Zanidatamab Agreement1: On October 19, 2022, the Company and Zymeworks Inc. announced an exclusive licensing and collaboration agreement1 and on December 21, 2022, Jazz and Zymeworks announced Jazz exercised its option to continue with the exclusive development and commercialization rights to zanidatamab in key markets, including the U.S., Europe and Japan. Initial focus is in BTC and GEA with potential to transform the current standard of care in multiple HER2-expressing cancers. In December 2022, Zymeworks announced positive top-line data from the pivotal HERIZON-BTC-01 clinical trial investigating zanidatamab as monotherapy in patients with previously treated HER2-amplified and expressing BTC. Zanidatamab as monotherapy produced a confirmed objective response rate (cORR) of 41.3% and median duration of response of 12.9 months in patients. In January 2023, the Company and Zymeworks announced the first overall survival data of 84% at 18 months from a Phase 2 trial of zanidatamab in combination with chemotherapy in 1L patients with HER2-expressing metastatic GEA. The pivotal trial, HERIZON-GEA-01, evaluating zanidatamab in 1L GEA is ongoing and top-line data are expected in 2024. Key Pipeline Highlights JZP150: JZP150, a selective fatty acid amide hydrolase, or FAAH, inhibitor, is in clinical development for the potential treatment of post-traumatic stress disorder (PTSD). Patient enrollment is ongoing and top-line data read-out is anticipated in late 2023. The Company received Fast Track Designation for JZP150 development in PTSD from FDA, underscoring the significant unmet medical needs of patients. Suvecaltamide (JZP385): Suvecaltamide, a highly selective modulator of T-type calcium channels, is in clinical development for the treatment of essential tremor (ET) and Parkinson's disease tremor. Patient enrollment is ongoing in the Phase 2b ET trial and top-line data read-out is anticipated in 1H24. In 4Q22, the first patient was enrolled in a Phase 2 trial in patients with Parkinson's disease tremor. JZP441: JZP441, is a potent, highly selective oral orexin-2 receptor agonist designed to activate orexin signaling with the potential to be applicable in the treatment of narcolepsy, IH and other sleep disorders. In 4Q22, the first participant was enrolled into the Phase 1 development program to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of JZP441 in sleep-deprived healthy volunteers. The Company expects initial proof of concept in healthy volunteers in 2023. JZP815: The Company enrolled the first patient in a Phase 1 trial evaluating JZP815 in patients with advanced or metastatic solid tumors with MAPK pathway alterations. The pan-RAF inhibitor program is part of a novel class of next-generation precision oncology therapies that has the potential to benefit cancer patients with high unmet needs in multiple different solid tumors. JZP898: JZP898 is an engineered IFNα cytokine pro-drug that is activated specifically within the tumor microenvironment where it can stimulate IFNα receptors on cancer-fighting immune effector cells. The aim is to minimize the severe toxicities that have been observed with systemically active recombinant IFNα therapy and maximize clinical benefit when administered as monotherapy or in combination with other agents. Type 1 interferon signal transduction by IFNα agonism is a clinically validated mechanism of action, and IFNα has been shown to work synergistically in combination with other proven therapies including immune checkpoint inhibitors, targeted therapies and chemotherapy. This allows for potential application across a wide range of cancer types, combination regimens and lines of therapy. The Company expects to file an Investigational New Drug application for JZP898 in the U.S. this year. Financial Highlights GAAP net loss for 2022 was $(224.1) million, or $(3.58) per diluted share, compared to $(329.7) million, or $(5.52) per diluted share, for 2021. GAAP net loss for 4Q22 was $(240.7) million, or $(3.82) per diluted share, compared to $(35.4) million, or $(0.57) per diluted share, for 4Q21. Non-GAAP adjusted net income for 2022 was $933.6 million, or $13.20 per diluted share, compared to $992.8 million, or $16.23 per diluted share, for 2021. Non-GAAP adjusted net loss for 4Q22 was $(4.2) million, or $(0.07) per diluted share, compared to non-GAAP adjusted net income of $262.0 million, or $4.21 per diluted share, for 4Q21. Reconciliations of applicable GAAP reported to non-GAAP adjusted information are included at the end of this press release. Total Revenues Total revenues increased 18% in 2022 and 8% in 4Q22 compared to the same periods in 2021. Neuroscience net product sales in 2022 increased 18% to $2,760.9 million compared to 2021 primarily driven by the inclusion of Epidiolex/Epidyolex net product sales for the full year and oxybate net product sales which increased 10% to $1,978.9 million. Neuroscience net product sales in 4Q22 increased 8% to $740.6 million compared to 4Q21 primarily driven by increased Xywav and Epidiolex net product sales, partially offset by the decline in Xyrem revenues, reflecting the continued adoption of Xywav by patients with narcolepsy. Oncology net product sales in 2022 increased 19% to $873.8 million compared to 2021 primarily driven by the inclusion of Rylaze net product sales for the full year, following its launch in July 2021. Oncology net product sales in 4Q22 increased 8% to $223.9 million compared to 4Q21 primarily driven by Rylaze net product sales, which increased 25% to $81.0 million. Operating Expenses and Effective Tax Rate Changes in operating expenses in 2022 and 4Q22 over the prior year periods are primarily due to the following: Cost of product sales increased in 2022 and 4Q22 compared to the same periods in 2021, on a GAAP and on a non-GAAP adjusted basis, due to an expense for past royalties payable under a settlement agreement with Otsuka Pharmaceutical Co., Ltd. In addition, cost of product sales, on a GAAP basis, in 2022 included increased inventory fair value step-up expense of $50.3 million compared to 2021, driven by the inclusion of a full year expense. Selling, general and administrative (SG&A) expenses, on a GAAP basis, decreased in 2022 and 4Q22 compared to the same periods in 2021, due to lower GW acquisition related transaction and integration expenses and lower Sunosi® (solriamfetol) related costs, offset by restructuring costs and costs related to program terminations and increased investment in sales and marketing, primarily relating to Xywav and, for the full year period, the inclusion of GW related headcount costs for the full year and the loss on the disposal of Sunosi. SG&A expenses, on a non-GAAP adjusted basis, increased in 2022 compared to 2021 primarily due to the inclusion of GW related headcount costs for the full year and increased investment in sales and marketing, offset by lower Sunosi related costs. SG&A expenses, on a non-GAAP adjusted basis, decreased in 4Q22 compared to 4Q21 primarily due to lower Sunosi related costs, offset by increased investment in sales and marketing. Research and development (R&D) expenses increased in 2022 and 4Q22 compared to the same periods in 2021, on a GAAP and on a non-GAAP adjusted basis, primarily due to the addition of costs related to zanidatamab, JZP898 and JZP441, and increased costs for JZP150, offset by a reduction in costs related to JZP458 (Rylaze), following its approval. R&D costs also increased in 2022, on a GAAP and on a non-GAAP adjusted basis, due to increased compensation related expenses driven by the inclusion of GW related headcount costs for the full period. Acquired in-process research and development (IPR&D) expense in 4Q22, on a GAAP and on a non-GAAP adjusted basis, related to payments of $375.0 million to Zymeworks, in connection with our licensing and collaboration agreement. Acquired IPR&D expense in 2022, on a GAAP and on a non-GAAP adjusted basis, also included upfront payments of $50.0 million to Sumitomo in relation to our licensing agreement and $15.0 million to Werewolf, in connection with our licensing and collaboration agreement. The impairment charge in 2022, on a GAAP basis, related to an acquired IPR&D asset impairment relating to the discontinuation of our nabiximols program. Cash Flow and Balance Sheet As of December 31, 2022, cash and cash equivalents were $881.5 million, and the outstanding principal balance of the Company's long-term debt was $5.8 billion compared to $6.4 billion as of December 31, 2021. In addition, the Company had undrawn borrowing capacity under a revolving credit facility of $500 million. For the year ended December 31, 2022, the Company generated $1,272.0 million of cash from operations. In September 2022 the Company made a voluntary payment of $300.0 million on the Dollar Term Loan and in March 2022 the Company repaid in full the $251.0 million remaining aggregate principal amount of the Euro Term Loan B. 2023 Financial Guidance Jazz Pharmaceuticals' full year 2023 financial guidance is as follows: Conference Call Details Jazz Pharmaceuticals will host an investor conference call and live audio webcast today at 4:30 p.m. ET (9:30 p.m. GMT) to provide a business and financial update and discuss its 2022 full year and 4Q22 results and 2023 guidance. Interested parties may register for the call in advance here or via the Investors section of the Jazz Pharmaceuticals website at . To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. A replay of the webcast will be available via the Investors section of the Jazz Pharmaceuticals website at . About Jazz Pharmaceuticals Jazz Pharmaceuticals plc (NASDAQ: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases - often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. Within these therapeutic areas, we are identifying new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. Please visit for more information. Non-GAAP Financial Measures To supplement Jazz Pharmaceuticals' financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP (also referred to as adjusted or non-GAAP adjusted) financial measures in this press release and the accompanying tables. In particular, the Company presents non-GAAP adjusted net income (loss) (and the related per share measure) and its line item components, as well as certain non-GAAP adjusted financial measures derived therefrom, including non-GAAP adjusted gross margin percentage and non-GAAP adjusted effective tax rate. Non-GAAP adjusted net income (loss) (and the related per share measure) and its line item components exclude from GAAP reported net loss (and the related per share measure) and its line item components certain items, as detailed in the reconciliation tables that follow, and in the case of non-GAAP adjusted net income (loss) (and the related per share measure), adjust for the income tax effect of the non-GAAP adjustments and the impact of the change in the statutory tax rate in the U.K. In this regard, the components of non-GAAP adjusted net income (loss), including non-GAAP adjusted cost of product sales, SG&A expenses and R&D expenses, are income statement line items prepared on the same basis as, and therefore components of, the overall non-GAAP adjusted net income (loss) measure. The Company also uses a non-GAAP net leverage ratio calculated as net debt (defined as total GAAP debt, net of cash and cash equivalents) divided by non-GAAP adjusted EBITDA for the most recent period of four consecutive completed fiscal quarters. EBITDA is defined as net loss before income taxes, interest expense, depreciation and amortization. Non-GAAP adjusted EBITDA is defined as EBITDA further adjusted to exclude certain other charges and adjustments as detailed in the non-GAAP net leverage ratio reconciliation table that follows and is calculated in accordance with the definition of Adjusted Consolidated EBITDA as set out in the Company's credit agreement entered into in May 2021 (the Credit Agreement). The Company believes that each of these non-GAAP financial measures provides useful supplementary information to, and facilitates additional analysis by, investors and analysts and that each of these non-GAAP financial measures, when considered together with the Company's financial information prepared in accordance with GAAP, can enhance investors' and analysts' ability to meaningfully compare the Company's results from period to period and to its forward-looking guidance, to identify operating trends in the Company's business and to understand the Company's ability to pay off its incurred debt. In addition, these non-GAAP financial measures are regularly used by investors and analysts to model and track the Company's financial performance. Jazz Pharmaceuticals' management also regularly uses these non-GAAP financial measures internally to understand, manage and evaluate the Company's business and to make operating decisions, and compensation of executives is based in part on certain of these non-GAAP financial measures. Because these non-GAAP financial measures are important internal measurements for Jazz Pharmaceuticals' management, the Company also believes that these non-GAAP financial measures are useful to investors and analysts since these measures allow for greater transparency with respect to key financial metrics the Company uses in assessing its own operating performance and making operating decisions. These non-GAAP financial measures are not meant to be considered in isolation or as a substitute for comparable GAAP measures; should be read in conjunction with the Company's consolidated financial statements prepared in accordance with GAAP; have no standardized meaning prescribed by GAAP; and are not prepared under any comprehensive set of accounting rules or principles in the reconciliation tables that follow. In addition, from time to time in the future there may be other items that the Company may exclude for purposes of its non-GAAP financial measures; and the Company has ceased, and may in the future cease, to exclude items that it has historically excluded for purposes of its non-GAAP financial measures. Likewise, the Company may determine to modify the nature of its adjustments to arrive at its non-GAAP financial measures. Because of the non-standardized definitions of non-GAAP financial measures, the non-GAAP financial measures as used by Jazz Pharmaceuticals in this press release and the accompanying tables have limits in their usefulness to investors and may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by other companies. Caution Concerning Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to: the Company's growth prospects and future financial and operating results, including the Company's 2023 financial guidance and the Company's expectations related thereto and anticipated catalysts; the Company's expectations for total revenue growth in 2023 and anticipated product sales; expectations of continued growth in net sales of Xywav, Epidiolex/Epidyolex and the oncology portfolio; Vision 2025 and the Company's progress related thereto; the Company's development, regulatory and commercialization strategy; the Company's advancement of pipeline programs and the timing of development activities, regulatory activities and submissions related thereto; the Company's expectations for the potential of strategic transactions to create meaningful value for patients and shareholders; the Company's expectations with respect to its products and product candidates and the potential of the Company's products and product candidates, including the potential of zanidatamab to transform the current standard of care in multiple HER2-expressing cancers; expectations with respect to the Company's license agreement with Zymeworks Inc.; expectations that Xywav will remain the oxybate of choice in 2023; the Company's capital allocation and corporate development strategy; the potential successful future development, manufacturing, regulatory and commercialization activities; the Company's expectation of sustainable growth and enhanced value as part of its Vision 2025; growing and diversifying the Company's revenue, investing in its pipeline of novel therapies, and delivering innovative therapies for patients and the potential benefits of such therapies; the Company's ability to realize the commercial potential of its products; the Company's net product sales and goals for net product sales from new and acquired products; the Company's views and expectations relating to its patent portfolio, including with respect to expected patent protection, as well as expectations with respect to exclusivity; planned or anticipated clinical trial events, including with respect to initiations, enrollment and data read-outs, and the anticipated timing thereof; the Company's clinical trials confirming clinical benefit or enabling regulatory submissions; planned or anticipated regulatory submissions and filings, and the anticipated timing thereof; potential regulatory approvals, including for Rylaze; the anticipated launch of Epidyolex in new markets and indications; and other statements that are not historical facts. These forward-looking statements are based on the Company's current plans, objectives, estimates, expectations and intentions 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 and uncertainties associated with: maintaining or increasing sales of and revenue from the Company's oxybate products, Zepzelca and other key marketed products; effectively launching and commercializing the Company's other products and product candidates; the successful completion of development and regulatory activities with respect to the Company's product candidates, obtaining and maintaining adequate coverage and reimbursement for the Company's products; the time-consuming and uncertain regulatory approval process, including the risk that the Company's current and/or planned regulatory submissions may not be submitted, accepted or approved by applicable regulatory authorities in a timely manner or at all; the costly and time-consuming pharmaceutical product development and the uncertainty of clinical success, including risks related to failure or delays in successfully initiating or completing clinical trials and assessing patients such as those being experienced, and expected to continue to be experienced, by the Company as a result of the effects of the COVID-19 pandemic; the Company's failure to realize the expected benefits of its acquisition of GW Pharmaceuticals, including the failure to realize the blockbuster potential of Epidiolex; the ultimate duration and severity of the COVID-19 pandemic and resulting global economic, financial, and healthcare system disruptions and the current and potential future negative impacts to the Company's business operations and financial results; geopolitical events, including the conflict between Russia and Ukraine and related sanctions; macroeconomic conditions, including global financial markets, rising interest rates and inflation; regulatory initiatives and changes in tax laws; market volatility; protecting and enhancing the Company's intellectual property rights and the Company's commercial success being dependent upon the Company obtaining, maintaining and defending intellectual property protection for its products and product candidates; delays or problems in the supply or manufacture of the Company's products and product candidates; complying with applicable U.S. and non-U.S. regulatory requirements, including those governing the research, development, manufacturing and distribution of controlled substances; government investigations, legal proceedings and other actions; identifying and consummating corporate development transactions, financing these transactions and successfully integrating acquired product candidates, products and businesses; the Company's ability to realize the anticipated benefits of its collaborations and license agreements with third parties; the sufficiency of the Company's cash flows and capital resources; the Company's ability to achieve targeted or expected future financial performance and results and the uncertainty of future tax, accounting and other provisions and estimates; the Company's ability to meet its projected long-term goals and objectives, including as part of Vision 2025, in the time periods that the Company anticipates, or at all, and the inherent uncertainty and significant judgments and assumptions underlying the Company's long-term goals and objectives; and other risks and uncertainties affecting the Company, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals' Securities and Exchange Commission filings and reports, including the Company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2022, and future filings and reports by the Company including the Company's Annual Report on Form 10-K for the year ended December 31, 2022. Other risks and uncertainties of which the Company is not currently aware may also affect the Company's forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. Contacts: Investors: Andrea N. Flynn, Ph.D. Vice President, Head, Investor Relations Jazz Pharmaceuticals plc [email protected] Ireland +353 1 634 3211 U.S. +1 650 496 2717 Media: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc [email protected] Ireland +353 1 637 2141 U.S. +1 215 867 4948 Logo - SOURCE Jazz Pharmaceuticals plc

First HER2-directed medicine to be approved for gastric cancer in the EU in more than a decade Based on DESTINY-Gastric02 and DESTINY-Gastric01 where AstraZeneca and Daiichi Sankyo’s Enhertu demonstrated clinically meaningful efficacy LONDON, UK I December 19, 2022 I AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has been approved in the European Union (EU) as monotherapy for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use in November 2022 and is based on results from the DESTINY-Gastric02 and DESTINY-Gastric01 Phase II trials. In DESTINY-Gastric02, which enrolled patients from North America and Europe, treatment with Enhertu resulted in a confirmed objective response rate (ORR) of 41.8% as assessed by independent central review (ICR). Median duration of response (DoR) was 8.1 months. In DESTINY-Gastric01, which enrolled patients from Japan and South Korea, treatment with Enhertu resulted in a confirmed ORR of 40.5% versus 11.3% with chemotherapy (irinotecan or paclitaxel) as assessed by ICR. The median DoR was 11.3 months with Enhertu versus 3.9 months with chemotherapy. Patients treated with Enhertu had a 41% reduction in the risk of death versus patients treated with chemotherapy (based on a hazard ratio of 0.59; 95% confidence interval: 0.39-0.88; p=0.0097) with a median overall survival (OS) of 12.5 months versus 8.4 months. Approximately 136,000 cases of gastric cancer are diagnosed annually in Europe, where it represents the sixth leading cause of cancer death. 1,2 Gastric cancer is typically diagnosed in the advanced stage. Even when the disease is diagnosed at earlier stages, the survival rate remains modest. 3,4 Approximately one in five gastric cancers are HER2-positive. 5,6 Eric Van Cutsem, MD, PhD, Head of Department of Oncology at the University of Leuven, Belgium and Founding Chair of the ESMO-GI/World Congress of Gastrointestinal Cancers, said: “Today’s news is a welcome advance for patients with HER2-positive advanced gastric cancer. Patients with this disease face poor outcomes following progression on initial treatment with a HER2-directed medicine as many do not respond to further treatment, and even those that do respond often do not have durable responses. Data from the DESTINY-Gastric02 and DESTINY-Gastric01 trials support Enhertu becoming a new standard of care for patients in this setting.” Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “Today’s important approval makes Enhertu the first HER2-directed medicine to be approved for gastric cancer in the European Union in more than a decade. Patients across the EU with advanced HER2-positive disease who have progressed following treatment in the first-line setting, may now have the opportunity to benefit from treatment with Enhertu .” Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: “ Enhertu is the first antibody drug conjugate to be approved in Europe for advanced gastric cancer, representing a major advance in treating this difficult-to-treat cancer. With this approval, we can now offer patients with previously treated HER2-positive gastric cancer a treatment with clinically meaningful efficacy.” In both trials, the safety profiles observed in patients treated with Enhertu were consistent with those seen in other trials of Enhertu with no new safety signals identified. Enhertu is also approved in the US and several other countries for locally advanced or metastatic HER2-positive gastric cancer. Notes Financial considerations Following EU approval, an amount of $35m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the previously treated HER2-positive gastric indication. The milestone payment will be capitalised as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalised milestones. Sales of Enhertu in most EU territories are recognised by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from Enhertu sales in those territories as collaboration revenue in the Company’s financial statements. AstraZeneca will record product sales in respect of sales made in territories where AstraZeneca is the selling party. Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration. HER2-positive gastric cancer Gastric (stomach) cancer is the fifth most common cancer worldwide and the fourth highest leading cause of cancer mortality, with a five-year global survival rate of 5% to 10% for advanced or metastatic disease. 3,7,8 Approximately one million new patients were diagnosed with gastric cancer in 2020, with 768,000 deaths reported globally. 2 In Europe, approximately 136,000 cases of gastric cancer are diagnosed annually, and Eastern Europe has the second highest incidence of gastric cancer worldwide after Eastern Asia. 2,8 Gastric cancer is the sixth leading cause of cancer death in Europe and is typically diagnosed in the advanced stage. Even when diagnosed in earlier stages of the disease, the survival rate remains modest. 1,3,4 Approximately one in five gastric cancers are HER2-positive. 5,6 HER2 is a tyrosine kinase receptor growth promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. 5 HER2 overexpression may be associated with a specific HER2 gene alteration known as HER2 amplification. 6 Recommended first-line treatment in the EU for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy. 9,10 For patients with metastatic gastric cancer that progresses following initial treatment with a trastuzumab-based regimen, there were previously no other approved HER2-directed medicines in the EU prior to the approval of Enhertu . 7,11,12 DESTINY-Gastric02 DESTINY-Gastric02 is an open-label, single-arm Phase II trial in patients evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients with HER2-positive metastatic and/or unresectable gastric or GEJ adenocarcinoma with disease progression on or after a trastuzumab-containing regimen. The primary endpoint of DESTINY-Gastric02 is confirmed ORR based on ICR. Secondary endpoints include progression-free survival (PFS), OS, DoR and safety. DESTINY-Gastric02 enrolled 79 patients at multiple sites in North America and Europe. For more information about the trial, visit ClinicalTrials.gov . DESTINY-Gastric01 DESTINY-Gastric01 is a randomised, open-label Phase II trial evaluating the efficacy and safety of Enhertu (6.4mg/kg) in patients with primarily HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in-situ hybridisation [ISH]+) advanced gastric cancer or GEJ adenocarcinoma with disease progression following two or more prior treatment regimens including fluoropyrimidine (5-FU), platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or physician’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). The primary endpoint of DESTINY-Gastric01 is ORR. Secondary endpoints include OS, PFS, DoR, disease control rate and time to treatment failure, as well as pharmacokinetic and safety endpoints. DESTINY-Gastric01 enrolled 187 patients at multiple sites in Japan and South Korea. For more information about the trial, visit ClinicalTrials.gov . Enhert u Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker . Enhertu (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. Enhertu (5.4mg/kg) is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial. Enhertu (5.4mg/kg) is approved in Brazil and the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy, based on the results of the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trial. Enhertu development programme A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. Regulatory applications for Enhertu in breast, non-small cell lung and gastric cancer are currently under review in several countries. Daiichi Sankyo collaboration Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019 , and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan. AstraZeneca in gastrointestinal cancers AstraZeneca has a broad development programme for the treatment of gastrointestinal (GI) cancers across several medicines and a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths. 13 Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic and colorectal cancers. Imfinzi (durvalumab) is approved in the US in combination with chemotherapy (gemcitabine plus cisplatin) for advanced biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma. Imfinzi is being assessed in combinations, including with Imjudo in liver, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings. Enhertu , a HER2-directed antibody drug conjugate, is approved in HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. Lynparza (olaparib), a first-in-class PARP inhibitor, is approved in BRCA-mutated metastatic pancreatic cancer. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada). AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @ AstraZeneca . References 1. WHO. Cancer Today Europe Mortality. Available at: https://gco.iarc.fr/today/online-analysis-table. Accessed December 2022. 2. WHO. International Agency of Cancer Research. Cancer Today. Stomach Incidence. 2020. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf . Accessed December 2022. 3. SEER Cancer Stat Facts: Stomach Cancer. Available at: https://seer.cancer.gov/statfacts/html/stomach.html . Accessed December 2022. 4. Cancer Research UK. Stomach Cancer Survival Statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/stomach-cancer/survival#heading-Zero . Accessed December 2022. 5. 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Thuss-Patience PC, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol . 2017; 18(5):640-653. 12. Satoh T, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in asian populations: TyTAN—a randomized, phase III study. J Clin Oncol . 2014; 32(19):2039‐2049. 13. WHO. World Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf . Accessed December 2022. SOURCE: AstraZeneca