Suvecaltamide

– Record total revenues of $4.1 billion in 2024 and $1.1 billion in 4Q24 –– Xywav® and Epidiolex® revenues grew 16% and 15% year-over-year, respectively, in 2024 –– Oncology revenues grew 9% year-over-year in 2024, surpassed $1.1 billion –– Ziihera® approved in 2L HER2+ (IHC3+) BTC; first sales achieved in December 2024 –– 2025 guidance reflects continued top- and bottom-line growth – DUBLIN , Feb. 25, 2025 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced financial results for the full year and fourth quarter of 2024 and provided guidance for 2025. "2024 was another strong year as our proven team delivered significant top- and bottom-line growth along with record total revenues of over $4 billion . Our diversified portfolio spanning sleep1, epilepsy and oncology, with each annualizing at over $1 billion , continued to drive growth," said Bruce Cozadd , chairman and chief executive officer, Jazz Pharmaceuticals . "We are pleased with the continued progress of our late-stage pipeline assets, including the recent launch of Ziihera in 2L HER2+ (IHC3+) BTC, upcoming top-line data readout from the HERIZON-GEA-01 trial in 1L GEA, which we now expect in the second half of 2025, and highly encouraging results from the Phase 3 IMforte trial, which we expect to submit as part of an sNDA for Zepzelca® in 1L ES-SCLC in the first half of 2025." Mr. Cozadd continued, "The strength of our 2024 results reinforces our confidence that Jazz is well-positioned to deliver top- and bottom-line growth in 2025 and drive long-term shareholder value. Our focus remains on disciplined capital allocation, which we expect to drive growth of our diversified commercial portfolio, continue advancement of our pipeline and provide flexibility to remain active in corporate development." Key Highlights Total revenues in 2024 grew 6% year-over-year; generated over $1.4 billion in cash from operations. Zanidatamab: Received U.S. FDA approval of and launched Ziihera in 2L HER2+ (IHC3+) BTC. Top-line PFS data from zanidatamab in Phase 3 1L GEA expected in 2H25. On track to submit an sNDA in 1H25 for Zepzelca in combination with Tecentriq® (atezolizumab) as maintenance therapy in 1L ES-SCLC based on the potentially practice-changing results from the Phase 3 IMforte trial. Top- and bottom-line growth expected in 2025; 2025 total revenue guidance of $4.15 - $4.40 billion , representing 5% growth at the midpoint. Total revenue guidance is underpinned by expected continued growth in diversified commercial portfolio spanning sleep1, epilepsy and oncology. Received U.S. FDA approval of and launched Ziihera in 2L HER2+ (IHC3+) BTC. Top-line PFS data from zanidatamab in Phase 3 1L GEA expected in 2H25. Total revenue guidance is underpinned by expected continued growth in diversified commercial portfolio spanning sleep1, epilepsy and oncology. ________________________________ 1 Total sleep revenue includes: Xywav, branded Xyrem and high-sodium oxybate authorized generic royalty revenues. Business Updates Commercial Updates Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution: Xywav net product sales increased 16% to $1,473.2 million in 2024 and increased 19% to $401.0 million in 4Q24 compared to the same periods in 2023. Meaningful Xywav net patient adds in 4Q24 (approximately 525 patients) with approximately 14,150 active Xywav patients exiting 4Q24, comprised of: Approximately 10,250 narcolepsy patients. Approximately 3,900 idiopathic hypersomnia (IH) patients, with 350 net patient adds. Xywav is the only low-sodium oxybate, the #1 branded treatment for narcolepsy2 and the only FDA-approved therapy to treat IH. Approximately 10,250 narcolepsy patients. Approximately 3,900 idiopathic hypersomnia (IH) patients, with 350 net patient adds. Xyrem® (sodium oxybate) oral solution and high-sodium oxybate authorized generic (AG) royalties: Xyrem net product sales decreased 59% to $233.8 million in 2024 and decreased 54% to $49 .3 million in 4Q24 compared to the same periods in 2023. Royalties from high-sodium oxybate AGs increased by $141 .7 million to $217 .6 million in 2024 and increased $15 .9 million to $55 .3 million in 4Q24, compared to the same periods in 2023. Epidiolex/Epidyolex® (cannabidiol): Epidiolex/Epidyolex net product sales increased 15% to $972.4 million in 2024 and increased 14% to $275.0 million in 4Q24 compared to the same periods in 2023. Outside of the U.S. , Epidyolex is approved in more than 35 countries. Presented data at the American Epilepsy Society 2024 Annual meeting, including novel findings from the BECOME-LTC, BECOME-TSC and EpiCom studies, demonstrating the meaningful impact of Epidiolex in the treatment of patients with rare epilepsies including benefits of Epidiolex's benefits beyond seizure control. Remain confident in achieving blockbuster status for Epidiolex/Epidyolex in 2025. Rylaze®/Enrylaze® (asparaginase erwinia chrysanthemi (recombinant)-rywn): Rylaze/Enrylaze net product sales increased 4% to $410.8 million in 2024 and were in line in 4Q24 compared to the same periods in 2023 despite headwinds from Children's Oncology Group (COG) protocol changes that impacted timing of asparaginase administration. The temporary impact to Rylaze net product sales due to previously announced COG pediatric acute lymphoblastic leukemia (ALL) protocol updates is still expected to normalize by early 2025. Zepzelca (lurbinectedin): Zepzelca net product sales increased 11% to $320.3 million in 2024 and increased 6% to $78.3 million in 4Q24 compared to the same periods in 2023. Based on potentially practice-changing positive results from the Phase 3 IMforte trial, the Company plans to submit a supplemental New Drug Application (sNDA) for Zepzelca's use in combination with Tecentriq as maintenance therapy in first-line (1L) extensive-stage (ES) small cell lung cancer (SCLC) in 1H25. Ziihera (zanidatamab-hrii): Ziihera net product sales were $1.1 million in 2024 and 4Q24 after the initial product launch and availability in December of 2024 following FDA approval in November. Initial positive reception by prescribers with the first patient treated in December. Ziihera added to National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology. Ziihera added to European Society for Medical Oncology ® (ESMO®) Clinical Practice Guidelines for Biliary Tract Cancers. __________________________ 2 Based on 4Q24 Xywav net product sales. Key Pipeline Highlights Zanidatamab: In 4Q24, announced U.S. FDA granted accelerated approval of Ziihera (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). The pivotal HERIZON-GEA-01 trial, evaluating zanidatamab in 1L gastroesophageal adenocarcinoma (GEA), is expected to read out in 2H25 based on an updated assessment of progression events. Recruitment for the trial remains on track. Data presented at the San Antonio Breast Cancer Symposium 2024 continued to underscore zanidatamab's potential for patients previously treated with trastuzumab deruxtecan (T-DXd) and showcased the advancement of our clinical program in breast cancer. The Phase 3 EmpowHER-BC-303 trial to evaluate zanidatamab plus chemotherapy or trastuzumab plus chemotherapy in patients with HER2-positive breast cancer whose disease has progressed on previous T-DXd treatment continues to enroll patients. First patient enrolled in the Phase 2 pan-tumor trial to evaluate HER2-positive solid tumors. Financial Highlights Three Months Ended December 31 , Year Ended December 31 , (In thousands, except per share amounts) 2024 2023 2024 2023 Total revenues $ 1,088,173 $ 1,011,935 $ 4,068,950 $ 3,834,204 GAAP net income $ 191,115 $ 94,154 $ 560,120 $ 414,832 Non-GAAP adjusted net income $ 405,863 $ 345,286 $ 1,369,729 $ 1,295,824 GAAP earnings per share $ 3.11 $ 1.42 $ 8.65 $ 6.10 Non-GAAP adjusted EPS $ 6.60 $ 5.02 $ 20.90 $ 18.29 GAAP net income for 2024 was $560.1 million , or $8.65 per diluted share, compared to $414.8 million , or $6.10 per diluted share, for 2023. GAAP net income for 4Q24 was $191.1 million , or $3.11 per diluted share, compared to a GAAP net income of $94.2 million , or $1.42 per diluted share, for 4Q23. Non-GAAP adjusted net income for 2024 was $1,369 .7 million, or $20.90 per diluted share, compared to $1,295 .8 million, or $18.29 per diluted share, for 2023. Non-GAAP adjusted net income for 4Q24 was $405 .9 million, or $6.60 per diluted share, compared to $345 .3 million, or $5.02 per diluted share, for 4Q23. Reconciliations of applicable GAAP reported to non-GAAP adjusted information are included at the end of this press release. Total Revenues Three Months Ended December 31 , Year Ended December 31 , (In thousands) 2024 2023 2024 2023 Xywav $ 400,964 $ 337,019 $ 1,473,202 $ 1,272,977 Xyrem 49,290 106,721 233,816 569,730 Epidiolex/Epidyolex 275,047 240,622 972,423 845,468 Sativex 5,173 5,137 18,877 19,668 Total Neuroscience 730,474 689,499 2,698,318 2,707,843 Rylaze/Enrylaze 101,487 101,747 410,846 394,226 Zepzelca 78,328 74,010 320,318 289,533 Defitelio/defibrotide 57,650 51,083 216,565 184,000 Vyxeos 53,247 46,912 162,595 147,495 Ziihera 1,051 — 1,051 — Total Oncology 291,763 273,752 1,111,375 1,015,254 Other 2,974 4,088 11,471 13,846 Product sales, net 1,025,211 967,339 3,821,164 3,736,943 High-sodium oxybate AG royalty revenue 55,307 39,387 217,575 75,918 Other royalty and contract revenues 7,655 5,209 30,211 21,343 Total revenues $ 1,088,173 $ 1,011,935 $ 4,068,950 $ 3,834,204 Total revenues increased 6% in 2024 and 8% in 4Q24 compared to the same periods in 2023. Total neuroscience revenue, including high-sodium oxybate AG royalty revenue, was $2,915 .9 million in 2024, an increase of 5% compared to $2,783.8 million in 2023 and $785 .8 million in 4Q24, an increase of 8% compared to $728.9 million in 4Q23. The increase in 2024 and 4Q24 was due to higher Xywav and Epidiolex/Epidyolex net product sales together with increased high-sodium oxybate AG royalty revenue, partially offset by decreased Xyrem net product sales. Oncology net product sales were $1,111 .4 million in 2024, an increase of 9% compared to $1,015 .3 million in 2023 and $291 .8 million in 4Q24, an increase of 7% compared to $273 .8 million in 2023, and included higher net product sales from Defitelio/defibrotide which increased 18% in 2024 and 13% in 4Q24 and Zepzelca which increased 11% in 2024 and 6% in 4Q24. In 4Q24, Rylaze net product sales were negatively impacted due to an update to the COG pediatric treatment protocols for ALL, which impacts the timing of asparaginase administration. Operating Expenses and Effective Tax Rate Three Months Ended December 31 , Year Ended December 31 , (In thousands, except percentages) 2024 2023 2024 2023 GAAP: Cost of product sales $ 128,713 $ 107,243 $ 445,713 $ 435,577 Gross margin 87.4 % 88.9 % 88.3 % 88.3 % Selling, general and administrative $ 369,287 $ 396,034 $ 1,385,294 $ 1,343,105 % of total revenues 33.9 % 39.1 % 34.0 % 35.0 % Research and development $ 240,500 $ 216,608 $ 884,000 $ 849,658 % of total revenues 22.1 % 21.4 % 21.7 % 22.2 % Acquired in-process research and development $ — $ 18,000 $ 10,000 $ 19,000 Income tax benefit1 $ (57,912) $ (33,089) $ (91,429) $ (119,912) Effective tax rate 1 (43.5) % (53.8) % (19.4) % (40.2) % _________________________ 1. The GAAP income tax benefit increased in the three months ended December 31, 2024 , compared to the same period in 2023, primarily due to patent box benefits recognized in the period and decreased in the year ended December 31, 2024 , compared to the same period in 2023, primarily due to the change in income mix across our jurisdictions, partially offset by patent box benefits. Three Months Ended December 31 , Year Ended December 31 , (In thousands, except percentages) 2024 2023 2024 2023 Non-GAAP adjusted: Cost of product sales $ 86,492 $ 71,238 $ 295,897 $ 269,079 Gross margin 91.6 % 92.6 % 92.3 % 92.8 % Selling, general and administrative $ 323,167 $ 300,520 $ 1,226,724 $ 1,110,948 % of total revenues 29.7 % 29.7 % 30.1 % 29.0 % Research and development $ 220,857 $ 201,107 $ 809,327 $ 784,811 % of total revenues 20.3 % 19.9 % 19.9 % 20.5 % Acquired in-process research and development $ — $ 18,000 $ 10,000 $ 19,000 Income tax expense1 $ 308 $ 20,475 $ 131,307 $ 93,260 Effective tax rate1 0.1 % 5.6 % 8.7 % 6.7 % _________________________ 1. The non-GAAP income tax expense decreased in the three months ended December 31, 2024 , compared to the same period in 2023, primarily due to patent box benefits recognized in the period and increased in the year ended December 31, 2024 , compared to the same period in 2023, due to the change in income mix across our jurisdictions, partially offset by patent box benefits. Changes in operating expenses in 2024 and 4Q24 over the prior year periods are primarily due to the following: Cost of product sales, on a GAAP and non-GAAP adjusted basis, increased in 2024 and 4Q24, compared to the same periods in 2023, primarily due to higher inventory provisions and changes in product mix. Cost of product sales, on a GAAP basis, included lower acquisition accounting inventory fair value step up expense in 2024 as compared to the previous period. Selling, general and administrative (SG&A) expenses, on a GAAP and non-GAAP adjusted basis, increased in 2024 compared to the same period in 2023, primarily due to higher compensation-related expenses, increased investment in sales and marketing and increased litigation costs, partially offset, on a GAAP basis, by costs related to impairment of facility assets and program terminations in 2023. SG&A expenses, on a GAAP basis, decreased in 4Q24 compared to the same period in 2023, primarily due to the impairment of facility assets in 4Q23, partially offset by higher compensation related expenses. SG&A expenses, on a non-GAAP adjusted basis, increased in 4Q24 primarily due to higher compensation-related expenses. Research and development (R&D) expenses, on a GAAP and non-GAAP adjusted basis, increased in 2024 and 4Q24, compared to the same period in 2023, primarily due to increased compensation related expenses and clinical study costs primarily related to zanidatamab, partially offset by reduced costs related to JZP150 and JZP385. Acquired in-process research and development (IPR&D) expense in 2024, on a GAAP and non-GAAP adjusted basis, related to an upfront payment made in connection with our asset purchase and collaboration agreement with Redx Pharma plc . Acquired IPR&D expense in 2023, on a GAAP and non-GAAP adjusted basis, primarily related to an upfront payment made in connection with our licensing and collaboration agreement with Autifony Therapeutics Limited . Cash Flow and Balance Sheet As of December 31, 2024 , cash, cash equivalents and investments were $3.0 billion , and the outstanding principal balance of the Company's long-term debt was $6.2 billion . In addition, the Company had undrawn borrowing capacity under a revolving credit facility of $885.0 million . For the year ended December 31, 2024 , the Company generated $1.4 billion of cash from operations reflecting strong business performance and continued financial discipline. In January 2025 , the Company made a voluntary prepayment of $750.0 million principal amount on the Term Loan B. 2025 Financial Guidance Jazz Pharmaceutical's full year 2025 financial guidance is as follows: (In millions) Guidance Total Revenues $4,150 - $4,400 (In millions, except per share amounts and percentages) GAAP Non-GAAP Gross margin % 88 % 92%1,6 SG&A expenses $1,404 - $1,483 $1,250 - $1,310 2,6 R&D expenses $792 - $851 $720 - $770 3,6 Effective tax rate (5)% - 10% 13% - 15%4,6 Net income $560 - $720 $1,400 - $1,500 5,6 Net income per diluted share $9.15 - $11.50 $22.50 - $24.00 5,6 Weighted-average ordinary shares used in per share calculations 62 - 63 62 - 63 ___________________________ 1. Excludes $135-$155 million of amortization of acquisition-related inventory fair value step-up and $14-$16 million of share-based compensation expense. 2. Excludes $154-$173 million of share-based compensation expense. 3. Excludes $72-$81 million of share-based compensation expense. 4. Excludes 18%-5% from the GAAP effective tax rate of (5)%-10% relating to the income tax effect of adjustments between GAAP net income and non-GAAP adjusted net income, resulting in a non-GAAP adjusted effective tax rate of 13%-15%. 5. Beginning with the 2025 financial guidance presented in this press release, the company will no longer include an adjustment for non-cash interest expense in its non-GAAP adjusted financial measures. Accordingly, any historical non-GAAP adjusted financial measures presented by the company in the future, beginning with the company's earnings press release for the first quarter of 2025, will not include an adjustment for non-cash interest expense. Any comparative historical periods presented will also be updated to reflect this change beginning with the company's earnings press release for the first quarter of 2025. However, for purposes of comparability with the company's prior presentations of non-GAAP financial measures, the historical non-GAAP financial measures presented in this press release include an adjustment for non-cash interest expense. 6. See "Non-GAAP Financial Measures" below. Reconciliations of non-GAAP adjusted guidance measures are included above and in the table titled "Reconciliation of GAAP to non-GAAP Adjusted 2025 Net Income Guidance" at the end of this press release. 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 2024 full year and 4Q24 results and 2025 guidance. Audio webcast/conference call: U.S. Dial-In Number: +1 800 715 9871Ireland Dial-In Number: +353 1800 943 926Additional global dial-in numbers are available here.Passcode: 5080203 Interested parties may access the live audio webcast via the Investors section of the Jazz Pharmaceuticals website at www.jazzpharmaceuticals.com. 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 www.jazzpharmaceuticals.com. 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, including leading therapies for sleep disorders and epilepsy, and a growing portfolio of cancer treatments. Our patient-focused and science-driven approach powers pioneering research and development advancements across our robust pipeline of innovative therapeutics in oncology and neuroscience. Jazz is headquartered in Dublin, Ireland with research and development laboratories, manufacturing facilities and employees in multiple countries committed to serving patients worldwide. Please visit www.jazzpharmaceuticals.com 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. In this regard, the company has determined that, beginning with the 2025 financial guidance presented in this press release, it will no longer include an adjustment for non-cash interest expense in its non-GAAP adjusted financial measures. Accordingly, any historical non-GAAP adjusted financial measures presented by the company in the future, beginning with the company's earnings press release for the first quarter of 2025, will not include an adjustment for non-cash interest expense. Any comparative historical periods presented will also be updated to reflect this change beginning with the company's earnings press release for the first quarter of 2025. However, for purposes of comparability with the company's prior presentations of non-GAAP financial measures, the historical non-GAAP financial measures presented in this press release include an adjustment for non-cash interest expense. 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 2025 financial guidance and the Company's expectations related thereto and anticipated catalysts; expectations that Xywav will remain the #1 branded treatment for narcolepsy and Epidiolex achieving blockbuster status in 2025; the ability to generate growth and long-term shareholder value; the Company's advancement of pipeline programs and the timing of development activities, regulatory activities and submissions related thereto, including plans to submit a sNDA for Zepzelca in 1L ES-SCLC in the first half of 2025; planned or anticipated clinical trial events, including with respect to initiations, enrollment and data read-outs, and the anticipated timing thereof, including: top-line PFS data from a Phase 3 trial of zanidatamab in 1L GEA; and the Company's development, regulatory and commercialization strategy; the Company's expectations with respect to its products and product candidates and the potential of the Company's products and product candidates and the potential regulatory path related thereto, including Zepzelca's potential to change current practice in 1L ES-SCLC; the Company's capital allocation and corporate development strategy; the potential successful future development, manufacturing, regulatory and commercialization activities; 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; 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; 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, Xywav, Rylaze and Epidiolex/Epidyolex and other marketed products; the introduction of new products into the U.S. market that compete with, or otherwise disrupt the market for the Company's products and product candidates; 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; 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 international tariffs and the conflict between Russia and Ukraine and related sanctions; macroeconomic conditions, including global financial markets, rising interest rates and inflation and recent and potential banking disruptions; 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 and exclusivity 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 corporate development transactions and 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, 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; fluctuations in the market price and trading volume of the Company's ordinary shares; the timing and availability of alternative investment opportunities; 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, 2024 , 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. JAZZ PHARMACEUTICALS PLC CONDENSED CONSOLIDATED STATEMENTS OF INCOME(In thousands, except per share amounts)(Unaudited) Three Months Ended December 31 , Year Ended December 31 , 2024 2023 2024 2023 Revenues: Product sales, net $ 1,025,211 $ 967,339 $ 3,821,164 $ 3,736,943 Royalties and contract revenues 62,962 44,596 247,786 97,261 Total revenues 1,088,173 1,011,935 4,068,950 3,834,204 Operating expenses: Cost of product sales (excluding amortization of acquired developed technologies) 128,713 107,243 445,713 435,577 Selling, general and administrative 369,287 396,034 1,385,294 1,343,105 Research and development 240,500 216,608 884,000 849,658 Intangible asset amortization 158,903 151,553 627,313 608,284 Acquired in-process research and development — 18,000 10,000 19,000 Total operating expenses 897,403 889,438 3,352,320 3,255,624 Income from operations 190,770 122,497 716,630 578,580 Interest expense, net (51,256) (70,324) (238,097) (289,438) Foreign exchange gain (loss) (6,295) 9,353 (8,182) 8,787 Income before income tax benefit and equity in loss ofinvestees 133,219 61,526 470,351 297,929 Income tax benefit (57,912) (33,089) (91,429) (119,912) Equity in loss of investees 16 461 1,660 3,009 Net income $ 191,115 $ 94,154 $ 560,120 $ 414,832 Net income per ordinary share: Basic $ 3.16 $ 1.50 $ 9.06 $ 6.55 Diluted $ 3.11 $ 1.42 $ 8.65 $ 6.10 Weighted-average ordinary shares used in per share calculations - basic 60,538 62,578 61,838 63,291 Weighted-average ordinary shares used in per share calculations - diluted 61,503 69,673 66,007 72,066 JAZZ PHARMACEUTICALS PLC CONDENSED CONSOLIDATED BALANCE SHEETS(In thousands)(Unaudited) December 31 ,2024 December 31 ,2023 ASSETS Current assets: Cash and cash equivalents $ 2,412,864 $ 1,506,310 Investments 580,000 120,000 Accounts receivable, net of allowances 716,765 705,794 Inventories 480,445 597,039 Prepaid expenses 177,411 185,476 Other current assets 261,543 320,809 Total current assets 4,629,028 3,435,428 Property, plant and equipment, net 173,413 169,646 Operating lease assets 53,582 65,340 Intangible assets, net 4,755,695 5,418,039 Goodwill 1,716,323 1,753,130 Deferred tax assets, net 560,245 477,834 Deferred financing costs 9,489 6,478 Other non-current assets 114,482 67,464 Total assets $ 12,012,257 $ 11,393,359 LIABILITIES AND SHAREHOLDERS' EQUITY Current liabilities: Accounts payable $ 77,869 $ 102,750 Accrued liabilities 910,947 793,914 Current portion of long-term debt 31,000 604,954 Income taxes payable 18,757 35,074 Total current liabilities 1,038,573 1,536,692 Long-term debt, less current portion 6,077,640 5,107,988 Operating lease liabilities, less current portion 38,938 59,225 Deferred tax liabilities, net 676,736 847,706 Other non-current liabilities 86,614 104,751 Total shareholders' equity 4,093,756 3,736,997 Total liabilities and shareholders' equity $ 12,012,257 $ 11,393,359 JAZZ PHARMACEUTICALS PLC SUMMARY OF CASH FLOWS (In thousands)(Unaudited) Year Ended December 31 , 2024 2023 Net cash provided by operating activities $ 1,395,908 $ 1,092,007 Net cash used in investing activities (508,195) (163,062) Net cash provided by (used in) financing activities 20,516 (305,254) Effect of exchange rates on cash and cash equivalents (1,675) 1,137 Net increase in cash and cash equivalents $ 906,554 $ 624,828 JAZZ PHARMACEUTICALS PLC RECONCILIATIONS OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATION(In thousands, except per share amounts)(Unaudited) Three Months Ended December 31 , Year Ended December 31 , 2024 2023 2024 2023 Net Income DilutedEPS1 Net Income Diluted EPS1 NetIncome DilutedEPS1 NetIncome Diluted EPS1 GAAP reported $ 191,115 $ 3.11 $ 94,154 $ 1.42 $ 560,120 $ 8.65 $ 414,832 $ 6.10 Intangible asset amortization 158,903 2.58 151,553 2.18 627,313 9.50 608,284 8.44 Share-based compensation expense 70,190 1.14 52,941 0.76 248,045 3.76 226,841 3.15 Acquisition accountinginventory fair value step-up 37,794 0.61 32,352 0.46 135,014 2.05 151,446 2.10 Other costs2 — — 61,727 0.89 — — 85,215 1.18 Non-cash interest expense3 6,081 0.10 6,123 0.09 21,973 0.33 22,378 0.31 Income tax effect of above adjustments (58,220) (0.94) (53,564) (0.77) (222,736) (3.37) (213,172) (2.95) Effect of assumed conversion of the 2024 Notes and the2026 Notes1 — — — (0.01) — (0.02) — (0.04) Non-GAAP adjusted $ 405,863 $ 6.60 $ 345,286 $ 5.02 $ 1,369,729 $ 20.90 $ 1,295,824 $ 18.29 Weighted-average ordinaryshares used in diluted per share calculations - GAAP and non-GAAP1 61,503 69,673 66,007 72,066 ________________________________________________ Explanation of Adjustments and Certain Line Items: 1. Diluted EPS was calculated using the "if-converted" method in relation to the 1.50% exchangeable senior notes due 2024, or the 2024 Notes and the 2.000% exchangeable senior notes due 2026, or the 2026 Notes. In August 2023 and July 2024 , we made irrevocable elections to net share settle the 2024 Notes and the 2026 Notes, respectively. As a result, the assumed issuance of ordinary shares upon exchange of the 2024 Notes and the 2026 Notes have only been included in the calculation of diluted net income per ordinary share, on a GAAP and on a non-GAAP adjusted basis, in each period up to the date each irrevocable election was made. Net income per diluted share, on a GAAP and on a non-GAAP adjusted basis, for the year ended December 31, 2024 , included 3.5 million shares related to the assumed conversion of the 2026 Notes and the associated interest expense, net of tax, add-back to GAAP reported net income and non-GAAP adjusted net income of $10.8 million and $9.7 million , respectively. Net income per diluted share, on a GAAP and on a non-GAAP adjusted basis, for the three months and the year ended December 31, 2023 included 6.4 million shares and 8.0 million shares, respectively, related to the assumed conversion of the 2024 Notes and the 2026 Notes and the associated interest expense, net of tax, add-back to GAAP reported net income of $4.9 million and $24.9 million , respectively, and the associated interest expense, net of tax, add-back to non-GAAP adjusted net income of $4.4 million and $22.2 million , respectively. 2. Includes costs related to the impairment of facility assets and program terminations. 3. Non-cash interest expense associated with debt issuance costs. JAZZ PHARMACEUTICALS PLC RECONCILIATIONS OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATIONCERTAIN LINE ITEMS - FOR THE THREE MONTHS ENDED DECEMBER 31, 2024 AND 2023(In thousands, except percentages)(Unaudited) Three months ended December 31, 2024 Cost ofproductsales Grossmargin Selling, general andadministrative Researchanddevelopment Intangible assetamortization Interestexpense, net Income tax expense (benefit) Effectivetax rate GAAP Reported $ 128,713 87.4 % $ 369,287 $ 240,500 $ 158,903 $ 51,256 $ (57,912) (43.5) % Non-GAAP Adjustments: Intangible asset amortization — — — — (158,903) — — — Share-based compensationexpense (4,427) 0.5 (46,120) (19,643) — — — — Acquisition accountinginventory fair value step-up (37,794) 3.7 — — — — — — Non-cash interest expense — — — — — (6,081) — — Income tax effect of above adjustments — — — — — — 58,220 43.6 Total of non-GAAP adjustments (42,221) 4.2 (46,120) (19,643) (158,903) (6,081) 58,220 43.6 Non-GAAP Adjusted $ 86,492 91.6 % $ 323,167 $ 220,857 $ — $ 45,175 $ 308 0.1 % Three months ended December 31, 2023 Cost ofproductsales Gross margin Selling, general and administrative Research anddevelopment Intangibleassetamortization AcquiredIPR&D Interest expense, net Income tax expense(benefit) Effective tax rate GAAP Reported $ 107,243 88.9 % $ 396,034 $ 216,608 $ 151,553 $ 18,000 $ 70,324 $ (33,089) (53.8) % Non-GAAP Adjustments: Intangible asset amortization — — — — (151,553) — — — — Share-based compensationexpense (3,653) 0.4 (33,787) (15,501) — — — — — Restructuring and othercosts — — (61,727) — — — — — — Non-cash interest expense — — — — — — (6,123) — — Acquisition accountinginventory fair value step-up (32,352) 3.3 — — — — — — — Income tax effect of aboveadjustments — — — — — — — 53,564 59.4 Total of non-GAAP adjustments (36,005) 3.7 (95,514) (15,501) (151,553) — (6,123) 53,564 59.4 Non-GAAP Adjusted $ 71,238 92.6 % $ 300,520 $ 201,107 $ — $ 18,000 $ 64,201 $ 20,475 5.6 % JAZZ PHARMACEUTICALS PLC RECONCILIATIONS OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATIONCERTAIN LINE ITEMS - FOR THE YEAR ENDED DECEMBER 31, 2024 AND 2023(In thousands, except percentages)(Unaudited) Year ended December 31, 2024 Cost of product sales Gross margin Selling, general andadministrative Research and development Intangible assetamortization AcquiredIPR&D Interest expense, net Income tax expense(benefit) Effective tax rate GAAP Reported $ 445,713 88.3 % $ 1,385,294 $ 884,000 $ 627,313 $ 10,000 $ 238,097 $ (91,429) (19.4) % Non-GAAP Adjustments: Intangible asset amortization — — — — (627,313) — — — — Share-based compensation expense (14,802) 0.5 (158,570) (74,673) — — — — — Non-cash interest expense — — — — — — (21,973) — — Acquisition accounting inventory fairvalue step-up (135,014) 3.5 — — — — — — — Income tax effect of above adjustments — — — — — — — 222,736 28.1 Total of non-GAAP adjustments (149,816) 4.0 (158,570) (74,673) (627,313) — (21,973) 222,736 28.1 Non-GAAP Adjusted $ 295,897 92.3 % $ 1,226,724 $ 809,327 $ — $ 10,000 $ 216,124 $ 131,307 8.7 % Year ended December 31, 2023 Cost ofproduct sales Gross margin Selling, general and administrative Research and development Intangible asset amortization AcquiredIPR&D Interest expense, net Income tax expense (benefit) Effective tax rate GAAP Reported $ 435,577 88.3 % $ 1,343,105 $ 849,658 $ 608,284 $ 19,000 $ 289,438 $ (119,912) (40.2) % Non-GAAP Adjustments: Intangible asset amortization — — — — (608,284) — — — — Share-based compensation expense (15,052) 0.4 (146,942) (64,847) — — — — — Other costs — — (85,215) — — — — — — Non-cash interest expense — — — — — — (22,378) — — Acquisition accounting inventory fair value step-up (151,446) 4.1 — — — — — — — Income tax effect of above adjustments — — — — — — — 213,172 46.9 Total of non-GAAP adjustments (166,498) 4.5 (232,157) (64,847) (608,284) — (22,378) 213,172 46.9 Non-GAAP Adjusted $ 269,079 92.8 % $ 1,110,948 $ 784,811 $ — $ 19,000 $ 267,060 $ 93,260 6.7 % JAZZ PHARMACEUTICALS PLC RECONCILIATION OF GAAP TO NON-GAAP ADJUSTED 2025 NET INCOME AND DILUTED EPS GUIDANCE(In millions, except per share amounts)(Unaudited) Net Income Diluted EPS GAAP guidance $560 - $720 $9.15 - $11.50 Intangible asset amortization 610 - 660 9.70 - 10.60 Acquisition accounting inventory fair value step-up 135 - 155 2.15 - 2.50 Share-based compensation expense 240 - 270 3.80 - 4.35 Income tax effect of above adjustments (215) - (235) (3.40) - (3.75) Non-GAAP guidance $1,400 - $1,500 $22.50 - $24.00 Weighted-average ordinary shares used in per share calculations - GAAP and non-GAAP 62 - 63 Contacts: Investors: Jeff Macdonald Executive Director, Investor Relations Jazz Pharmaceuticals plc InvestorInfo@jazzpharma.com Ireland +353 1 634 3211 U.S. +1 650 496 2717 Media: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc CorporateAffairsMediaInfo@jazzpharma.com Ireland +353 1 637 2141 U.S. +1 215 867 4948 View original content to download multimedia:https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-full-year-and-fourth-quarter-2024-financial-results-and-provides-2025-financial-guidance-302385001.html SOURCE Jazz Pharmaceuticals plc

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。 2024年，全球医药研发领域经历了一系列令人瞩目的临床试验失败事件，这些失败不仅揭示了新药研发过程的复杂性和挑战，也促使制药企业重新审视其研发策略和临床试验设计。从慢性阻塞性肺病药物到帕金森病治疗药物，从肿瘤免疫疗法到基因疗法，多个领域的临床研究在历经长时间和大量资源投入后，未能达到其主要终点或关键次要终点。 本文汇总了2024年发生的110个重要临床试验失败案例，并对一些失败研究进行详细介绍，探讨失败的原因、影响及对未来新药研发的启示，以期提供参考和借鉴。 一月 1月5日，Theravance Biopharma宣布Yupelri（revfenacin）吸入溶液用于慢性阻塞性肺病（COPD）维持治疗的IV期PIFR-2研究未达主要终点。Yupelri 是美国批准用于慢阻肺维持治疗的唯一每日一次的雾化长效毒蕈碱拮抗剂（LAMA）。 1月16日，Allakos宣布lirentelimab在治疗特应性皮炎患者的2期临床试验（ATLAS）和治疗慢性自发性荨麻疹患者的2b期临床试验（MAVERICK）中均未达主要终点。 1月22日，吉利德公布Trop2 ADC新药Trodelvy治疗非小细胞肺癌的三期临床EVOKE-01研究没有达到OS主要终点。EVOKE-01正在评估Trop2 ADC药物Trodelvy®（sacituzumab-govitecan-hziy；SG）与多西他赛在铂类化疗和检查点抑制剂治疗期间或之后进展的转移性或晚期NSCLC患者中的疗效。 1月29日，百时美施贵宝（BMS）宣布其PD-1抑制剂Opdivo在III期CheckMate-914研究的B部分中失败，对于术后存在高复发风险的局部肾细胞癌患者未带来显著的无病生存益处。 1月29号，来凯医药公布afuresertib联合紫杉醇治疗耐药卵巢癌（PROC）（PROFECTA-II）的顶线数据。试验结果表明，afuresertib联合紫杉醇治疗可以降低疾病展或死亡的风险（无进展生存期，PFS )，HR为0.744（95%CI:0.502-1.102），但试验结果不具有统计学意义。 二月 2月5日，亚虹医药发布公告宣布其产品APL1202与化疗灌注联合使用治疗化疗灌注复发的中高危非肌层浸润性膀胱癌（NMIBC）的随机、双盲、对照、多中心的关键性临床试验未达到主要研究终点，公司决定终止APL-1202与化疗灌注联合使用在该适应症的进一步开发。 2月7日，Gilead宣布终止CD47单抗magrolimab治疗急性髓性白血病（AML）的3期ENHANCE-3研究，FDA将所有magrolimab治疗骨髓增生异常综合征（MDS）和急性髓性白血病的研究，包括相关的扩大准入项目置于全面临床搁置状态。这些决定是根据独立数据监测委员会的建议做出的，该委员会审查了ENHANCE-3总生存期（OS）中期分析计划的一线数据。在该分析中，magrolimab与阿扎胞苷和venetoclax联用显示出无治疗效果，并观察到死亡风险增加，主要是由感染和呼吸衰竭引起的。 2月8日，Synlogic公司宣布终止Synpheny-3研究，该研究是对labafenogene marselecobac (SYNB1934)作为苯丙酮尿症（PKU）的一种潜在治疗方法正在进行的Ⅲ期临床研究。SYNB1934是利用合成生物学改造的细菌菌株，具有降解苯丙氨酸的能力。终止Synpheny-3试验的决定是基于即将进行的独立数据监测委员会（DMC）评估前的内部审查结果，该结果表明该试验不太可能达到主要终点。 2月8日，阿斯利康在2023年全年业绩报告上公布因疗效不佳，决定终止抗IL-33单抗Tozorakimab联合达格列净治疗糖尿病肾病的IIb期临床研究（NCT04170543）。 2月12日，AN2 Therapeutics宣布自愿暂停无缝II/III期临床试验（EBO-301）中III期研究部分的患者入组，该试验旨在评估口服小分子细菌leucyl-tRNA合成酶抑制剂epetraborole治疗由鸟分枝杆菌复合体（MAC）引起的难治性肺病的疗效与安全性。在对正在进行的第二阶段研究进行盲法汇总分析后，发现疗效可能低于预期，因此决定自愿暂停试验。 2月12日，大冢制药公布了AVP-786（氘代右美沙芬+奎尼丁）治疗阿尔茨海默病痴呆相关激越的III期临床试验（NCT03393520）未达主要疗效终点。 2月13日，Roivant Sciences在财报中披露终止开发SF3B1调节剂RVT-2001用于治疗骨髓增生异常综合征的临床I/II期试验，原因是期中分析结果后有效性不及预期。 2月16日，Denali Therapeutics在SEC文件中透露，DNL788（SAR443820）治疗肌萎缩侧索硬化症（ALS）的II期HIMALAYA研究未能达到显著改善修订版ALS功能评定量表（ALSFRS-R）评分的主要终点。受此消息影响，Denali的股价下跌了近8%。 三月 3月4日，Vivoryon Therapeutics公布了口服谷氨酰胺酰环化酶（QPCT）抑制剂varoglutamstat（PQ912）治疗早期阿尔茨海默病（AD）IIb期VIVIAD研究的初步结果。结果显示，VIVIAD研究未达到其主要终点，也未显示出认知能力随时间推移而发生变化的显著统计学差异。此外，该研究未达到测量认知能力、日常生活活动工具问卷和脑电图 全局θ功率的关键次要终点。 3月7日，MacroGenics在2023年财报中透露因IMGC936在针对晚期恶性实体瘤的I/II期临床试验中未达到预期内的安全性和有效性目标，将终止该药物的开发。IMGC-936是由MacroGenics原研，后与ImmunoGen（现已被艾伯维收购）合作开发的一款ADAM9 ADC药物。 3月8日，Amylyx Pharmaceuticals公布AMX0035治疗肌萎缩性侧索硬化症（ALS）三期临床PHOENIX的顶线数据，研究没有达到主要终点和次要终点。Amylyx将与监管进行沟通，包括自愿撤市的计划。 3月11日，Acadia Pharmaceuticals公布Pimavanserin治疗精神分裂阴性症状三期临床ADVANCE-2的最新研究结果未达主要终点。研究的主要终点为NSA-16总分从基线到第26周的变化，治疗组和安慰机组26周NSA-16评分分别为-11.8 vs -11.1%，结果不具有统计学意义。安全性和耐受性与之前的临床试验一致，不良事件发生率较低。 3月21日，罗氏合作伙伴Chugai制药（中外制药）公布了Enspryng（萨特利珠单抗）治疗全身型重症肌无力（gMG）的III期LUMINESCE研究结果。虽在其主要终点观察到具有统计学意义的数据，但结果没有达到对临床获益程度的预期。 3月21日，默沙东宣布其PD-1疗法Keytruda联合维持性PARP抑制剂Lynparza（奥拉帕利）一线治疗某些转移性非鳞状非小细胞肺癌（NSCLC）患者的III期KEYLYNK-006试验未达到总生存期（OS）和无进展生存期（PFS）的双重主要终点。 3月28日，BMS宣布1-磷酸鞘氨醇 (S1P) 受体口服小分子调节剂 Zeposia（ozanimod），治疗中重度活动性克罗恩病患者的安慰剂对照临床III期试验YELLOWSTONE研究失败，在第12周未达到临床缓解的主要终点。 四月 4月1日，Gritstone bio宣布其个性化癌症疫苗GRANITE在一线转移性微卫星稳定结直肠癌（MSS-CRC）中正在进行的II/III期研究的II期部分的数据。总体来说，该癌症疫苗未能触发循环肿瘤DNA（ctDNA）的变化，导致II期试验未达主要终点。 4月4日，eFFECTOR Therapeutics公布了tomivosertib的一项随机、安慰剂对照II期KICKSTART研究的主要分析结果。基于分层对数秩检验，PFS双侧P值为0.21，未达到p≤0.2的预设阈值。Tomivosertib组的中位生存期为13.0周，安慰剂组的中位生存期为11.7周。总生存期结果仍不成熟，但没有观察到有利于tomivosertib的趋势。 4月15日，Marius Pharmaceuticals公布静脉注射ganaxolone（加奈索隆）治疗难治性癫痫持续状态（RSE）的三期临床RAISE最新数据，此次中期分析未达到预设的终止标准。IDMC建议临床试验继续，Marinus决定完成RAISE试验约100例患者的入组工作，预计在今年夏季得出顶线结果，结果出来后决定是否继续开发。 4月17日，Sage Therapeutics宣布一项针对帕金森病 (PD) 轻度认知障碍 (MCI) 患者的研究性口服药物dalzanemdor (SAGE-718) 的双盲、安慰剂对照2期研究PRECEDENT研究的初步结果未达到主要终点，即在第42天时接受每日一次dalzanemdor治疗的患者与接受安慰剂治疗的患者在WAIS-IV编码测试得分方面与基线相比不存在显著统计学差异。Dalzanemdor (SAGE-718)的耐受性总体良好，没有发现新的安全信号。 4月18日，Biosplice Therapeutics宣布CLK/DYRK激酶抑制剂lorecivivint治疗膝骨关节炎的III期试验OA-21短期疼痛研究未达到第12周疼痛减轻的主要终点。Biosplice目前正在分析这些初步的OA-21试验结果。 五月 5月6日，Lyra Therapeutics的核心管线LYR-210在治疗慢性鼻窦炎（CRS）的3期研究中未能达到临床主要终点。后续，Lyra公司宣布，将裁撤管线、停止制造和商业化活动、裁员75%等措施来削减成本以节省资金，保证资金继续推动LYR-210的3期研究和公司运营。 5月6日，GlycoMimetics宣布其主要候选产品uproleselan，在与化疗联合治疗成人复发或难治性急性髓系白血病（R/R AML）的III期研究中未达到总生存期（OS）主要终点。结果显示，与单独化疗相比，uproleselan联合化疗组的OS并没有统计学意义的显著改善。 5月10日，百时美施贵宝（BMS）宣布纳武利尤单抗（Opdivo，O药）治疗不可切除的局部晚期III期NSCLC患者的III期CheckMate-73L研究未达到主要终点。 5月13日，默沙东宣布终止3期KeyVibe-010试验中的抗TIGIT药物vibostolimab 和抗PD-1pembrolizumab（帕博利珠单抗） 联合制剂组治疗皮肤癌的后期试验，由于免疫副作用导致大量患者退出。该试验正在评估vibostolimab和帕博利珠单抗的研究组合，与单独使用帕博利珠单抗相比，作为切除的高风险黑色素瘤(ⅡB -Ⅳ期)患者的辅助治疗。 5月13日，盐野义公布新冠口服药Ensitrelvir三期临床最新数据，研究没有达到主要终点治疗到持续症状缓解的时间，尽管数据有所降低，但没有达到统计学显著性差异。盐野义将继续与监管层沟通。 5月28日，康宁杰瑞宣布在未接受系统性治疗的不可切除局部晚期或转移性胰腺导管腺癌(PDAC)患者中，评估其自主研发的PD-L1/CTLA-4双特异性抗体KN046联合白蛋白紫杉醇及吉西他滨对比安慰剂联合白蛋白紫杉醇及吉西他滨的疗效及安全性的III期KN046-303研究已经达到预设的死亡事件数，总生存期(OS)结果未达到预设的统计学终点。 5月30日，吉利德公布Trop2 ADC治疗晚期尿路上皮癌（mUC）三期临床TROPiCS-04的最新数据，研究没有达到OS主要终点，此外，试验还发现，Trodelvy与更多的早期死亡病例相关，主要由于中性粒细胞减少导致的副作用。吉利德正在进一步分析数据，并将与FDA讨论。 六月 6月12日，辉瑞宣布其杜氏肌营养不良症基因疗法PF-06939926治疗杜氏肌营养不良症（DMD）的III期临床CIFFREO失败，与安慰剂相比，PF-06939926在III期试验中未达到主要和关键次要终点。 6月17日，武田公布了其同类首创的强效选择性胆固醇24-羟化酶 (CH24H) 抑制剂Soticlestat (TAK-935)的SKYLINE和SKYWAY研究的顶线数据。SKYWAY (TAK-935-3002)3期研究评估了 Soticlestat 联合标准治疗与安慰剂联合标准治疗对难治性Lennox-Gastaut综合征 (LGS)患者的疗效。与安慰剂相比，Soticlestat未能达到降低严重运动减退性癫痫发作频率的主要终点。 6月17日，Marinus Pharmaceuticals宣布了3期双盲、随机、安慰剂对照RAISE试验（NCT04391569）的初步结果仅达到了两个关键终点中的一个。公司将继续分析RAISE的全部数据集，并计划与美国FDA接触，讨论静脉注射加奈索隆治疗RSE的潜在发展方向。 6月18日，阿斯利康宣布其首创AKT抑制剂Truqap（capivasertib）与紫杉醇联合治疗局部晚期（无法手术）或转移性三阴性乳腺癌（TNBC）患者的CAPItello-290 III期试验未达到双重主要终点，即在整个试验人群或肿瘤携带特定生物标志物改变（PIK3CA、AKT1或PTEN）的亚组患者中，总生存期（OS）与紫杉醇联合安慰剂相比均有所改善。在CAPItello-290中，Truqap与紫杉醇联用的安全性与每种药物的已知安全性基本一致，没有发现新的安全性问题。 6月20日，Jazz制药公布了T型钙通道调节剂suvecaltamide（JZP385）在成人原发性震颤（ET）患者中的IIb期临床试验（NCT05122650）主要结果，与安慰剂相比，30mg suvecaltamide在主要终点（原发性震颤分级评估量表（TETRAS）改良综合结局评分从基线到第12周的变化）和次要终点（临床总体印象-严重程度量表（CGI-S）评分）上，没有达到统计学意义。 6月24日，德国默克宣布终止TrilynX III期随机研究，该研究评估了口服的凋亡抑制蛋白（IAPs）拮抗剂xevinapant联合化放疗（CRT）治疗未切除的局部晚期头颈部鳞状细胞癌（LA SCCHN）患者的效果。该决定是在该研究的独立数据监控委员会进行了预先计划的中期分析后做出的，该委员会认为该试验不太可能达到延长无事件生存期的主要目标。消息发布后，德国默克股价下跌8%。 6月24日，G1 Therapeutics公布了其3期PRESERVE 2试验的最终OS分析结果，该试验评估了CDK4/6抑制剂曲拉西利（trilaciclib）在转移性三阴性乳腺癌（TNBC）患者化疗（吉西他滨和卡铂；GCb）前给药的疗效和安全性，该研究未显示出具有统计学意义的治疗效果。 七月 7月4日，罗氏宣布II/III期SKYSCRAPER-06研究未达到主要终点，该研究旨在评估tiragolumab+Tecentriq (atezolizumab)+化疗 vs. pembrolizumab+化疗一线治疗局部晚期不可切除或转移性非鳞状非小细胞肺癌患者。该研究的主要终点无进展生存期（PFS）的风险比（HR）为1. 27（95%CI：1.02,1.57），总生存期（OS）的HR为1.33（95%CI：1.02,1.73）。 7月8日，HilleVax公司公布了NEST-IN1的初步数据结果未达主要终点。受此消息影响，Hillevax当天股价大跌88%。 7月12日，据clinicaltrials.gov网站显示，礼来终止了BTLA单抗LY3361237治疗中度活动型系统性红斑狼疮（SLE）的一项II期研究（NCT05123586），原因为缺乏疗效。 7月18日，AVEO Oncology宣布其口服的下一代血管内皮生长因子受体 (VEGFR) 酪氨酸激酶抑制剂 (TKI) Tivozanib（商品名：Fotivda）联合纳武利尤单抗（O药）二线/三线治疗晚期转移性肾细胞癌（RCC）患者的III期TiNivo-2研究未达到主要终点。试验的主要结果是无进展生存期，次要终点包括总生存期、总缓解率、缓解持续时间和安全性。 7月24日，Sage Therapeutics和Biogen宣布了口服研究药物SAGE-324 (BIIB124)治疗特发性震颤（ET）的KINETIC 2 2期剂量范围研究未达主要终点。SAGE-324是一款在研口服神经活性类固醇（NAS）GABAA 受体正性异位调节剂（PAM）。 7月29日，Ventyx Biosciences宣布，其变构TYK2抑制剂VTX958在中度至重度活动性克罗恩病患者进行的II期研究未达主要终点。Ventyx计划对现有数据进行进一步分析，并且不打算推进额外的临床试验。 八月 8月1日，Agios Pharmaceuticals公布了全球3期ACTIVATE-KidsT研究的初步结果未达主要终点，该研究针对1至18岁患有PK缺乏症且定期输血的儿童进行了Pyrukynd (mitapivat)治疗。 8月8日，礼来公司第二季度业绩电话会议上，首席科学官Daniel Skovronsky 透露口服抗 tau 药物LY3372689（一种 O-GlcNAcase (OGA) 抑制剂）在治疗早期症状性阿尔茨海默病的2 期研究中失败。试验组所有剂量与安慰剂相比均未达到首要终点，即预设的综合阿尔茨海默病评定量表 (iADRS) 较基线的变化。 8月21日，LEO Pharma 旗下公司Timber Pharmaceuticals公布了异维A酸外用软膏配方TMB-001治疗中重度先天性鱼鳞病患者的为期12周的3期ASCEND研究结果未达到所有主要和次要终点。与安慰剂相比，对TMB-001治疗有反应的中重度先天性鱼鳞病患者的比例没有统计学意义上的显著差异。 8月29日，Merck宣布终止抗PD-1单抗帕博利珠单抗（Keytruda）两项3期试验 KEYNOTE-867和 KEYNOTE-630。KEYNOTE-867（NCT03924869)研究中，Keytruda联合SBRT与安慰剂联合SBRT相比，在无事件生存期（EFS）或总生存期（OS）（分别为研究的主要终点和关键次要终点）方面均未显示出改善；KEYNOTE-630 (NCT03833167)研究中，Keytruda在主要终点RFS方面未达到统计学显著性。目前该研究的关键次要终点OS尚未正式得出，但已有分析结果显示Keytruda并不优于安慰剂。 九月 9月3日，Athira Pharma宣布了其fosgonimeton在轻度至中度阿尔茨海默病 (AD) 患者中的II/III期LIFT-AD临床试验的顶线结果。与安慰剂相比，该试验的主要终点全球统计检验（GST）评分及其关键次要终点ADAS-Cog11和ADCS-ADL23评分在26周时均未达到统计学意义。 9月8日，阿斯利康公布了其抗IL-33单克隆抗体tozorakimab在慢性阻塞性肺病（COPD）的2a期FRONTIER-4研究结果。该研究未能达到改善支气管扩张剂前的用力呼气量（FEV）（即患者用力呼气时所能呼出的空气量）这一主要终点。 9月11日，GSK宣布将停止其单纯疱疹病毒（HSV）疫苗GSK3943104的研发，该疫苗未通过TH HSV REC-003研究，未达有效性主要终点，后续不会进入3期研究。TH HSV REC-003试验是一项联合阶段I/II期概念验证研究，以评估GSK3943104的潜在临床有效性。 9月12日，Neurocrine Biosciences宣布其在研化合物luvadaxistat (NBI-1065844) 的ERUDITE II期临床研究未能达到其作为改善精神分裂症患者认知障碍的潜在治疗方法的主要终点。 9月12日，Fulcrum Therapeutics宣布losmapimod治疗面肩肱型肌营养不良症（FSHD）的III期REACH试验未能达到主要终点。此外，次要终点也没有统计学意义。losmapimod的安全性和耐受性与之前报告的研究结果一致。 9月13日，Atea Pharmaceuticals宣布了评估口服核苷酸聚合酶抑制剂bemnifosbuvir与安慰剂治疗COVID-19的全球III期SUNRISE-3试验未达到主要终点，即在2221名轻度至中度COVID-19高危患者组成的单药治疗队列中，到第29天全因住院或死亡人数的减少具有统计学意义。在SUNRISE-3研究中，bemnifosbuvir总体上安全且耐受性良好。 9月23日，阿斯利康和第一三共共同宣布TROP2 ADC德达博妥单抗（Dato-DXd）二/三线治疗HER2低表达或阴性乳腺癌患者的III期TROPION-Breast01研究未达到总生存期（OS）的主要终点。 9月25日，默沙东宣布，其PD-1抑制剂Keytruda与抗LAG-3抗体favezelimab的联合疗法，在一项针对微卫星稳定（MSS）转移性结直肠癌（mCRC）患者的临床III期试验（KEYFORM-007）中未能显著改善总生存期（OS）。 十月 10月8日，Sage Therapeutics宣布其在研NMDA受体正向变构调节剂 Dalzanemdor治疗阿尔茨海默病（AD）的II 期LIGHTWAVE研究未达到主要终点。 10月14日，Transgene公布了其治疗性癌症疫苗Tipapkinogen sovacivec（TG4001）最新的2期临床研究结果，与PD-L1抑制剂阿维鲁单抗（Avelumab）联用治疗HPV16阳性宫颈和肛门生殖器肿瘤未达到主要终点（改善无进展生存期）。 10月22日，Alto Neuroscience发布其在研疗法ALTO-100治疗重度抑郁症（Major depressive disorder）Ⅱb期研究未达到其主要终点。该临床试验结果的公布使得Alto股价在周二晚间的盘后交易中下跌了76%，市值也仅剩1.2亿美金。 10月29日，Spero Therapeutics宣布其在研非结核分枝杆菌肺病小分子治疗药物候选抗生素SPR720（Fobrepodacin）的Ⅱa期研究的中期分析未达到主要终点。公司暂停该项目，内部重组裁员约39%。 十一月 11月12日，Syros Pharmaceuticals公司宣布，tamibarotene治疗新诊断RARA基因过表达高危骨髓增生异常综合征患者的III期临床SELECT-MDS-1未能达到主要终点，与对照组相比，Tamibarotene+Azacitidine联合疗法未能显著提高某些MDS患者的完全缓解率。 11月12日，艾伯维宣布其用于治疗精神分裂症的M4激动剂Emraclidine在两项名为EMPOWER-1和EMPOWER-2的临床二期试验中，未达到其主要终点。受此消息的影响，艾伯维股价大跌超12%，市值蒸发约400亿美元。 11月15日，眼科公司Eyenovia宣布验证MicroPine（阿托品局部微量制剂）延缓儿童近视进展效果的III期CHAPERONE研究未达到主要终点（3年内视力进展低于0.5屈光度）。Eyenovia计划终止这项研究，更彻底地审查数据，并评估下一步工作。受此消息影响，Eyenovia股价下跌了70%。 11月24日，天士力医药集团股份有限公司宣布：因临床试验结果不达预期，其间接控股子公司赛远生物安美木单抗项目临床试验暂停，目前该试验处于II期临床阶段，并对开发支出余额1.62亿元全额计提资产减值准备。 11月25日，Cassava Sciences宣布Simufilam治疗轻度至中度阿尔茨海默病（AD）的III期ReThink-ALZ研究未达到预先指定的双重主要终点以及次要终点和探索性生物标志物终点。受此消息影响，Cassava Sciences的股价当日下跌了84%。 2024年11月26日，罗氏宣布其TIGIT抗体tiragolumab在3期 SKYSCRAPER-01研究中的最新进展，该研究评估了Tiragolumab联合 Tecentriq与单独使用Tecentriq对 PD-L1 高表达、局部晚期或转移性非小细胞肺癌 (NSCLC) 患者的疗效，该研究在最终分析时没有达到总生存率的主要终点。 十二月 12月3日，Roivant 旗下Kinevant Sciences 公司公告其核心资产namilumab用于结节病的中期临床试验失败，将终止开发。该研究主要终点和次要终点均没有达到。 12月4日，Relmada Therapeutics报告称REL-1017治疗重度抑郁症的3期 Reliance II 试验不太可能达到疗效目标。公司将重新评估数据，同时继续推进治疗代谢性疾病的 REL-P11项目。 12月7日，微芯生物公告其在研新药西奥罗尼胶囊单药治疗三线及以上小细胞肺癌Ⅲ期临床试验结果，在经过广泛抗肿瘤免疫治疗后的总体人群中，虽然西奥罗尼中位PFS（无进展生存期）显著延长，降低疾病进展风险70%以上，但在另一主要终点mOS（中位总生存期）上，与安慰剂组相比不具显著差异。 12月11日，Corcept Therapeutics发布了Dazucorilant治疗肌萎缩侧索硬化症（ALS）2期临床试验DAZALS的研究结果。DAZALS未达到其主要终点，即与接受安慰剂的患者相比，接受Dazucorilant治疗的患者在ALS功能评分量表-修订版（ALSFRS-R）中的变化。 2024年12月16日，UCB宣布，与诺华合作开发的 minzasolmin（一种研究性口服小分子 α-突触核蛋白错误折叠抑制剂）的 ORCHESTRA 帕金森病概念验证研究未达到其主要和次要临床终点。 12月19日，罗氏宣布了IIb期PADOVA研究的结果，该临床研究α-突触核蛋白（α-Syn）单抗 prasinezumab 在586名早期帕金森病患者中的疗效，这些患者接受了至少18个月的稳定症状治疗。Prasinezumab 在主要终点“确认运动进展时间”方面显示出潜在的临床疗效，HR=0.84 [0.69-1.01]，p=0.0657，未达到统计学显著性。 2024年12月20日，Galectin Therapeutics 宣布其代谢功能障碍相关脂肪性肝炎（MASH）新药Belapectin的III期NAVIGATE研究顶线结果。结果显示，试验组未显示出具有统计学意义的临床获益，未达主要终点。 总结 2024年失败的临床研究中，53个为III期研究，27个为II期研究，8个为IIb期研究，5个为I/II期研究，5个为II/III期研究，4个为IIa期研究，2个为I期研究，1个为I/IIb期研究，1个为II/IIb期研究，1个为IV期研究。由此可见III期临床研究失败率最高，特别是在肿瘤领域，由于药物的特殊性以及对疗效和安全性的严格要求，III期临床研究的失败率可能会更高。例如，有数据显示在III期临床开发与监管申请递交之间，肿瘤临床研究的失败率为48%，明显高于非肿瘤临床研究的29%。 导致III期临床研究失败的原因多种多样，主要包括无法达到预期的疗效终点、严重的不良反应事件、疗效不佳等，基础研究不足、临床研究设计缺陷、剂量选择不当、数据收集和分析问题以及操作执行问题等，也可能导致III期临床研究失败。即使临床试验失利的消息频传，实际上能够挺进临床环节的分子已是百里挑一。我们仍要保持积极态度看待，毕竟新药研发之路处处存在反转，只要一息尚存，就有赢的可能。 参考资料：各公司公告