Slides
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Ziihera® (zanidatamab-hrii) Investor Call Innovating to Transform the Lives of Patients and Their Families December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Transforming Lives. Redefining Possibilities. Caution Concerning Forward-Looking Statements This presentation contains forward-looking statements and financial targets, including, but not limited to, statements related t o: the Company’s development, regulatory and commercialization strategy; the advancement of pipeline programs and the timing of development activities, regulatory activities and submissions r elated thereto; 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 z anidatamab to be more than a two billion dollar peak potential, the potential regulatory path and anticipated commercial timeline related thereto, including the potential EMA approval in BTC and potential GEA launch in 2026, and the potential to displace Herceptin as the preferred HER2-targeted therapy of choice; the Company’s ability to realize the commercial potential of its products; planned or anticipated clinical trial events, including with respect to initiations, enrollment and data read-outs, and the anticipated timing thereof, including top line GEA results in 2025; 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 regulat ory 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: the successful completion of development and regulatory activities with respect to t he 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, inc luding 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; 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; government investigations, legal proceedings and other actions; the sufficiency of the Company’s cash flows and capital resources; 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, 2023 as supplemented by the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 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 t o differ materially from those anticipated. 2Intended for U.S investor audiences only.
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Introduction and Overview Renée Galá President and Chief Operating Officer December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Now Available 4 The first and only dual HER2-targeted bispecific antibody approved for HER2+ (IHC3+) BTC in the U.S. Intended for U.S investor audiences only. BTC = biliary tract cancer; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; IV = intravenous. Please see full prescribing information available at www.ziihera.com, including BOXED Warnings.
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December 11, 2024 Agenda Introduction and Overview Renée Galá President and Chief Operating Officer Clinical Perspectives on BTC and Results from the HERIZON-BTC-01 Trial Shubham Pant, M.D., M.B.B.S. Dept. of Gastrointestinal Medical Oncology & Dept. of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center Ziihera: Clinical and Development Overview Rob Iannone, M.D., M.S.C.E. Executive Vice President, Global Head of Research and Development and Chief Medical Officer Ziihera: Commercial Overview Abizer Gaslightwala Senior Vice President, Jazz Oncology, U.S. Business Unit Head 5 Intended for U.S investor audiences only.
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December 11, 20246 OncologyNeuroscience Ziihera Launch Enhances Growing Oncology Portfolio Intended for U.S investor audiences only.
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HERIZON-BTC-01 Trial Results Shubham Pant, M.D., M.B.B.S. Dept. of Gastrointestinal Medical Oncology & Dept. of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center December 11, 2024 Intended for U.S. investor audiences only.
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Shubham Pant, M.D., MBBS Dept. of Gastrointestinal Medical Oncology & Dept. of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center 8 Dr. Shubham Pant is a Professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, Texas. Dr. Pant is a key opinion leader in the fields of GI Cancers including pancreatic, biliary, gall bladder and Phase 1 trials. He also serves as the Director of Clinical Research and Associate Director for Early Phase Drug Development at the Sheikh Ahmed Bin Zayed Center. He has an expertise in Targeted therapy and Immunotherapy and has co-authored more than 100 peer-review articles and has presented research in national and international meetings including ASCO, AACR and ESMO. Dr. Pant completed his fellowship from the James Cancer Hospital/Solove Research Institute at the Ohio State University where he was elected Chief Fellow. He has previously served as the Director of Clinical Trials, Section of Hematology/Oncology and was recipient of the Mai Eager Anderson Endowed Chair in Cancer Clinical Trials at the University Of Oklahoma. He has been the recipient of ASCO/AACR Workshop Methods in Clinical Cancer Research and was selected for the American Society of Clinical Oncology (ASCO) Leadership Development Program. He has served as a member on the ASCO Annual Meeting Educational Committee (GI-Non Colorectal Track) and is a member of the ASCO Gastrointestinal Guidelines Committee. He has a keen interest in Global Health and held a grant through the Global Academic Program to study Gall Bladder Cancer in India and Chile. In his free time, Dr. Pant enjoys writing on diet and cancer, is the author of the Bestselling novel: Food Matters: The role your diet plays in the fight against cancer (Publisher: Harper Collins, In). Intended for U.S investor audiences only.
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Unmet Need in Patients with Biliary Tract Cancer (BTC) Shubham Pant, MD • ~12,000 HER2+ BTC cases annually1 in the U.S., Europe2, and Japan • For patients with locally advanced/metastatic BTC, standard 2L+ offers limited clinical benefit ORR 5 – 15%3,4 mPFS 4.0 mo3 • HER2 amplification/overexpression is observed in a subset of BTC 19 – 31% of GBC, 17 – 19% of ECC, 4 – 5% of ICC5,6 • HER2-targeted therapies have clinical benefit in breast, gastric cancer and lung cancer. There are no approved HER2-targeted therapies specifically for BTC. Intended for U.S. investor audiences only. 2L+ = second line or later (treatment); ECC = extrahepatic cholangiocarcinoma; GBC = gallbladder cancer; HER2 = human epidermal growth factor receptor 2; ICC = intrahepatic cholangiocarcinoma; mPFS = median progression-free survival; ORR = overall response rate; 1Incidence sources: Kantar reports; ToGA surveillance report; SEER, cancer.gov; ClearView Analysis; GLOBOCAN, Data on file; 2Major markets, U.K, France, Germany, Spain, Italy. 3 Lamarca A, et al. Lancet Oncol 2021;22:690–701. 4 Yoo C, et al. Lancet Oncol 2021;22:1560–72. 5 Galdy S, et al. Cancer Metastasis Rev 2017;36:141–57. 6 Hiraoka N, et al. Hum Path 2020;105:9–19. 9
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Zanidatamab is a HER2-targeted Bispecific Antibody with a Unique Mechanism of Action (MOA) Shubham Pant, MDIntended for U.S. investor audiences only. ADCC = antibody-dependent cellular cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; BTC = biliary tract cancer; HER2 = human epidermal growth factor receptor 2; 1 Weisser NE, et al. Nature Commun 2023;14:1394. 2 Meric-Bernstam F, et al. Lancet Oncol 2022;23:1558–1570. • Zanidatamab simultaneously binds 2 separate HER2 molecules in trans1 • Unique binding properties of zanidatamab to HER2 result in multiple MOAs including1: • Induction of complement-dependent cytotoxicity • Other immune-mediated effects (ADCC, ADCP) • Prevention of HER2 dimerization and intracellular signaling • Facilitating HER2 internalization and subsequent degradation • Preclinical studies demonstrate greater activity than trastuzumab ± pertuzumab1 • Zanidatamab has shown a manageable safety profile and encouraging antitumor activity in patients with HER2-expressing BTC in a Phase 1 trial 2 ECD = extracellular domain 10
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HERIZON-BTC-01: Introduction Shubham Pant, MD 11 • HERIZON-BTC-01 is a global, single-arm phase 2b trial of zanidatamab monotherapy in patients with locally advanced or metastatic HER2-amplified BTC that progressed after treatment with a gemcitabine-containing regimen • Updated dataset as presented at ASCO 20241 Patients aged ≥18 years Pathologically confirmed, unresectable, locally advanced or metastatic, HER2-amplified gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma Received ≥1 previous gemcitabine-containing systemic chemotherapy regimen for unresectable, locally advanced or metastatic disease or in the neoadjuvant or adjuvant setting with progression or recurrence within 6 months of completion ≥1 measurable target lesion per RECIST v1.12, adequate organ function (including cardiac functiona), and ECOG PS ≤1 No prior HER2-targeted therapies No untreated or symptomatic CNS metastases Key Eligibility Criteria Intended for U.S. investor audiences only. ASCO = American Society of Clinical oncology; BTC, biliary tract cancer; CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; LVEF, left ventricular ejection fraction; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1. 1Pant S, et al. Presented at ASCO 2024, Poster 4091; 2Eisenhauer EA, et al. Eur J Cancer. 2009;45:228-47.
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HERIZON-BTC-01 Study Design Shubham Pant, MD Intended for U.S. investor audiences only. aTrial recruited patients with unresectable, locally advanced, or metastatic HER2-amplified BTC at 32 clinical trial sites in Canada, Chile, China, France, Italy, South Korea, Spain, the UK, and the USA. bAs of January 2023. cMandatory prophylactic treatment for potential infusion reactions 30 to 60 minutes before the start of each zanidatamab infusion should i nclude corticosteroids (either hydrocortisone 100 mg IV or dexamethasone 10 mg IV), antihistamines (diphenhydramine 50 mg PO/IV), and acetaminophen 650-1000 mg PO. dEfficacy is presented only for cohort 1 as that is the primary efficacy population. ePer ICR. fPer investigator assessment. gSafety is reported for all patients (cohort 1 and cohort 2). AE, adverse event; BTC, biliary tract cancer; cORR, confirmed objective response rate; CT, computed tomography; HER2, human epidermal growth factor receptor 2; HRQoL, health-related quality of life; ICR, independent central review; IHC, immunohistochemistry; IRR, infusion-related reaction; IV, intravenous; MRI, magnetic resonance imaging; PO, oral; Q2W, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event. Source: Pant S, et al. Presented at ASCO 2024, Poster 4091. 12 Primary Endpoint:d (Assessed in Cohort 1) • cORR (per ICR) Selected Secondary Endpoints: • cORR (per investigator assessment) • Duration of responsed,e,f • Disease control rated,e,f • Progression-free survivald,e,f • Overall survival • Safety endpointsg Selected Exploratory Endpoints: • HRQoL • Disease related pain • Opioid use Patients with HER2-amplified BTC Cohort 1 (HER2-positive): • IHC 2+ or 3+ Cohort 2: • IHC 0 or 1+ Actual enrollment:b 87 Overall Study Design With mandatory premedication for IRR prophylaxisc Every 8 weeks CT/MRI per RECIST v1.1 28-day cycles Zanidatamab 20mg/kg IV (Q2W) Day 1 Day 15
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Demographics and Baseline Disease Characteristics Shubham Pant, MD 13 Disease Characteristics Cohort 1 (n=80) Cohort 2 (n=7) Disease subtype, n (%) Gallbladder cancer Intrahepatic cholangiocarcinoma Extrahepatic cholangiocarcinoma 41 (51) 23 (29) 16 (20) 4 (57) 3 (43) 0 (0) HER2 status by IHC score (via central assessment), n (%) 3+ 2+ 1+ 0 62 (78) 18 (23) 0 (0) 0 (0) 0 (0) 0 (0) 3 (43) 4 (57) AJCC tumor stage at study entry, n (%) III IV 9 (11) 71 (89) 1 (14) 6 (86) Baseline Demographics Cohort 1 (n=80) Cohort 2 (n=7) Median age, years (IQR) 64 (58-70) 62 (58-77) Race, n (%) Asian White Other 52 (65) 23 (29) 5 (6) 5 (71) 2 (29) 0 (0) Geographical region, n (%) North America Asia Other 18 (23) 50 (63) 12 (15) 0 (0) 5 (71) 2 (29) ECOG performance status, n (%) 0 1 22 (28) 58 (73) 1 (14) 6 (86) Intended for U.S. investor audiences only. Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; IQR, interquartile range Source: Pant S, et al. Presented at ASCO 2024, Poster 4091.
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Disease Response in Patients with HER2-positive BTC (Cohort 1) Shubham Pant, MD Intended for U.S. investor audiences only. aPer independent central review; bOne patient was not evaluable; cBest overall response of stable disease or confirmed complete response or partial response; dConfirmed best overall response of partial response or complete response; eOne patient was a conversion from PR in previously reported data. Sources: 1. Harding JJ, et al. Lancet Oncol. 2023;24(7):772-782. 2. Pant S, et al. Presented at ASCO 2024, Poster 4091. 14 • Confirmed objective response rate was 41.3% and disease control rate was 68.8% • Two patients achieved a complete response (n=2; 2.5%)e • Median duration of response was 14.9 months • Although the trial was not designed to detect treatment effects by HER2 status, in a pre- planned subgroup analysis of cORR by HER2 expression, responses were observed in patients with IHC 3+ tumors (cORR: 51.6%) and IHC 2+ tumors (cORR: 5.6%) Disease Response Endpointsa Long-Term Follow-Up1 (n=80) DCO: July 28, 2023 Confirmed objective response rate,b n (%) [95% CI] 33 (41.3) [30.4, 52.8] Confirmed best overall response, n (%) Complete response, n (%) Partial response, n (%) Stable disease, n (%) Progressive disease, n (%) 2 (2.5) 31 (38.8) 22 (27.5) 24 (30.0) Disease control rate, c n (%) [95% CI] 55 (68.8) [57.4, 78.7] Duration of response,d median (95% CI), months 14.9 (7.4, NR) Progression-free survival, median (95% CI), months 5.5 (3.6, 7.3)
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Target Lesion Reduction in Patients with HER2-Positive BTC (Cohort 1)a Intended for U.S. investor audiences only. Source: Pant S, et al. Presented at ASCO 2024, Poster 4091. *Indicates patients with IHC 2+ status; all other patients had IHC status of 3+. aOnly patients with measurable disease at baseline and at least 1 post-baseline assessment were included (n=79). Dotted lines indicated 20% increase and 30% decrease in sum of diameters of target tumors. BTC, biliary tract cancer; eCCA, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; HER2, human epidermal growth factor receptor 2; iCCA, intrahepatic cholangiocarcinoma; IHC, immunohistochemistry. 15 Target Lesion Reduction in Patients With HER2-Positive BTCa 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 * * * * * * * * * * * * * * * * Percent change from baseline in sum of diameters * BTC subtype GBC iCCA eCCA • A total of 68% (n=54) of patients had a decrease in measured tumor lesions
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Duration of Response in Patients with HER2-Positive BTC (Cohort 1)a-c 16 Intended for U.S. investor audiences only. Source: Pant S, et al. Presented at ASCO 2024, Poster 4091.aPer ICR in patients with confirmed responses (n=33); bEstimates per Kaplan-Meier method; median DOR CIs based on the Brookmeyer and Crowley method with log-log transformations; cCIs at 16 weeks, 6 months, and 12 months based on the Greenwood method Sources: 1. Pant S, et al. Presented at ASCO 2024, Poster 4091; 2. Harding JJ, et al. Lancet Oncol. 2023;24(7):772-822. BTC, biliary tract cancer; CI, confidence interval; DOR, duration of response; HER2, human epidermal growth factor receptor 2; ICR, independent central review; NR, not reached. • The median DOR (95% CI) increased ~2 months to 14.9 (7.4, not reached) months compared to the primary analysis 2 • The median DOR (95% CI) in patients with IHC 3+ tumors was 14.9 (7.4, NR) months; the DOR in the 1 responder with IHC 2+ tumors was 7.5 months • Median progression-free survival (PFS) was 5.5 months [95% CI: 3.6, 7.3]; the longest PFS time was 25.7 months, which was ongoing at the time of data cutoff • In patients with IHC 3+ tumors, the median PFS was 7.2 (95% CI: 5.4, 9.4) months • In patients with IHC 2+ tumors, the median PFS was 1.7 (95% CI: 1.0, 3.3) months Duration of Response in Patients with HER2-Positive BTC1a-c 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 DOR probability (%) DOR (months)Number of patients at risk: Cohort 1 33 30 24 20 16 15 14 9 6 4 2 0 16 weeks 93.1 (75.1, 98.2) 6 months 72.2 (52.1, 85.0) 12 months 60.7 (40.1, 76.1) Median DOR, months (95% CI): 14.9 (7.4, NR) months
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Overall Survival at Long-Term Follow-Up (Cohort 1) 17Intended for U.S. investor audiences only. Source: Pant S, et al. Presented at ASCO 2024, Poster 4091. aCIs for 6-month and 12-month OS based on the Greenwood method; bEstimates per KM method; median OS CIs based on the Brookmeyer and Crowley method with log-log transformations. BTC, biliary tract cancer; CI, confidence interval; IHC, immunohistochemistry; KM, Kaplan- Meier; OS, overall survival. • Median OS (95% CI) was 15.5 (10.4, 18.5) months • The longest survival time was 31.8 months, which was censored without death at the time of data cutoff. KM-estimated OS in Patients with HER2-Positive BTC 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 OS probability (%) Time from treatment start (months) Number of patients at risk: Cohort 1 IHC 3+ IHC 2+ 80 62 18 71 59 12 60 54 6 52 47 5 42 39 3 35 33 2 24 23 1 13 13 0 7 7 0 3 3 0 1 1 0 0 0 0 Survival probability, % (95% CI):a 6-month OS Cohort 1: 80.3 (69.4, 87.6) • IHC 3+: 90.1 (79.2, 95.4) • IHC 2+: 41.7 (17.5, 64.4) 12-month OS Cohort 1: 56.2 (44.3, 66.5) • IHC 3+: 65.0 (51.6, 75.6) • IHC 2+: 20.8 (5.1, 43.7) Median OS, months (95% CI):b Cohort 1: 15.5 (10.4, 18.5) •IHC 3+: 18.1 (12.2, 23.2) •IHC 2+: 5.2 (3.1, 10.2) Note: Treatment effects for this study based on time-based endpoints, such as PFS and OS, can be difficult to interpret in the absence of a comparator arm
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Shubham Pant, MD Overall Safety of Zanidatamab (Cohorts 1 and 2) • With additional follow-up, zanidatamab continued to have a manageable safety profile with no new safety signals identified • The majority of TRAEs were low grade • There were no deaths related to zanidatamab treatment • One patient experienced serious TRAEs since the primary analysis • TRAEs leading to dose reductions were infrequent • No patients discontinued treatment due to TRAEs since the primary analysis 1 18 Intended for U.S. investor audiences only. aAspartate aminotransferase increased. bIncluded alanine aminotransferase increased and aspartate aminotransferase increased (occurring in one patient), anemia, diarrhea, ejection fraction decreased, enteritis, infusion-related reaction, oral candidiasis, and pneumonitis (each occurring in one patient); cOne was due to pneumonitis and the other was due to ejection fraction decreased. Sources: 1. Harding JJ, et al. Lancet Oncol. 2023;24(7):772-782. 2. Pant S, et al. Presented at ASCO 2024, Poster 4091. AE, adverse event; DCO, data cutoff; TRAE, treatment-related adverse event. Primary Analysis1 (n=87) Long-Term Follow-Up2 (n=87) Any treatment-emergent AE, n (%) 84 (96.6) 84 (96.6) Any treatment-related AE, n (%) 63 (72.4) 63 (72.4) Grade 1-2 treatment-related AE 47 (54.0) 45 (51.7) Grade 3 treatment-related AE 16 (18.4) 17 (19.5) Grade 4 treatment-related AE 0 (0) 1 (1.1)a Treatment-related AE leading to death 0 (0) 0 (0) Serious treatment-related AEs, n (%) 7 (8.0) 8 (9.2)b Treatment-related discontinuations, n (%) 2 (2.3) 2 (2.3)c
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Conclusions • In this long-term analysis, zanidatamab monotherapy demonstrated durable and sustained antitumor activity in previously treated patients with HER2-positive unresectable, locally advanced, or metastatic BTC The cORR was 41.3% and two patients achieved a complete response The median DOR was 14.9 months Zanidatamab led to a median OS of 15.5 months (18.1 months in patients with IHC 3+ tumors) • The safety profile of zanidatamab monotherapy was manageable with favorable tolerability Serious or high-grade TRAEs were infrequent (9.2%), as were treatment discontinuations due to TRAEs (2.3%) There were no treatment-related deaths • The efficacy (including OS) and manageable safety profile of zanidatamab is notable in this patient population who historically have had poor outcomes and high unmet needs • The results from this trial were used as the basis for the submission of the BLA filing to the FDA and recent approval of zanidatamab Shubham Pant, MDIntended for U.S. investor audiences only. BTC, biliary tract cancer; cORR, confirmed objective response rate; CR, complete response; DOR, duration of response; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; OS, overall survival; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event. Source: Pant S, et al. Presented at ASCO 2024, Poster 4091. 19 Note: Treatment effects for this study based on time-based endpoints, such as PFS and OS, can be difficult to interpret in the absence of a comparator arm
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Acknowledgement, Disclosure Shubham Pant, MD We sincerely thank all patients and their caregivers. Thanks to all the investigators, clinical trial researchers, personnel and staff who contributed to the trial in any way. The HERIZON-BTC-01 study is funded by Zymeworks BC Inc., Jazz Pharmaceuticals, Inc., and BeiGene Ltd. 20 Intended for U.S. investor audiences only.
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Clinical and Development Overview Rob Iannone, M.D., M.S.C.E. Executive Vice President, Global Head of Research and Development and Chief Medical Officer December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Zanidatamab’s Dual HER2-Targeted Binding Drives Unique MOA and Clinical Activity Intended for U.S. investor audiences only. ADCC / ADCP = antibody-dependent cellular cytotoxicity / phagocytosis; C1q: complement component 1q protein complex; EGFR = epidermal growth factor receptor; Fc receptor = fragment crystallizable receptor; HER2 / 3 = human epidermal growth facto receptor 2 / 3; MOA = mechanism of action; NK cell = natural killer cell. Source: Weisser et al. Nat Commun. 2023;14(1):1394. • Zanidatamab simultaneously binds two non-overlapping extracellular domains of HER2 (biparatopic binding) • Unique geometry and binding properties result in multiple mechanisms of action 22
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December 11, 2024 Zanidatamab’s Dual HER2-Targeted Binding Drives Unique MOA and Clinical Activity Intended for U.S. investor audiences only. CDC = complement-dependent cytotoxicity; HER2 = human epidermal growth factor receptor 2; MOA = mechanism of action.1Weisser et al. Nat Commun. 2023;14(1):1394. • Binding properties of zanidatamab are believed to form the foundation of the unique and diverse mechanisms of action observed preclinically and clinically to-date • Dual HER2-targeted binding and engagement of HER2 in trans results in formation of distinct and large HER2 caps / clusters on cell surface Zanidatamab Clusters HER2 Receptors on Cell Surface1 23
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December 11, 2024 Zanidatamab’s Dual HER2-Targeted Binding Drives Unique MOA and Clinical Activity Intended for U.S. investor audiences only. ADCC = antibody-dependent cellular cytotoxicity; C1q = complement component 1q protein complex; C3a = 77 residue anaphylatoxin; C5a = protein fragment released from cleavage of complement component C5; MOA = mechanism of action; Reference image created with BioRender.com. 1Weisser et al. Nat Commun. 2023;14(1):1394. CDC1 • Cap formation is believed to induce meaningful effector activity1 • Zanidatamab exhibits strong activation of complement-dependent cytotoxicity (CDC)1 Negative ControlZanidatamab Trastuzumab Pertuzumab Trastuzumab and Pertuzumab 24
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December 11, 2024 Ziihera U.S. Label 25Intended for U.S. investor audiences only. Please see full prescribing information available at www.ziihera.com, including BOXED Warnings. HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry. Indications and Usage ZIIHERA is a bispecific HER2-directed antibody indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Dosage and Administration Premedicate patients with acetaminophen, an antihistamine and a corticosteroid, 30- 60 minutes prior to each administration of ZIIHERA infusion to prevent potential infusion-related reactions (IRRs) The recommended dosage of ZIIHERA is 20 mg/kg given as an intravenous infusion once every 2 weeks Dosage Forms and Strengths For injection: 300 mg lyophilized powder in a single-dose vial Warnings and Precautions BOXED Warning on Embryo-Fetal Toxicity. Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. Ventricular Dysfunction: Assess left ventricular ejection fraction (LVEF) prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold or permanently discontinue ZIIHERA based on severity. Infusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity. Diarrhea: ZIIHERA can cause severe diarrhea. Administer antidiarrheal treatment as clinically indicated. Withhold or permanently discontinue Ziihera based on severity. Adverse Reactions Most common adverse reactions (≥ 20%) are diarrhea, infusion-related reaction, abdominal pain, and fatigue Highlights of Prescribing Information
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December 11, 2024 Observed Clinical Activity in 2L+ BTC Intended for U.S. investor audiences only. BTC = biliary tract cancer; BLA = biologics license application; cORR = confirmed overall response rate; HER2+ = human epidermal growth factor receptor 2+; mDOR = median duration of response; mOS = median overall survival; mPFS = median progression-free survival; NR = not reported. 1Javle M et. al., Lancet Oncol. 2021; 2HER2+ Includes IHC3+, FISH/ISH 2+, or confirmation via next-gen sequencing; 3Lamarca A, et al., Lancet Oncol 2021. MyPathway Results1 HER2+ Biliary tract cancer cohort2 ABC-06 Results3 Biliary tract cancer allcomers Regimen Trastuzumab + Pertuzumab mFOLFOX N 39 evaluable 81 evaluable cORR % (95% CI) 23.1% (11, 39) 5.0% (24.4, 67.8) mDOR months (95% CI) 10.8m (0.7, 25.4) NR mPFS months (95% CI) 4.0m (1.8, 5.7) 4.0m (3.2, 5.0) mOS months (95% CI) 10.9m (5.2, 15.6) 6.2m (5.4, 7.6) 26
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December 11, 2024 Observed Clinical Activity in HER2+ (IHC3+) 2L+ BTC Intended for U.S. investor audiences only. 2L+ = second-line plus; BTC = biliary tract cancer; cORR = confirmed overall response rate; HER2 = human epidermal growth factor receptor 2; IHC3+ = immunohistochemistry 3+; mDOR = median duration of response; mPFS = median progression-free survival; mOS = median overall survival; NR = not reached; T-DXd = trastuzumab deruxatecan, or Enhertu®. 1HER2+ IHC3+ patients only. Pant et al. ASCO 2024;. 2Data from pre-planned subgroup analysis of cORR by HER2 expression; 3HER2+ (IHC3+) BTC patients from DESTINY-PanTumor02 primary analysis; 4Table 24, Highlights of Prescribing information: https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true; 5https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-survival-across-multiple-her2-expressing-advanced-solid-tumours-in-destiny-pantumor02-phase-ii-trial.html. Herizon-BTC-01 Results1 Cohort 1 in HER2+ IHC3+ patients DESTINY- PanTumour02 Results3 HER2+ IHC3+ BTC Patients Regimen Zanidatamab monotherapy T-DXd N 62 HER2+ (IHC3+) 22 HER2+ (IHC3+)4 cORR % (95% CI) 51.6% (13.9, 54.9)2 45.5% (24.4, 67.8)4 mDOR months (95% CI) 14.9m (7.4, NR) 8.6m (2.1, NR)5 mPFS months (95% CI) 7.2m (5.4, 9.4) 7.4m (2.8, 12.5)5 mOS months (95% CI) 18.1m (12.2, 23.2) 12.4m (2.8, NR)5 Note: Single-arm trials do not adequately characterize time-to-event endpoints such as PFS or OS. Thus, these data from HERIZON- BTC-01 cannot be directly interpreted as having a survival benefit. 27
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Commercial Overview Abizer Gaslightwala Senior VP, Jazz Oncology, U.S. Business Unit Head December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Unmet Needs Intended for U.S. investor audiences only. 1L /2L /3L = first-, second-, third-line; BTC = biliary tract cancer; HER2 = human epidermal growth factor receptor 2. 1BTC overall diagnosed patients as per SEER 22; 2Assumes anatomic subsites intrahepatic CCA, extrahepatic CCA, gallbladder cancer, and BTC unspecified; 3Assumes HER2 positivity rates per anatomical subsite from: Galdy, S., Lamarca, A., McNamara, M.G. et al. Cancer Metastasis Rev 36, 141–157 (2017), Nobuyoshi Hiraoka, et al. Human Pathology, Volume 105, 2020, Pages 9-19; 4Major markets: U.K, France, Germany, Spain, Italy. Note: HER2+ BTC patients in Jazz controlled commercial territories, which includes Japan, and excludes other certain Asia Pacific countries licensed to BeiGene, Ltd; 5 Niu D, et al. Pathol Oncol Res. 2020;26:2577-2585. brahao-Machado LF, et al. World J Gastroenterol. 2016;22(19):4619-4625. Shim, H. Bispecific Antibodies and Antibody-Drug Conjugates for Cancer Therapy: Technology Considerations. Biomolecules. 2023; doi: 10.3390/biom10030360.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175114/. Accessed April 10, 2024; 7Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9 BTC is a Heterogenous Group of Rare But Aggressive Malignancies With Many Unmet Needs 29 Better Tolerated Treatments Improved Outcomes Improved Quality of Life Better Symptom Control Differentiated Treatments Median OS for second-line treatment of BTC is only ~6 months with current standard of care7 Epidemiology <5% Five-year survival rate in mBTC5 ~12K Global HER2+ BTC 1L & 2L2,4 ~3K U.S. HER2+ BTC 1L & 2L1-3 Median # days on treatment before moving to next line of therapy 100 days1L 90 days2L 60 days3L Progression is quicker with each line of therapy
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December 11, 2024 Ziihera is Well Positioned to Differentiate in 2L+ BTC 30Intended for U.S. investor audiences only. HER2 = human epidermal growth factor receptor 2. 2 31 Chemotherapy-free approach provides tolerable safety profile and improved quality of life for patients Compelling and durable responses help drive improved patient outcomes in pretreated HER2+ patients Unique dual-targeting HER2 bispecific antibody provides differentiated treatment
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December 11, 2024 Unique MOA Drives Compelling Clinical Profile and Patient Outcomes Launch objectives Goal to establish Ziihera as the standard of care for 2L HER2+ BTC Build momentum for Ziihera’s potential as a transformative next-generation HER2-targeting agent Ziihera Clinical Data1 Intended for U.S. investor audiences only. 2L = second-line; BTC = biliary tract cancer; HER2 = human epidermal growth factor receptor 2; M = month; MOA = mechanism of action. 1Data as presented by Pant et al. at ASCO 2024. Mark Ziihera patient living with Biliary Tract Cancer 51.6% Overall Response Rate 14.9m Median Duration of Response 2.5% Discontinuation Rate 31
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December 11, 2024 Ziihera Launch Driven by Proven Jazz Oncology Team and Infrastructure Right Team, Right Capabilities • Proven team with deep oncology experience, including extensive expertise in the HER2 therapy space will help drive additional adoption and uptake • Infrastructure in place for a successful Ziihera launch • Significant overlap in existing call universe covering key customers and accounts • Leverage Jazz’s established presence across sales, marketing, medical and access Key Customer Focus • Access, distribution, reimbursement, and patient support services ensure customers can readily order Ziihera, help patients navigate reimbursement approvals, and provide patient support through dedicated Jazz Resources and the JazzCare suite of services Robust Access and Patient Support Services 32Intended for U.S. investor audiences only.
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Ziihera: Continued Clinical Development Program Rob Iannone, M.D., M.S.C.E. Executive Vice President, Global Head of Research and Development December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Zanidatamab: De-Risked Near-Term Opportunity $2B+ Peak Potential Initiated U.S. launch activities in 2L BTC 1L BTC confirmatory trial ongoing HERIZON-BTC-01: Updated data at ASCO Expanded opportunity across lines of therapy1: • Early lines of therapy (neoadjuvant) • Post T-DXd (Ph3 EmpowHER trial) • Novel combinations Initiated Ph3 EmpowHER trial 2H24: • Zanidatamab + chemo vs. tras + chemo in patients with HER2+ BC whose disease has progressed on previous T-DXd treatment Potential for novel chemo-free regimen for HER2+/HR+ patients1 Ongoing trials in early breast cancer: • I-SPY2 Trial4 • MD Anderson collaboration Significant regulatory progress: • Ziihera® now approved in the U.S. for the treatment of adults with previously treated, unresectable or metastatic HER2+ (IHC3+) BTC • EMA validated MAA; potential approval as early as 2Q25 Biliary Tract Cancer Gastroesophageal Adenocarcinoma Breast Cancer Path to approval in 1L GEA with sBLA submission HER2+/PD-L1 negative: opportunity to address unmet need and replace trastuzumab1 HER2+/PD-L1 positive: opportunity to replace trastuzumab as HER2-targeted therapy of choice1 Opportunity to explore potential in neoadjuvant populations1 Intended for U.S. investor audiences only. 1L = first line; 2L = second line; ASCO = American Society of Clinical Oncology; BC = breast cancer; BTC = biliary tract cancer; EMA = European Medicines Agency; GEA = gastroesophageal adenocarcinoma; HER2 = human epidermal growth factor receptor 2; HR+ = hormone receptor positive; IHC = immunohistochemistry; MAA = marketing authorization application; NSCLC = non-small cell lung cancer; PD-L1 = programmed cell death ligand 1; sBLA = supplemental biologics license application; T-DXd = trastuzumab deruxtecan; tras = trastuzumab. 1Pending regulatory approvals; 2Incidence sources: Kantar reports, ToGA surveillance report; SEER, cancer.gov; ClearView Analysis; GLOBOCAN, Data on file; 3Major markets, U.K, France, Germany, Spain, Italy; 4NCT01042379, in collaboration with QuantumLeap Healthcare Collaborative; 5Incidence source estimates derived from multiple sources: Decision Resources Group, Kantar Health, Jazz Market Research, data on file; 6Funda Meric-Bernstam et al, Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study, The Lancet Oncology, Volume 23, Issue 12, 2022, Pages 1558-1570, ISSN 1470-2045, https://doi.org/10.1016/S1470-2045(22)00621-0. 34 ~12,000 BTC cases annually2 in U.S., Europe3 and Japan ~150,000 BC cases annually5 in U.S., Europe3 and Japan ~63,000 GEA cases annually2 in U.S., Europe3 and Japan Broad Potential Beyond BTC, GEA, and BC Other HER2-Expressing Cancers Broad potential beyond BTC, GEA, and BC in multiple HER2-expressing indications based on compelling clinical activity from early trials6: • Colorectal • NSCLC • Ovarian • Endometrial • Pancreatic • Bladder • Salivary Gland • Ampullary • Other HER2-expressing solid tumors Initiated Phase 2 DiscovHER-Pan-206 • Zanidatamab monotherapy in previously-treated patients with no available treatment options
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December 11, 2024 Upcoming Zanidatamab Milestones Intended for U.S. investor audiences only. 1L= first-line; BC = breast cancer; EMA = European Medicines Agency; EU = European Union; GEA = gastroesophageal adenocarcinoma; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; MAA = marketing authorization application; sBLA = supplemental biologics license application. 2025 2024 2026 and Beyond BTC • Complete 1L confirmatory trial GEA • Potential 1L approval and launch • Expanded market strategy BC • Ongoing execution of EmpowHER-BC-303 trial Pan Tumor • Ongoing execution of DiscovHER-Pan-206 trial BTC Ziihera approved on November 20 Initiated 1L confirmatory trial MAA validated by EMA GEA Enrollment on track for Phase 3 HERIZON-GEA-01 trial BC Phase 3 EmpowHER-BC-303 trial initiated Pan Tumor Phase 2 DiscovHER-Pan-206 trial initiated BTC • Potential EU approval as early as 2Q25 GEA • HERIZON-GEA-01 top-line results estimated 2Q25 • Submit sBLA in 1L • Potential further development in neoadjuvant / adjuvant GEA population 35 Goal of becoming the preferred HER2-targeted therapy of choice
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December 11, 2024 36 … to the numerous patients and their families who participated in our clinical development program. … to the clinical investigators, physicians, nurses, site coordinators, and countless support staff. … to the Jazz team continuously working to deliver this important medicine to BTC patients. Intended for U.S. investor audiences only. Thank You December 11, 2024
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Q&A December 11, 2024 Intended for U.S. investor audiences only.
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December 11, 2024 Thank You Intended for U.S. investor audiences only.