Slides
Page 1
Rusfertide Investor Call on Phase 3 PV Data Presented at ASCO 2025 June 1st, 2025 ET / June 2nd, 2025 JST This material is prepared and distributed solely for the purpose of providing information about Takeda's management or business to shareholders, investors, and analysts, and is not intended to induce purchase or prescription of any specific drugs and other products. This material is not intended for healthcare professionals, patients, or other persons other than those mentioned above. This material is prohibited from being used by persons other than those mentioned above and for the purpose other than one mentioned above.
Page 2
For the purposes of this notice, “presentation” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this presentation. This presentation (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this presentation. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This presentation is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws. The companies in which Takeda directly and indirectly owns investments are separate entities. In this presentation, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies. The product names appearing in this document are trademarks or registered trademarks owned by Takeda, or their respective owners. Forward-Looking Statements This presentation and any materials distributed in connection with this presentation may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could”, “anticipates”, “estimates”, “projects”, “forecasts”, “outlook” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States and with respect to international trade relations; competitive pressures and developments; changes to applicable laws and regulations, including tax, tariff and other trade-related rules; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic; the success of our environmental sustainability efforts, in enabling us to reduce our greenhouse gas emissions or meet our other environmental goals; the extent to which our efforts to increase efficiency, productivity or cost-savings, such as the integration of digital technologies, including artificial intelligence, in our business or other initiatives to restructure our operations will lead to the expected benefits; and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/sec-filings-and-security-reports/ or at www.sec.gov. Takeda does not undertake to update any of the forward-looking statements contained in this presentation or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this presentation may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Financial Information and Certain Non-IFRS Financial Measures Takeda’s financial statements are prepared in accordance with International Financial Reporting Standards (“IFRS”). This presentation and materials distributed in connection with this presentation include certain financial measures not presented in accordance with IFRS, such as Core Revenue, Core Operating Profit, Core Net Profit, Core EPS, Constant Exchange Rate (“CER”) change, Net Debt, EBITDA, Adjusted EBITDA, Free Cash Flow and Adjusted Free Cash Flow. Takeda’s management evaluates results and makes operating and investment decisions using both IFRS and non-IFRS measures included in this presentation. These non-IFRS measures exclude certain income, cost and cash flow items which are included in, or are calculated differently from, the most closely comparable measures presented in accordance with IFRS. Takeda’s non-IFRS measures are not prepared in accordance with IFRS and such non-IFRS measures should be considered a supplement to, and not a substitute for, measures prepared in accordance with IFRS (which we sometimes refer to as “reported” measures). Investors are encouraged to review the definitions and reconciliations of non-IFRS financial measures to their most directly comparable IFRS measures, which are in the financial appendix appearing at the end of this presentation. Beginning in the first quarter of FY24, Takeda (i) changed its methodology for CER adjustments to results of subsidiaries in hyperinflation countries to present those results in a manner consistent with IAS 29, Financial Reporting in Hyperinflation Economies, and (ii) re-named Free Cash Flow as previously calculated as “Adjusted Free Cash Flow” (with “Free Cash Flow” now reported as Operating Cash Flow less Property, Plant and Equipment), and (iii) re-named Net Debt as previously calculated as “Adjusted Net Debt” (with “Net Debt” to be reported as the book value of bonds and loans less cash and cash equivalents). For more information about the changes, including how the new methodology would have impacted Takeda’s FY23 results, as well as other important information about Takeda's non-IFRS measures, including the limitations on the usefulness thereof, refer to the Financial Appendix. Peak Revenue Potential and PTRS Estimates References in this presentation to peak revenue ranges are estimates that have not been adjusted for probability of technical and regulatory success (PTRS) and should not be considered a forecast or target. These peak revenue ranges represent Takeda’s assessments of various possible future commercial scenarios that may or may not occur. References in this presentation to PTRS are to internal estimates of Takeda regarding the likelihood of obtaining regulatory approval for a particular product in a particular indication. These estimates reflect the subjective judgment of responsible Takeda personnel and have been approved by Takeda’s Portfolio Review Committee for use in internal planning. Exchange Rates In this presentation, certain amounts presented in Japanese yen have been translated to US dollars solely for the convenience of the reader. Except where otherwise noted, these convenience translations have been made at an exchange rate of 1USD = 149.90, the Noon Buying Rate certified by the Federal Reserve Bank of New York on March 31, 2025. The rate and methodologies used for these convenience translations differ from the currency exchange rates and translation methodologies under IFRS used for the preparation of Takeda’s consolidated financial statements. These translations should not be construed as a representation that the relevant Japanese yen amounts could be converted into U.S. dollars at this or any other rate. Medical information This presentation contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. Important Notice 2
Page 3
Agenda 3 Today’s Topics Efficacy and Safety Results from the Ph3 Trial of Rusfertide in PV Patients Q&A Session Market Opportunity P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit Panelists P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit
Page 4
PRESENTED BY: 4 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Phase 3 VERIFY study compared the hepcidin mimetic rusfertide to placebo (each added to current standard-of- care) in patients with polycythemia vera 1 Rusfertide met its primary endpoint, all key secondary endpoints, and had a manageable safety profile consistent with prior studies 2 Rusfertide led to statistically significant improvements in several patient reported outcome measures 3 Key Takeaway Points/Conclusions
Page 5
PRESENTED BY: Background 5 • Polycythemia vera (PV) is a myeloproliferative neoplasm driven by acquired JAK2 mutations1-3 • PV is characterized by excessive production of blood cells which contributes to an increased risk of cardiovascular and thrombotic events • Primary goal of PV treatment aims to reduce thrombotic risk by achieving and maintaining Hct <45% 2,3 • Current standard-of-care for PV: phlebotomy ± cytoreductive therapy • Frequent phlebotomy is burdensome and often insufficient for durable Hct control <45% 4-6 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Hct, hematocrit; PHL, phlebotomy; PV, polycythemia vera. 1. Mora B, Passamonti F. Clin Lymphoma Myeloma Leuk. 2023;23(2):79-85; 2. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33; 3. Tremblay D, et al. JAMA. 2025;333(2):153-60; 4. Alvarez-Larrán A, et al. Haematologica. 2016;102(1):103-9; 5. Verstovsek S, et al. Ann Hematol. 2023;102(3):571-81. 6. Ginzburg YZ, Leukemia. 2018;32(10):2105-16.
Page 6
PRESENTED BY: Polycythemia Vera and the Role of Iron and Hepcidin in Red Blood Cell Production 6 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Images created in BioRender. (2025) https://BioRender.com/y23e071
Page 7
PRESENTED BY: Rusfertide in Polycythemia Vera (PV) 7 • Rusfertide is a first-in-class subcutaneous peptide mimetic of the endogenous hormone hepcidin, the principal regulator of iron homeostasis • In the phase 2 REVIVE study (NCT04057040), rusfertide met the primary endpoint for response (ie, Hct control and absence of PHL eligibility) in patients with PV1 • VERIFY (NCT05210790) is a global, ongoing phase 3 study designed to confirm the benefit of adding rusfertide to current standard-of-care (CSC) therapy vs placebo with CSC in patients with PV who require frequent phlebotomies Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) 1. Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35. Hct, hematocrit; PHL, phlebotomy; PV, polycythemia vera.
Page 8
PRESENTED BY: Phase 3 VERIFY Study (NCT05210790) Design in PV 8 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Key Inclusion Criteria: ≥3 PHL (28 weeks prior) OR ≥5 PHL (1 year prior) Stratified by CSC* at randomization (1:1) *PHL ± CRT CRT, cytoreductive therapy; CSC, current standard-of-care; PHL, phlebotomy; PV, polycythemia vera; QW, once-weekly; R, randomization; SC, subcutaneous.
Page 9
PRESENTED BY: Phase 3 VERIFY Study (NCT05210790) in PV Prespecified Primary and Key Secondary Endpoints 9 Rusfertide with CSC vs placebo with CSC: • Primary endpoint (US FDA): Weeks 20-32 Clinical response (absence of phlebotomy eligibility, ie, confirmed Hct ≥45% and ≥3% higher than baseline Hct OR Hct ≥48%) • Key secondary endpoints: Weeks 0-32 Mean number of phlebotomies (EU EMA) Proportion of patients with Hct <45% Mean change from baseline in PROMIS Fatigue SF-8a Score Mean change from baseline in MFSAF TSS7 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; Hct, hematocrit; MFSAF TSS, Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score; PROMIS, Patient-Reported Outcomes Measurement Information System; PV, polycythemia vera; SF, short form.
Page 10
PRESENTED BY: 10 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Total (N=293) Age, years, median (range) 57 (27-82) 58 (28-86) 57 (27-86) Gender, n (%) Male 108 (74.0) 106 (72.1) 214 (73.0) Female 38 (26.0) 41 (27.9) 79 (27.0) Risk Category, n (%) High risk (age ≥60 years old and/or prior TE) 70 (47.9) 66 (44.9) 136 (46.4) Disease Characteristics Age at PV diagnosis (years), median (range) 51 (22-81) 53 (17-84) 52 (17-84) PV duration (years), median (range) 3 (0.2-29.2) 2.8 (0.2-26.4) 2.9 (0.2-29.2) Phlebotomy History – 28 Weeks Prior to Study Treatment Number of TPs, mean ± SD 4.1 ± 1.4 4.2 ± 1.6 4.2 ± 1.5 Patients requiring ≥7 TPs, n (%) 7 (4.8) 16 (10.9) 23 (7.8) CSC, current standard-of-care; PV, polycythemia vera; SD, standard deviation; TE, thromboembolic event; TP, therapeutic phlebotomy. Data cutoff: 7 January 2025 Baseline Demographics and Disease Characteristics
Page 11
PRESENTED BY: Concurrent Cytoreductive Therapy During Part 1a 11 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) CSC, current standard-of-care; JAK, Janus Kinase. n (%) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Total (N=293) Patients With Concurrent Cytoreductive Medication 81 (55.5) 83 (56.5) 164 (56.0) Hydroxyurea 57 (39.0) 58 (39.5) 115 (39.2) Interferons Interferon, peginterferon alpha-2a, or ropeginterferon alfa-2b 20 (13.7) 19 (12.9) 39 (13.3) JAK1/JAK2 Inhibitor Ruxolitinib 3 (2.1) 5 (3.4) 8 (2.7) Data cutoff: 7 January 2025
Page 12
PRESENTED BY: VERIFY Study Met Its Primary Endpoint During Weeks 20-32 (Part 1a) 12 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) 0 20 40 60 80 100 Intent-to-Treat Population % of Responders Placebo (n=146) Rusfertide (n=147) 32.9% n=48 76.9% n=113 Placebo + CSC (n=146) Rusfertide + CSC (n=147) Responders, n (%)a 48 (32.9) 113 (76.9) p-value* <0.0001 Non-responders, n (%) 98 (67.1) 34 (23.1) aResponder = absence of phlebotomy eligibility (confirmed Hct ≥45% and ≥3% higher than baseline Hct OR Hct ≥48%), no phlebotomies, and completion of Part 1a. *p-value based on Cochran-Mantel-Haenszel test. Hct, hematocrit. Data cutoff: 7 January 2025
Page 13
PRESENTED BY: Rusfertide + CSC Benefit Maintained vs. Placebo + CSC for Response* Across Subgroups, Including Risk Status and Concurrent Therapy 13 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Data cutoff: 7 January 2025 *Common risk difference for primary endpoint of response. CRT, cytoreductive therapy; CSC, current standard-of- care; ITT, intent to treat.
Page 14
PRESENTED BY: Rusfertide + CSC Reduced the Mean Number of PHL From Weeks 0-32 vs Placebo + CSC (p<0.0001): Key Secondary Endpoint #1 14 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Number of Phlebotomies Placebo + CSC (n=146) Rusfertide + CSC (n=147) Mean (SD) 1.8 (1.5) 0.5 (1.2) p-value* <0.0001 0 0 20 40 60 80 No PHL During Part 1a (Weeks 0-32) % of Patients Placebo (N=146) Rusfertide (N=147) 72.8% n=107 21.9% n=32 *p-value associated with the LS means difference. LS, least-squares; SD, standard deviation. • Rusfertide reduced the mean number of PHL (Weeks 0-32) vs. placebo by a statistically significant margin across subgroups, including PV risk category, geographic region, and use of concurrent CRT Data cutoff: 7 January 2025 CRT, cytoreductive therapy; CSC, current standard-of-care; PHL, phlebotomy; PV, polycythemia vera.
Page 15
PRESENTED BY: Rusfertide + CSC More Likely to Maintain Hct <45% From Weeks 0-32 vs Placebo + CSC: Key Secondary Endpoint #2 15 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Hct <45% (Baseline through Week 32), n (%)a 21 (14.4) 92 (62.6) p-value* <0.0001 aHct <45% from baseline through Week 32 (a single Hct ≥45% was allowed, excluding intercurrent events classified as non-responders). *Cochran-Mantel-Haenszel test. -2 -1 0 1 2 3 Visit Week Mean (± SEM) Hct Change (%) 145n (Rusfertide) n (PBO→Rusfertide) 146 144 145 138 144 138 137 136 136 135 134 132 109 100 89 75 140 115 64 75 45 21 144 142 142 140 141 138 117 104 93 80 BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 96847266 144 Rusfertide Placebo Placebo → Rusfertide Data cutoff: 7 January 2025 CSC, current standard-of-care; Hct, hematocrit; PBO, placebo; SEM, standard error of measurement.
Page 16
PRESENTED BY: -3 -2 -1 0 1 2 -1.78 0.17 LS Means Difference at Week 32: Week 32 LS Means (SE) Δ -1.95 (0.88)* p=0.0268** Rusfertide (N=120) Placebo (N=116) Rusfertide Demonstrated an Improvement in the PROMIS Fatigue SF-8a Total T-Score at Week 32 vs. Placebo: Key Secondary Endpoint #3 16 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) *LS means (SE) difference (rusfertide – placebo) **p-value associated with the LS mean difference LS, least-squares; PROMIS, Patient-Reported Outcomes Measurement Information System; SE, standard error; SF, short form. Data cutoff: 7 January 2025
Page 17
PRESENTED BY: Rusfertide Demonstrated an Improvement in the MFSAF TSS7 at Week 32 vs. Placebo: Key Secondary Endpoint #4 17 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) -4 -3 -2 -1 0 -2.40 -0.54 LS Means Difference at Week 32: Week 32 LS Means (SE) Δ -1.87 (0.822)* p=0.0239** Rusfertide (N=126) Placebo (N=125) *LS means (SE) difference (rusfertide – placebo) **p-value associated with the LS mean difference LS, least-squares; MFSAF TSS7, Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score-7 item; SE, standard error. Data cutoff: 7 January 2025 • TSS7 includes fatigue, night sweats, itching, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain
Page 18
PRESENTED BY: Exposure and Treatment-Emergent Adverse Events (Part 1a)* 18 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) • Median treatment exposure was 32 weeks in both groups Median (min, max) dose was 30 (10, 90) mg in the rusfertide group • The most common TEAEs in the rusfertide group included localized injection site reactions and anemia • Discontinuation rates due to TEAEs were 2.7% (placebo) and 5.5% (rusfertide) Most Frequent TEAEs (≥6.5% in either group) in Part 1a, n (%) Placebo + CSC (n=146) Rusfertide + CSC (n=145) Patients with at least 1 TEAE 126 (86.3) 129 (89) Injection site reactionsa 48 (32.9) 81 (55.9) Anemia 6 (4.1) 23 (15.9) Fatigue 23 (15.8) 22 (15.2) Headache 17 (11.6) 15 (10.3) COVID-19 16 (11.0) 14 (9.7) Pruritus 14 (9.6) 14 (9.7) Diarrhea 8 (5.5) 12 (8.3) Dizziness 9 (6.2) 12 (8.3) Arthralgia 12 (8.2) 11 (7.6) Constipation 11 (7.5) 11 (7.6) Abdominal distension 8 (5.5) 10 (6.9) Thrombocytosis 0 10 (6.9) aInjection site reactions (grouped term); all other TEAEs are preferred terms. Data cutoff: 7 January 2025 *Safety analysis set. AE, adverse event; CSC, current standard-of-care; TEAE, treatment-emergent adverse event.
Page 19
PRESENTED BY: Cancer Events and Serious TEAEs (Part 1a)* 19 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) *Safety analysis set. AE, adverse event; MI, myocardial infarction; TE, thromboembolic event; TEAE, treatment-emergent adverse event. Cancer Events Placebo + CSC (n=146) Rusfertide + CSC (n=145) Patients with ≥1 Cancer Event, n (%) 7 (4.8) 1 (0.7) Basal cell carcinoma 3 (2.1) 0 Squamous cell carcinoma 1 (0.7) 1 (0.7) Malignant melanoma 1 (0.7) 0 Colorectal cancer 1 (0.7) 0 Prostate cancer 1 (0.7) 0 • 10 skin malignancies (including 1 melanoma) detected prior to randomization • During Part 1a, non-PV cancer events were reported in 8 patients • Serious AEs occurred in 3.4% (rusfertide) and 4.8% (placebo) of patients (none related to rusfertide) • There was 1 TE (acute MI; occurred ~2 weeks after treatment initiation) reported in the rusfertide group Data cutoff: 7 January 2025
Page 20
PRESENTED BY: Conclusions 20 • Rusfertide is an investigational weekly subcutaneous injection for PV • In the phase 3 VERIFY study that included patients with PV who were receiving CSC, rusfertide met its primary endpoint and all four key secondary endpoints vs. placebo In VERIFY Part 1a, rusfertide: o Significantly reduced the PHL eligibility and improved Hct vs. placebo o Demonstrated a statistically significant improvement in symptoms (assessed using two PRO instruments) • Rusfertide demonstrated a manageable safety profile consistent with prior studies • Rusfertide represents a potential new treatment option for PV These data will be used to file marketing authorizations throughout the world Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) CRT, cytoreductive therapy; CSC, current standard-of-care; Hct, hematocrit; PHL, phlebotomy; PRO, patient-reported outcome; PV, polycythemia vera.
Page 21
Agenda 21 Today’s Topics Efficacy and Safety Results from the Ph3 Trial of Rusfertide in PV Patients Q&A Session Market Opportunity P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit Panelists P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit
Page 22
PV patient journey highlights unmet need in current treatment paradigm as patients cycle through options with inconsistent HCT and tolerability Initial Presentation: Routine blood work or thrombotic event Work Up: Blood tests prompt a referral to Hematology/Oncologist Diagnosis: Hem/Onc diagnoses PV and assesses risk Immediate: Phlebotomy (PHL) after diagnosis • LOW RISK: Regular PHL to reduce HCT • PHL inconsistently, temporarily reduces HCT • PHL results in iron deficiency; amplifies PV symptoms • HIGH RISK: PHL with HU or Interferon if PHL alone is insufficient Initial Treatment and Management Monitor blood counts and treatment side effects Adjusts treatment as necessary Ongoing Management Presentation and Diagnosis 2L/3L options often add-on to PHL Cycling on through treatments “I don't love phlebotomy. Most patients hate it. It's exchanging PV for symptomatic iron deficiency…nobody can sustain that.” - MPN Specialist “There's side effects that make HU impossible to take for some patients…30% of patients drop off.” - MPN Specialist • Introduces 2L/3L treatments if not controlled and/or patient QoL is unmangable • 2L HU an off-label1 cytoreductive chemotherapy • Ruxolitinib or Ropeg-interferon added for HCT control or tolerability and/or based on HCP preference Current 2L+ therapies may have side effects and safety concerns *Recommended threshold levels for hematocrit = 45% in men and 42% in women 1. HU is an off-label treatment in the US 22
Page 23
Rusfertide aims to deliver rapid, consistent & sustained HCT control and is expected to be used at each step of the treatment landscape Engaging with key stakeholders to promote use of Rusfertide Working broad access and inclusion in guidelines Driving awareness of the unmet needs in PV Exploring digital solutions for optimal patient onboarding ~155k diagnosed patients in the US with ~78K treated ~41K Phlebotomy (PHL) ~26K Hydroxy Urea (HU) ~6K Ruxolitinib ~3K Ropeg- interferon And/Or And/Or And/Or Source: Komodo Health closed claims dataset (2016-2023); Note: ~2,000 patients are treated via a combination of other therapies; Please refer to the Important Notice at the start of this presentation for more information about peak revenue estimates. Rusfertide may provide consistent hematocrit control and reduce treatment burden to achieve peak revenue potential of $1-2B Unmet needs exist at each step of the treatment landscape, with potential for rusfertide to reach up to 10% of the treated population. Patients are often on polytherapy and will cycle through various treatments 23
Page 24
Rusfertide has the potential to be a new standard of care in PV based on Ph3 data Treatment Goals Emerging Rusfertide Profile1 Reduce treatment/symptom burden • 84% of patients report fatigue, and 23% report spending full days in bed because of symptoms3 Both PRO endpoints met with statistically significance Generally well tolerated safety profile with a majority of TEAEs being mild or moderate Consistently maintaining HCT<45% • Uncontrolled HCT is associated with ~4x higher risk of death from cardiovascular causes or thrombotic events2 63% of patients maintained HCT<45% vs 14% placebo 1. Target profile based on Ph3 data 2. Aaron T. Gerds, Ruben Mesa, John M. Burke, Michael R. Grunwald, Brady L. Stein, Peg Squier, Jingbo Yu, J. E. Hamer-Maansson, and Stephen T. Oh. Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL. Blood. 1646 18 APRIL 2024 | VOLUME 143, NUMBER 16 3. Mesa R, et al. BMC Cancer 2016;16,167 Deliver efficacy independent of current background treatment Demonstrated efficacy against placebo + background SOC including, PHL, HU, JAK and interferon Reduce burden of phlebotomies • PHLs results in iron deficiency and amplifies PV symptoms 77% of patients didn’t need a PHL in wks 20-32 >3x LESS mean number of PHL wks 0-32 vs placebo 24
Page 25
Unlocking full potential of rusfertide for patients with PV Potential to provide rapid, consistent &sustained hematocrit control with a manageable safety profile Approximately155,000 patients diagnosed with PV in US with only 78,000 currently on treatment The addition of rusfertide to on-going therapy represents a potential new standard of care for patients with PV and peakrevenue potential of $1-2B Hematocrit control (<45%) is primary treatment goal of physicians for PV, HCT >45% increases risk of thrombotic event and cardiovascular events 78% of patients remain uncontrolled with HCT cycling above 45% in-between treatments Current treatment options can exacerbate PV symptoms and/or cause significant side effects VERIFY study met all endpoints with 77% of patients no longer eligible for phlebotomy and a manageable safety profile 25
Page 26
Agenda 26 Today’s Topics Efficacy and Safety Results from the Ph3 Trial of Rusfertide in PV Patients Q&A Session Market Opportunity P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit Panelists P .K. Morrow Head of Oncology Therapeutic Area Unit Teresa Bitetti President, Global Oncology Business Unit
Page 27
Medical Presentation as presented at ASCO 2025
Page 28
PRESENTED BY: Results From VERIFY, a Phase 3, Double-Blind, Placebo (PBO)-Controlled Study of Rusfertide for Treatment of Polycythemia Vera (PV) Andrew T. Kuykendall1, Naveen Pemmaraju2, Kristen Pettit3, Joseph Shatzel4, Alessandro Lucchesi5, Valentín García-Guitérrez6, Jiri Mayer7, Abdulraheem Yacoub8, Harinder Gill9, Antonin Hlusi10, Daniel Sasca11, Joseph M. Scandura12, Marina Kremyanskaya13, Phil Dinh14, Sarita Khanna14, Suneel Gupta14, Arturo Molina14, Aniket Bankar15 on behalf of the VERIFY Investigators 1Moffitt Cancer Center, Tampa, FL, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3University of Michigan, Ann Arbor, MI, USA; 4Oregon Health & Science University, Portland, Oregon, USA; 5IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; 6Hospital Universitario Instituto Ramón y Cajal de Investigación Sanitaria, Universidad de Alcalá, Madrid, Spain; 7University Hospital and Masaryk University, Brno, Czech Republic; 8University of Kansas Cancer Center, Westwood, Kansas, USA; 9Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong; 10Palacky University and University Hospital Olomouc, Olomouc, Czech Republic; 11Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz, Mainz, Germany; 12New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY , USA; 13Mount Sinai Medical Center, New York, NY , USA; 14Protagonist Therapeutics, Inc., Newark, California, USA; 15Princess Margaret Cancer Centre, Toronto, ON, Canada. Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center)
Page 29
PRESENTED BY: Key Takeaway Points/Conclusions 29 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Phase 3 VERIFY study compared the hepcidin mimetic rusfertide to placebo (each added to current standard-of- care) in patients with polycythemia vera 1 Rusfertide met its primary endpoint, all key secondary endpoints, and had a manageable safety profile consistent with prior studies 2 Rusfertide led to statistically significant improvements in several patient reported outcome measures 3
Page 30
PRESENTED BY: Background 30 • Polycythemia vera (PV) is a myeloproliferative neoplasm driven by acquired JAK2 mutations1-3 • PV is characterized by excessive production of blood cells which contributes to an increased risk of cardiovascular and thrombotic events • Primary goal of PV treatment aims to reduce thrombotic risk by achieving and maintaining Hct <45% 2,3 • Current standard-of-care for PV: phlebotomy ± cytoreductive therapy • Frequent phlebotomy is burdensome and often insufficient for durable Hct control <45% 4-6 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Hct, hematocrit; PHL, phlebotomy; PV, polycythemia vera. 1. Mora B, Passamonti F. Clin Lymphoma Myeloma Leuk. 2023;23(2):79-85; 2. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33; 3. Tremblay D, et al. JAMA. 2025;333(2):153-60; 4. Alvarez-Larrán A, et al. Haematologica. 2016;102(1):103-9; 5. Verstovsek S, et al. Ann Hematol. 2023;102(3):571-81. 6. Ginzburg YZ, Leukemia. 2018;32(10):2105-16.
Page 31
PRESENTED BY: Polycythemia Vera and the Role of Iron and Hepcidin in Red Blood Cell Production 31 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Images created in BioRender. (2025) https://BioRender.com/y23e071
Page 32
PRESENTED BY: Rusfertide in Polycythemia Vera (PV) 32 • Rusfertide is a first-in-class subcutaneous peptide mimetic of the endogenous hormone hepcidin, the principal regulator of iron homeostasis • In the phase 2 REVIVE study (NCT04057040), rusfertide met the primary endpoint for response (ie, Hct control and absence of PHL eligibility) in patients with PV1 • VERIFY (NCT05210790) is a global, ongoing phase 3 study designed to confirm the benefit of adding rusfertide to current standard-of-care (CSC) therapy vs placebo with CSC in patients with PV who require frequent phlebotomies Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) 1. Kremyanskaya M, et al. N Engl J Med. 2024;390(8):723-35. Hct, hematocrit; PHL, phlebotomy; PV, polycythemia vera.
Page 33
PRESENTED BY: Phase 3 VERIFY Study (NCT05210790) Design in PV 33 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Key Inclusion Criteria: ≥3 PHL (28 weeks prior) OR ≥5 PHL (1 year prior) Stratified by CSC* at randomization (1:1) *PHL ± CRT CRT, cytoreductive therapy; CSC, current standard-of-care; PHL, phlebotomy; PV, polycythemia vera; QW, once-weekly; R, randomization; SC, subcutaneous.
Page 34
PRESENTED BY: Phase 3 VERIFY Study (NCT05210790) in PV Prespecified Primary and Key Secondary Endpoints 34 Rusfertide with CSC vs placebo with CSC: • Primary endpoint (US FDA): Weeks 20-32 Clinical response (absence of phlebotomy eligibility, ie, confirmed Hct ≥45% and ≥3% higher than baseline Hct OR Hct ≥48%) • Key secondary endpoints: Weeks 0-32 Mean number of phlebotomies (EU EMA) Proportion of patients with Hct <45% Mean change from baseline in PROMIS Fatigue SF-8a Score Mean change from baseline in MFSAF TSS7 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; Hct, hematocrit; MFSAF TSS, Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score; PROMIS, Patient-Reported Outcomes Measurement Information System; PV, polycythemia vera; SF, short form.
Page 35
PRESENTED BY: VERIFY Patient Disposition and Analysis Sets: Part 1a 35 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) FAS, all randomized patients according to the treatment assigned at randomization (ITT principle) who received at least one dose of study drug and had a baseline and at least one postbaseline assessment in Part 1a. CSC, current standard-of-care. Data cutoff: 7 January 2025
Page 36
PRESENTED BY: Baseline Demographics and Disease Characteristics 36 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Total (N=293) Age, years, median (range) 57 (27-82) 58 (28-86) 57 (27-86) Gender, n (%) Male 108 (74.0) 106 (72.1) 214 (73.0) Female 38 (26.0) 41 (27.9) 79 (27.0) Risk Category, n (%) High risk (age ≥60 years old and/or prior TE) 70 (47.9) 66 (44.9) 136 (46.4) Disease Characteristics Age at PV diagnosis (years), median (range) 51 (22-81) 53 (17-84) 52 (17-84) PV duration (years), median (range) 3 (0.2-29.2) 2.8 (0.2-26.4) 2.9 (0.2-29.2) Phlebotomy History – 28 Weeks Prior to Study Treatment Number of TPs, mean ± SD 4.1 ± 1.4 4.2 ± 1.6 4.2 ± 1.5 Patients requiring ≥7 TPs, n (%) 7 (4.8) 16 (10.9) 23 (7.8) CSC, current standard-of-care; PV, polycythemia vera; SD, standard deviation; TE, thromboembolic event; TP, therapeutic phlebotomy. Data cutoff: 7 January 2025
Page 37
PRESENTED BY: Concurrent Cytoreductive Therapy During Part 1a 37 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) CSC, current standard-of-care; JAK, Janus Kinase. n (%) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Total (N=293) Patients With Concurrent Cytoreductive Medication 81 (55.5) 83 (56.5) 164 (56.0) Hydroxyurea 57 (39.0) 58 (39.5) 115 (39.2) Interferons Interferon, peginterferon alpha-2a, or ropeginterferon alfa-2b 20 (13.7) 19 (12.9) 39 (13.3) JAK1/JAK2 Inhibitor Ruxolitinib 3 (2.1) 5 (3.4) 8 (2.7) Data cutoff: 7 January 2025
Page 38
PRESENTED BY: VERIFY Study Met Its Primary Endpoint During Weeks 20-32 (Part 1a) 38 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) 0 20 40 60 80 100 Intent-to-Treat Population % of Responders Placebo (n=146) Rusfertide (n=147) 32.9% n=48 76.9% n=113 Placebo + CSC (n=146) Rusfertide + CSC (n=147) Responders, n (%)a 48 (32.9) 113 (76.9) p-value* <0.0001 Non-responders, n (%) 98 (67.1) 34 (23.1) aResponder = absence of phlebotomy eligibility (confirmed Hct ≥45% and ≥3% higher than baseline Hct OR Hct ≥48%), no phlebotomies, and completion of Part 1a. *p-value based on Cochran-Mantel-Haenszel test. Hct, hematocrit. Data cutoff: 7 January 2025
Page 39
PRESENTED BY: Rusfertide + CSC Benefit Maintained vs. Placebo + CSC for Response* Across Subgroups, Including Risk Status and Concurrent Therapy 39 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Data cutoff: 7 January 2025 *Common risk difference for primary endpoint of response. CRT, cytoreductive therapy; CSC, current standard-of- care; ITT, intent to treat.
Page 40
PRESENTED BY: Rusfertide + CSC Reduced the Mean Number of PHL From Weeks 0-32 vs Placebo + CSC (p<0.0001): Key Secondary Endpoint #1 40 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Number of Phlebotomies Placebo + CSC (n=146) Rusfertide + CSC (n=147) Mean (SD) 1.8 (1.5) 0.5 (1.2) p-value* <0.0001 0 0 20 40 60 80 No PHL During Part 1a (Weeks 0-32) % of Patients Placebo (N=146) Rusfertide (N=147) 72.8% n=107 21.9% n=32 *p-value associated with the LS means difference. LS, least-squares; SD, standard deviation. • Rusfertide reduced the mean number of PHL (Weeks 0-32) vs. placebo by a statistically significant margin across subgroups, including PV risk category, geographic region, and use of concurrent CRT Data cutoff: 7 January 2025 CRT, cytoreductive therapy; CSC, current standard-of-care; PHL, phlebotomy; PV, polycythemia vera.
Page 41
PRESENTED BY: Rusfertide + CSC More Likely to Maintain Hct <45% From Weeks 0-32 vs Placebo + CSC: Key Secondary Endpoint #2 41 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) Placebo + CSC (n=146) Rusfertide + CSC (n=147) Hct <45% (Baseline through Week 32), n (%)a 21 (14.4) 92 (62.6) p-value* <0.0001 aHct <45% from baseline through Week 32 (a single Hct ≥45% was allowed, excluding intercurrent events classified as non-responders). *Cochran-Mantel-Haenszel test. -2 -1 0 1 2 3 Visit Week Mean (± SEM) Hct Change (%) 145n (Rusfertide) n (PBO→Rusfertide) 146 144 145 138 144 138 137 136 136 135 134 132 109 100 89 75 140 115 64 75 45 21 144 142 142 140 141 138 117 104 93 80 BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 96847266 144 Rusfertide Placebo Placebo → Rusfertide Data cutoff: 7 January 2025 CSC, current standard-of-care; Hct, hematocrit; PBO, placebo; SEM, standard error of measurement.
Page 42
PRESENTED BY: -3 -2 -1 0 1 2 -1.78 0.17 LS Means Difference at Week 32: Week 32 LS Means (SE) Δ -1.95 (0.88)* p=0.0268** Rusfertide (N=120) Placebo (N=116) Rusfertide Demonstrated an Improvement in the PROMIS Fatigue SF-8a Total T-Score at Week 32 vs. Placebo: Key Secondary Endpoint #3 42 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) *LS means (SE) difference (rusfertide – placebo) **p-value associated with the LS mean difference LS, least-squares; PROMIS, Patient-Reported Outcomes Measurement Information System; SE, standard error; SF, short form. Data cutoff: 7 January 2025
Page 43
PRESENTED BY: Rusfertide Demonstrated an Improvement in the MFSAF TSS7 at Week 32 vs. Placebo: Key Secondary Endpoint #4 43 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) -4 -3 -2 -1 0 -2.40 -0.54 LS Means Difference at Week 32: Week 32 LS Means (SE) Δ -1.87 (0.822)* p=0.0239** Rusfertide (N=126) Placebo (N=125) *LS means (SE) difference (rusfertide – placebo) **p-value associated with the LS mean difference LS, least-squares; MFSAF TSS7, Myelofibrosis Symptom Assessment Form version 4.0 Total Symptom Score-7 item; SE, standard error. Data cutoff: 7 January 2025 • TSS7 includes fatigue, night sweats, itching, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain
Page 44
PRESENTED BY: Exposure and Treatment-Emergent Adverse Events (Part 1a)* 44 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) • Median treatment exposure was 32 weeks in both groups Median (min, max) dose was 30 (10, 90) mg in the rusfertide group • The most common TEAEs in the rusfertide group included localized injection site reactions and anemia • Discontinuation rates due to TEAEs were 2.7% (placebo) and 5.5% (rusfertide) Most Frequent TEAEs (≥6.5% in either group) in Part 1a, n (%) Placebo + CSC (n=146) Rusfertide + CSC (n=145) Patients with at least 1 TEAE 126 (86.3) 129 (89) Injection site reactionsa 48 (32.9) 81 (55.9) Anemia 6 (4.1) 23 (15.9) Fatigue 23 (15.8) 22 (15.2) Headache 17 (11.6) 15 (10.3) COVID-19 16 (11.0) 14 (9.7) Pruritus 14 (9.6) 14 (9.7) Diarrhea 8 (5.5) 12 (8.3) Dizziness 9 (6.2) 12 (8.3) Arthralgia 12 (8.2) 11 (7.6) Constipation 11 (7.5) 11 (7.6) Abdominal distension 8 (5.5) 10 (6.9) Thrombocytosis 0 10 (6.9) aInjection site reactions (grouped term); all other TEAEs are preferred terms. Data cutoff: 7 January 2025 *Safety analysis set. AE, adverse event; CSC, current standard-of-care; TEAE, treatment-emergent adverse event.
Page 45
PRESENTED BY: Cancer Events and Serious TEAEs (Part 1a)* 45 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) *Safety analysis set. AE, adverse event; MI, myocardial infarction; TE, thromboembolic event; TEAE, treatment-emergent adverse event. Cancer Events Placebo + CSC (n=146) Rusfertide + CSC (n=145) Patients with ≥1 Cancer Event, n (%) 7 (4.8) 1 (0.7) Basal cell carcinoma 3 (2.1) 0 Squamous cell carcinoma 1 (0.7) 1 (0.7) Malignant melanoma 1 (0.7) 0 Colorectal cancer 1 (0.7) 0 Prostate cancer 1 (0.7) 0 • 10 skin malignancies (including 1 melanoma) detected prior to randomization • During Part 1a, non-PV cancer events were reported in 8 patients • Serious AEs occurred in 3.4% (rusfertide) and 4.8% (placebo) of patients (none related to rusfertide) • There was 1 TE (acute MI; occurred ~2 weeks after treatment initiation) reported in the rusfertide group Data cutoff: 7 January 2025
Page 46
PRESENTED BY: Limitations 46 • Heterogeneous patient population that may make interpretability of some of the secondary endpoints (eg, PROs) challenging • The placebo-controlled portion of VERIFY (Part 1a) was only 32 weeks long Long-term assessment of safety, thrombotic events, and disease transformation or progression is therefore limited and will continue for up to three years (Parts 1b and 2) Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) PRO, patient-reported outcome.
Page 47
PRESENTED BY: Conclusions 47 • Rusfertide is an investigational weekly subcutaneous injection for PV • In the phase 3 VERIFY study that included patients with PV who were receiving CSC, rusfertide met its primary endpoint and all four key secondary endpoints vs. placebo In VERIFY Part 1a, rusfertide: o Significantly reduced the PHL eligibility and improved Hct vs. placebo o Demonstrated a statistically significant improvement in symptoms (assessed using two PRO instruments) • Rusfertide demonstrated a manageable safety profile consistent with prior studies • Rusfertide represents a potential new treatment option for PV These data will be used to file marketing authorizations throughout the world Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) CRT, cytoreductive therapy; CSC, current standard-of-care; Hct, hematocrit; PHL, phlebotomy; PRO, patient-reported outcome; PV, polycythemia vera.
Page 48
PRESENTED BY: 48 Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center) We would like to thank all patients and their caregivers who participated in this study along with all investigators, study staff, and clinical trial sites who contributed to VERIFY Europe Austria, Belgium, Czechia, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, UK Turkey Chile Canada United States Mexico Hong Kong Australia Israel The study was sponsored by Protagonist Therapeutics, Inc. (Newark, CA, USA). Medical writing assistance was provided by Elizabeth Schoelwer, PharmD, of MedVal Scientific Information Services, LLC (Princeton, NJ, USA), and Peter Morello, Protagonist Therapeutics, Inc., and was funded by Protagonist Therapeutics, Inc. The study was sponsored by Protagonist Therapeutics, Inc. Protagonist is responsible for development of rusfertide in the U.S. through the completion of the Phase 3 VERIFY trial. Takeda Pharmaceuticals (Cambridge, MA) has rights for rusfertide ex-U.S. development and is responsible for leading global regulatory and commercialization activities.
Page 49
PRESENTED BY: Patient Lay Summary Slide 49 • Rusfertide is an investigational weekly subcutaneous injection for a type of blood cancer called polycythemia vera (PV) • Patients receiving rusfertide with current standard-of-care therapy saw a reduction in their average number of phlebotomies vs. placebo Red blood cell levels remained within the desired target range (hematocrit <45%) • Rusfertide was well tolerated and had a safety profile consistent with observations in prior studies • Rusfertide represents a potential new treatment option for patients with PV Andrew T. Kuykendall, MD (Associate Member, Dept. of Malignant Hematology, Moffitt Cancer Center)