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Post-ASCO Update: Phase 3 VERIFY Study Results Protagonist Therapeutics, Inc. Newark, CA June 2, 2025
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Forward-looking Statements 2 This presentation and the accompanying oral presentation contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, product candidates, capital resources, potential markets for our product candidates, our plans and expectations related to the impact on our business or product candidates of actions or determinations of the U.S. Food and Drug Administration (“FDA”), our collaboration with Johnson & Johnson Innovation, Inc. (”JNJ”), our collaboration with Takeda, our IL-17 and other discovery and pre-clinical programs including expectations regarding announcements related to those programs, our potential receipt of milestone payments and royalties under our collaboration agreements with JNJ and Takeda, and the timing of icotrokinra (JNJ-2113, formerly PN-235) and rusfertide clinical results, Janssen’s development plan for icotrokinra, and the potential market opportunity for rusfertide and icotrokinra, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially,” “predict,” “should,” “will,” or the negative of these terms or other similar expressions. The forward-looking statements made in this presentation involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These forward-looking statements are subject to risks and uncertainties, including those discussed in Protagonist’s filings with the Securities and Exchange Commission, including in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings and in the documents incorporated by reference therein. Because forward- looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation concerns products that are under clinical investigation and which have not yet been approved for marketing by the FDA. They are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. Nothing contained in this presentation is, or should be construed as, a recommendation, promise or representation by the presenter or Protagonist or any director, employee, agent or advisor of Protagonist. This presentation does not purport to be all inclusive or to contain all the information you may desire.
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Phase 3 VERIFY Study: Primary Results Data Presented at 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Plenary Presentation) by Andrew T. Kuykendall, MD (Moffitt Cancer Center, Tampa, FL) Sunday June 1, 2025 Arturo Molina, MD, MS, FACP Chief Medical Officer Protagonist Therapeutics, Inc. 3
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Key Takeaway Points from Phase 3 VERIFY Study in Polycythemia Vera (PV) 4 VERIFY is a global, randomized, double-blind phase 3 study investigating rusfertide or placebo with current standard-of-care therapy in patients with PV Rusfertide was well tolerated and had a safety profile that was consistent with prior observations in phase 2 studies of patients with PV, including REVIVE VERIFY met its prespecified primary endpoint (response) and all four key secondary endpoints, including reduction in phlebotomy and improvement in symptoms (assessed by PRO measures) vs. placebo
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5 Rusfertide Phase 3 VERIFY Study Primary endpoint:3 Wks 20-32 1. Clinical Response: rusfertide vs placebo Key 2° endpoints: Wks 0-32 1. Average number of PHLs4 2. Proportion of patients with Hct <45% 3. Average PROMIS Fatigue SF-8a Score5-6 4. Average MFSAF Total Symptom Score7-8 *Therapy could include therapeutic phlebotomy and/or cytoreductive therapy. 1. ClinicalTrials.gov. NCT05210790. https://clinicaltrials.gov/ct2/show/NCT05210790; 2. ASCO’24: Bankar A, et al. VERIFY: A randomized controlled phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera (PV). J Clin Oncol;2024;42;16_suppl. TPS6592. 3. US primary endpoint; 4. EU primary endpoint 5. Garcia SF, et al. J Clin Oncol. 2007;25:5106-12; 6. Cella D, et al. J Clin Epidemiol. 2016;73:128-34 7. Mesa RA, et al. Leuk Res. 2009;33:1199-203; 8. Gwaltney C, et al. Leuk Res. 2017;59:26-31 Inclusion Criteria ≥3 PHL (28 wks prior) OR ≥5 PHL (1 year prior) N = 293 1:1 randomization Part 1B Durability of Response (Wks 32-52) Placebo + Current Standard-of-Care Therapy* Part 1A: Double-Blind1,2 Rusfertide + Current standard-of-care therapy* Dose titration Wks 0-20 1° endpoint Wks 20-32 Clinical Study Design and Topline Results Part 1B and 2: Open-Label1,2 Part 2 Long-term safety (Wks 52-156)Rusfertide + Current Standard-of-Care Therapy*
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Baseline Demographics and Disease Characteristics Well Balanced Across Groups 6 Data cutoff: 7 January 2025 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.
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Concurrent Cytoreductive Therapy During Part 1a 7 CSC, current standard-of-care; JAK, Janus Kinase. Data cutoff: 7 January 2025 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 Inhibitors Ruxolitinib 3 (2.1) 5 (3.4) 8 (2.7) • Demographics in line with entire PV population showing generalizability of the data
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0 20 40 60 80 100 Intent-to-Treat Population % of Responders Placebo Group (n=146) Rusfertide Group (n=147) 32.9% n=48 76.9% n=113 VERIFY Study Met Its Primary Endpoint During Weeks 20-32 (Part 1a) 8 US FDA Primary Endpoint 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
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Rusfertide Benefit Maintained vs. Placebo for Response* Across Subgroups, Including Risk Status and Concurrent Therapy 9 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.
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Mean Number of Phlebotomies (Primary EU Endpoint) and Supportive Data (Freedom From Phlebotomy) 10 0 0 20 40 60 80 No PHL During Part 1a (Weeks 0-32) % of Patients Placebo Group (N=146) Rusfertide Group (N=147) 72.8% n=107 21.9% n=32PHL, phlebotomy. Data cutoff: 7 January 2025 Number of Phlebotomies Placebo (n=146) Rusfertide (n=147) Mean (SD) 1.8 (1.5) 0.5 (1.2) p-value* <0.0001 *p-value associated with the LS means difference. LS, least-squares; SD, standard deviation. Key Secondary Endpoint #1: Weeks 0-32 Mean Number of Phlebotomies (EU Primary Endpoint) Freedom From Phlebotomy During Weeks 0-32
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Rusfertide Reduced the Mean Number of PHL From Weeks 0-32 vs Placebo (p<0.0001) 11 • 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
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Rusfertide + CSC More Likely to Maintain Hct <45% From Weeks 0 -32 vs Placebo + CSC 12 Key Secondary Endpoint #2 Placebo (n=146) Rusfertide (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. Hct, hematocrit. -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 Hct, hematocrit; PBO, placebo; SEM, standard error of measurement; SOC, standard-of-care.
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VERIFY: Key PRO-Related Secondary Endpoints at Week 32 13 Includes All Patients* Regardless of Symptom Status at Baseline Endpoint Description Instrument Symptom(s) Comparison of rusfertide to placebo: PROMIS Fatigue SF-8a1,2 Fatigue • Mean change from baseline at end of Part 1a (Week 32) in the PROMIS SF-8a total T-score MFSAF version 4.03,4 Fatigue • Mean change from baseline at end of Part 1a (Week 32) in the MFSAF v4.0 TSS7 Night sweats Itching Abdominal discomfort Pain under the ribs Early satiety Bone pain 1. Garcia SF, et al. J Clin Oncol. 2007;25:5106-12; 2. Cella D, et al. J Clin Epidemiol. 2016;73:128-34; 3. Mesa RA, et al. Leuk Res. 2009;33:1199-203; 4. Gwaltney C, et al. Leuk Res. 2017;59:26-31. *Patients were not required to have symptoms (e.g., fatigue, night sweats, itching, etc.) to enroll in VERIFY . MFSAF TSS7, Myelofibrosis Symptom Assessment Form version 4.0 T otal Symptom Score 7; PRO, patient reported outcomes; PROMIS Fatigue SF-8a, Patient Reported Outcomes Measurement Information System (PROMIS®) Fatigue Short Form 8a; PV , polycythemia vera; TSS, total symptom score. SF-8aTSS-7
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Rusfertide Demonstrated an Improvement in the PROMIS Fatigue SF-8 vs Placebo at Week 32 14 Key Secondary Endpoint #3 Data cutoff: 7 January 2025 -3 -2 -1 0 1 2 -1.78 0.17 LS Means Difference at Week 32: Week 32 LS Means (SE) p=0.0268** Δ -1.95 (0.88)* Rusfertide Group (N=120) Placebo Group (N=116) *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.
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PROMIS Fatigue SF-8a Total T-Score (Week 32) 15 • The PROMIS Fatigue Short Form 8a contains 8 questions that ask about fatigue – Individual scores between 1 (not at all) and 5 (very much) used to generate a raw score, which is then converted to a T-score • There was a statistically significant improvement* in the PROMIS Fatigue SF-8a with rusfertide vs placebo at Week 32 during the end of Part 1a – LS means use modeling and include covariates and baseline adjustments • We look forward to presenting additional data at future medical meetings, including additional exploratory analyses Key Secondary Endpoint #3: Additional Context *LS mean (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.
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Rusfertide Demonstrated an Improvement in the MFSAF TSS7 vs Placebo at Week 32 16 Key Secondary Endpoint #4 -4 -3 -2 -1 0 -2.40 -0.54 LS Means Difference at Week 32: Week 32 LS Means (SE) p=0.0239** Δ -1.87 (0.822)* Rusfertide Group (N=126) Placebo Group (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
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Improvement With Rusfertide in MFSAF TSS7 at Week 32 17 • MFSAF scored between 0 (absent) and 10 (worst imaginable) for each individual symptom – Total symptom score (TSS) out of 70 • Unlike the PROMIS Fatigue SF-8a, raw data are used to score the TSS in the MFSAF • There was a statistically significant improvement* in the MFSAF TSS7 in the rusfertide vs placebo groups at Week 32 (end of Part 1a) – LS means use modeling and include covariates and baseline adjustments • To our knowledge, no other randomized Phase 3 trials in PV have demonstrated a statistically significant improvement with the MFSAF – Results from VERIFY confirm data from the open-label phase 2 results from REVIVE (MPN-SAF) • Like the PROMIS Fatigue SF-8a data, we look forward to presenting additional data from the MFSAF and other PRO-focused endpoints at future meetings Key Secondary Endpoint #4: Additional Context *LS mean (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.
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Exposure and Treatment-Emergent Adverse Events (Part 1a) 18 Data cutoff: 7 January 2025 • 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 (n=146) Rusfertide (n=145) Patients with at least 1 TEAE 126 (86.3) 129 (89) Injection site reactions a 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)*Safety analysis set. AE, adverse event; TEAE, treatment-emergent adverse event.
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Cancer Events and Serious TEAEs (Part 1a)* 19 • 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 Cancer Events Placebo (n=146) Rusfertide (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 Data cutoff: 7 January 2025 *Safety analysis set. AE, adverse event; MI, myocardial infarction; TE, thromboembolic event; TEAE, treatment-emergent adverse event.
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Phase 3 VERIFY Conclusions 20 • In the Phase 3 VERIFY study that included patients with PV receiving SOC therapy, rusfertide met its primary endpoint and all four key secondary endpoints vs. placebo – Rusfertide: ▪ Significantly reduced the mean number of PHL and improved Hct control in the desired target range (Hct <45%) vs. placebo ▪ Demonstrated a statistically significant improvement in symptoms measured by two PRO instruments vs. placebo • Rusfertide was well tolerated and had a 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 CRT, cytoreductive therapy; Hct, hematocrit; PHL, phlebotomy; PRO, patient-reported outcome; PV, polycythemia vera.
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Closing Remarks Dinesh V. Patel, PhD Director, President, and CEO Protagonist Therapeutics, Inc. Newark, CA 21
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22 Peak Revenue Potential of $1-2 Billion1 Treatment Goals Emerging Rusfertide Profile2 Consistently maintaining Hct<45% • Uncontrolled Hct is associated with ~4x higher risk of death from cardiovascular causes or thrombotic events3 • Up to 78% of patients have uncontrolled Hct>45%4 63% of patients maintained HCT<45% vs 14% placebo 1. Takeda R&D Day, December 2024 2. Target profile based on Ph3 data 3. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33. 4. Verstovsek S, et al. Ann Hematol. 2023;102(3):571-581. Reduce treatment/symptom burden • 84% of patients report fatigue, and 23% report spending full days in bed because of symptoms Both PRO endpoints met with statistical significance • Deliver efficacy independent of current standard of care 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 Rusfertide has the Potential to be a New SOC in PV Based on Ph3 Data • Provide safe and effective treatment option Generally well tolerated safety profile with a majority of TEAEs being mild or moderate
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Takeda Partnership 23 • Takeda is the perfect partner for Protagonist to help commercialize rusfertide – Leading hematology/oncology business worldwide – New strong leadership team – Leading Rusfertide NDA submission ▪ Pre-commercialization activities underway ▪ Priority near term launch for overall business • We look forward to partnering with Takeda as they complete and submit regulatory filings for rusfertide in key markets around the world, including the United States, Europe, and Japan Scenario Total $$ upfront + milestones Upfront Payable Opt-Out Potential Milestones Royalty Rates Comment OPT-IN $630M $300M ✓ - $330M 10-17% Ex-US 50:50 US profit/loss share OPT-OUT $1,675M $300M ✓ $400M $975M 14-29% worldwide Exclusive US rights to Takeda
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Rusfertide Clinical Development Program in PV 24 NDA Filing in Q4 2025 Discovery/Pre-Clinical Phase 1 Phase 2 Phase 3 Key Milestones PACIFIC Ph 2, Elevated Hct (>48%), n=20 REVIVE Ph 2, n=70 RUSFERTIDE Hepcidin Mimetic • Topline 32-Wk Primary EP results • Completed • Completed Polycythemia Vera (PV) VERIFY Ph 3, n=293 HEMATOLOGY THRIVE LTE, n=46 • Ongoing; for REVIVE patients in OLE ✓ ✓ ✓ ✓ Rusfertide has Orphan Drug designation and Fast Track status for PV Q1 2025 Q2 2025 Q3 2025 Q4 2025 ❖ PV Day1 ❖ Ph3 VERIFY topline ❖ Rat 2-year carcinogenicity study ❖ ASCO 2025 ❖ NDA filing ✓ ✓ ✓✓
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2024 Q1 2025 Q2 2025 Q4 2025 ❖ New Engl J Med, 2024; 390:723-35, REVIVE Ph2 ❖ Ph3 VERIFY enrollment completion ❖ PV day ❖ Topline results ❖ ASCO plenary session ❖ NDA filing ❖ ASH 2025 Icotrokinra Expected Clinical Trial Initiations, Data Readouts and Development Candidate Nominations Major Upcoming Catalysts in 2025 25 Discovery Rusfertide 1. PN-881 ✓ Oral IL-17 Antagonist Development Candidate (DC) 2. Oral Obesity DC ❖ Ph1 initiation 3. Oral Hepcidin DC ❖ New Engl J Med, 2024; 390:510-21, FRONTIER 1 Ph2 results ❖ Ph3 PsO LEAD ✓ ❖ Ph3 PsO TOTAL ✓ ❖ Medical Conferences ❖ Ph2b UC ANTHEM ✓ ❖ Ph3 ICONIC-PsA 1 Initiation ✓ ❖ Ph3 ICONIC-PsA 2 Initiation ✓ ❖ Ph3 PsO ADVANCE 1 ✓ ❖ Ph3 PsO ADVANCE 2 ✓ ❖ Ph3 PP/EP study ❖ Psoriasis NDA filing ❖ Ph3 ICONIC-ASCEND H2H vs. Stelara ❖ New UC study ❖ New Crohn’s study ✓ ✓ ✓ ✓
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26 Thank you
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Q&A Dinesh V. Patel, PhD Director, President, and CEO Arturo Molina, MD, MS, FACP EVP and Chief Medical Officer Samuel Saks, MD Clinical Advisor 27