Werewolf Therapeutics, Inc. · NASDAQ:HOWL

Werewolf Therapeutics — Investor Presentation (May 2025)

57 slides from Werewolf Therapeutics's investor presentation, May 8, 2025

  1. Slide 1: Delivering the Power of Immunotherapy

    ©2025 WEREWOLF THERAPEUTICS1 | Delivering the Power of Immunotherapy CORPORATE PRESENTATION | May 2025

  2. Slide 2: Cautionary Statements

    ©2025 WEREWOLF THERAPEUTICS2 | Cautionary Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding Werewolf Therapeutics

  3. Slide 3: Clinical-Stage Biopharma Company – Next Generation Conditionally Activated Therapies

    ©2025 WEREWOLF THERAPEUTICS3 | Clinical-Stage Biopharma Company – Next Generation Conditionally Activated Therapies Robust Discovery Engine Novel INDUKINETM and INDUCERTM molecules Clinical Focus High-Value Opportunities PREDATOR® Platform Validated & Differentiated Tunable, tissue-targeted INDUKINE

  4. Slide 4: Conditionally Activated Immunotherapy

    ©2025 WEREWOLF THERAPEUTICS4 | Suboptimal Pharmaceutical Properties Toxicity Our Solution: Conditionally Activated Immunotherapy The Challenge: Off-Tumor Cytokine Toxicity Limits Therapeutic Index Poor Clinical Outcomes With Optimized Therapeutic Index INDUKINEs (inactive cytokines) Activated cytoki

  5. Slide 5: PREDATOR Platform

    ©2025 WEREWOLF THERAPEUTICS5 | PREDATOR Platform Blocking Domain: Safety Peripheral inactivation Anti-HSA: Exposure Half-life extension Linker: Selectivity Proprietary tumor activation Native Cytokine: Potency antitumor immune response Tunable, Tissue-targeted Therapeutics for Cancer and other Disea

  6. Slide 6: A Portfolio of Novel Clinical and Preclinical Drug Candidates

    ©2025 WEREWOLF THERAPEUTICS6 | PROGRAM INDICATIONS DISCOVERY IND-ENABLING PHASE 1 PHASE 2 ANTICIPATED MILESTONES Cancer Indications Cancer IndicationsWTX-712 IL-21 INDUKINE Molecule Cancer Indications Exclusive global rights licensed to Jazz Pharmaceuticals JZP898 IFNα INDUKINE Molecule Advanced or

  7. Slide 7: WTX-124

    ©2025 WEREWOLF THERAPEUTICS7 | # ©2025 WEREWOLF THERAPEUTICS WTX-124

  8. Slide 8: WTX-124: Improving the Efficacy and Tolerability of IL-2

    ©2025 WEREWOLF THERAPEUTICS8 | THE CHALLENGE WTX-124: Improving the Efficacy and Tolerability of IL-2 Abbreviations: SOC-standard of care; ICI-immune checkpoint inhibitor Approved high-dose IL-2 therapy (HD IL-2) with aldesleukin (Proleukin®) produces durable responses in patients with cutaneous mel

  9. Slide 9: Goal to Significantly Expand Patient Populations Who Might Benefit from IL-2

    ©2025 WEREWOLF THERAPEUTICS9 | Goal to Significantly Expand Patient Populations Who Might Benefit from IL-2 Abbreviations: HD-high dose; CR-complete response; ORR-objective response rate Proleukin (aldesleukin) injection label, Reference ID: 3165255; Proleukin (aldesleukin) injection label (fda.gov)

  10. Slide 10: WTX-124 Delivers IL-2 Selectively to Tumors in Preclinical Models

    ©2025 WEREWOLF THERAPEUTICS10 | WTX-124 Delivers IL-2 Selectively to Tumors in Preclinical Models Wild type IL-2 released in the TME expands and activates antitumor CD8+ T effector cells preferentially over Tregs IL-2 WTX-124 INDUKINE WTX-124 Vehicle Abbreviations: TME-tumor microenvironment; TIL-tu

  11. Slide 11: WTX-124 Produces Complete Responses with an Improved Therapeutic Window vs. IL-2

    ©2025 WEREWOLF THERAPEUTICS11 | Incorporation of wild type IL-2 in WTX-124 is required for complete tumor regressions and immune memory formation WTX-124 Produces Complete Responses with an Improved Therapeutic Window vs. IL-2 WTX-124 activates long-term antitumor immune memory Improved therapeutic

  12. Slide 12: WTX-124 Monotherapy and Combination Expansion Arms are Actively Enrolling

    ©2025 WEREWOLF THERAPEUTICS12 | Trial Details mTPI-2 (Modified Toxicity Probability Interval 2) study design; enrolling ~175 patients with IO- sensitive tumors Monotherapy and combination therapy dose escalations enrolled in parallel with staggered start for combination Assessment of safety, efficac

  13. Slide 13: Data from Ongoing WTX-124 Phase 1/1b Study in ICI-treated Patient Population

    ©2025 WEREWOLF THERAPEUTICS13 | Data from Ongoing WTX-124 Phase 1/1b Study in ICI-treated Patient Population Safety • Generally well tolerated in the outpatient setting • No evidence of vascular leak syndrome, cytokine release syndrome (≥Grade 2) or infusion reactions • Majority of related TEAEs wer

  14. Slide 14: WTX-124 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting

    ©2025 WEREWOLF THERAPEUTICS14 | WTX-124 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting Key Safety Findings: • Most frequent related TEAEs were arthralgia, fatigue, pruritis and eosinophilia • Majority of related TEAEs were Grade 1 and 2, Grade 3 TEAEs at ≥18mg were manageabl

  15. Slide 15: WTX-124 Monotherapy Induced Rapid, Durable Regressions of Target Lesions

    ©2025 WEREWOLF THERAPEUTICS15 | WTX-124 Monotherapy Induced Rapid, Durable Regressions of Target Lesions Abbreviations: RDE-recommended dose for expansion; BCC-basal cell carcinoma; NSCLC-non-small cell lung cancer; HCC-hepatocellular carcinoma; RCC-renal cell carcinoma; GEJ-gastroesophageal junctio

  16. Slide 16: Complete Response Ongoing at >18 Months in ICI-Refractory Cutaneous SCC

    ©2025 WEREWOLF THERAPEUTICS16 | Complete Response Ongoing at >18 Months in a Patient with ICI-Refractory Cutaneous SCC 72-year-old man with metastatic cutaneous SCC who progressed on RT/cetuximab and had no response to four doses (12 weeks) of cemiplimab (Libtayo®; anti-PD-1) – panel a Initiated tre

  17. Slide 17: WTX-124 in Combination with Pembrolizumab Demonstrated Durable Responses

    ©2025 WEREWOLF THERAPEUTICS17 | WTX-124 in Combination with Pembrolizumab Demonstrated Durable Responses in ICI-treated Patients Dose DL Indication Prior therapies Response Status 12mg Melanoma 1. Pembrolizumab/propranolol 2. TVEC • 3w: Increased T cell activation (biopsy) • 8w: 28.7% ↓ of target le

  18. Slide 18: WTX-124 Effectively Limits Systemic Exposure of Active Cytokine

    ©2025 WEREWOLF THERAPEUTICS18 | WTX-124 Effectively Limits Systemic Exposure of Active Cytokine Data account for the improved safety profile and therapeutic index of WTX-124 compared to HD IL-2 Preliminary PK findings: • WTX-124 dosed at 18 mg IV Q2W has a ~1.5-fold higher Cmax than HD IL-2 • Peak f

  19. Slide 19: WTX-124 Treatment Causes Dose Dependent Increases in Intratumoral T-cell Activation

    ©2025 WEREWOLF THERAPEUTICS19 | WTX-124 Treatment Causes Dose Dependent Increases in Intratumoral T-cell Activation Note: Data presented for patients for whom on-treatment biopsies were available as of February 7, 2025. Treg gene Key insights from NanoString analysis of paired tumor biopsies: • Larg

  20. Slide 20: Preliminary WTX-124 Clinical Data Demonstrate Potential for Best-in-Class IL-2 Therapy

    ©2025 WEREWOLF THERAPEUTICS20 | Preliminary WTX-124 Clinical Data Demonstrate Potential for Best-in-Class IL-2 Therapy ©2025 WEREWOLF THERAPEUTICS Abbreviations: SOC-standard of care; ICI-immune checkpoint inhibitor; CSCC-cutaneous squamous cell carcinoma; RDE-recommended dose for expansion  Monoth

  21. Slide 21: Development Strategy Designed to Realize WTX-124 Commercial Opportunity

    ©2025 WEREWOLF THERAPEUTICS21 | Fast to Market Indication Expansion Move Upstream Priority Indications: Engaging with FDA on potential registrational path for monotherapy expansion indications in 2L+ melanoma, RCC, CSCC Other IO-Sensitive Tumors: Development in additional indications in expansion ba

  22. Slide 22: WTX-124 Has Opportunity to Address Unmet Need Within Four Priority Tumor Types

    ©2025 WEREWOLF THERAPEUTICS22 | Source: Bluestar analysis 1 Based on disclosed 2023 revenue for PD-(L)1 $4.1B $2.6B $8.3B $8.3B Melanoma CSCC PD-L1 ≥1% NSCLC RCC Future WTX-124 Development Plan WTX-124 has opportunity to address unmet need within four priority tumor types Market Size for Melanoma, C

  23. Slide 23: Market Potential in the US in Advanced/Metastatic Melanoma

    ©2025 WEREWOLF THERAPEUTICS23 | Market Potential in the US in Advanced/Metastatic Melanoma ~$4.1B Spanning 1L-3L US Incident Cases 14,500 1L Treatment (12,800 pts) 2L/3L Treatment (7,700) ~12,800 patients PD-1 monotherapy (KEYNOTE-006) Nivolumab + Ipilimumab (CheckMate- 067) Nivolumab + LAG3 (RELATI

  24. Slide 24: WTX-330

    ©2025 WEREWOLF THERAPEUTICS24 | # ©2025 WEREWOLF THERAPEUTICS WTX-330

  25. Slide 25: WTX-330: Key Opportunities and the IL-12 Challenge

    ©2025 WEREWOLF THERAPEUTICS25 | Key Opportunities • Enable patients to benefit from IL-12 therapy for the first time through improved tolerability • Leverage IL-12 biology to address a significant unmet medical need for patients with poorly immunogenic tumors or tumors resistant to SOC immunotherapi

  26. Slide 26: INDUKINE Delivers IL-12 Selectively to Tumor Tissue with an Improved Therapeutic Index

    ©2025 WEREWOLF THERAPEUTICS26 | MC38 tumor model mWTX-330 Vehicle Vehicle mWTX-330WTX-124 -1 0 1 mWTX-330 WTX-124 172 122 296 Differential Gene Signatures  Intratumoral IL-12 pathway activation  Activation of multiple antigen presentation mechanisms  Th1 lineage skewing  Treg fragility  Increas

  27. Slide 27: WTX-330 Phase 1 FIH Clinical Trial – WTX-330x2101 (Completed)

    ©2025 WEREWOLF THERAPEUTICS27 | WTX-330 Phase 1 FIH Clinical Trial – WTX-330x2101 (Completed) Twenty-five patients received at least one dose of WTX-330 to date (n=11 in escalation, n=14 in expansion) Trial Details Bayesian logistic regression model study design Monotherapy escalation followed by tw

  28. Slide 28: WTX-330x2101 FIH Patient Population was Heterogeneous and Heavily Pretreated

    ©2025 WEREWOLF THERAPEUTICS28 | WTX-330x2101 FIH Patient Population was Heterogeneous and Heavily Pretreated AGE (years) Mean (SD) 64.4 (9.4) Median 64.0 SEX, n (%) Female 12 (48.0%) Male 13 (52.0%) RACE, n (%) Black/African- American 2 (8.0%) White 21 (84.0%) Other/ Unknown 2 (8.0%) Demographics Tu

  29. Slide 29: WTX-330 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting

    ©2025 WEREWOLF THERAPEUTICS29 | WTX-330 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting Related TEAEs were primarily mild to moderate including at clinically active doses Key safety findings: • Most frequent related TEAEs were CRS1, chills, pyrexia and elevated liver function

  30. Slide 30: Early Signs of Clinical Antitumor Activity Across Solid Tumor Indications

    ©2025 WEREWOLF THERAPEUTICS30 | Microsatellite-stable colorectal cancer (MSS CRC) and other GI malignancies • 50-year-old man who had progressed on seven prior lines of therapy including investigational immunotherapies had stable disease for 24 weeks • 61-year-old woman who had progressed on SOC che

  31. Slide 31: WTX-330 Demonstrated Monotherapy Clinical Activity Across Diverse Tumor Types

    ©2025 WEREWOLF THERAPEUTICS31 | WTX-330 Demonstrated Monotherapy Clinical Activity Across Diverse Tumor Types One patient with a confirmed PR (RECIST 1.1) and an additional seven patients with stable target lesions (n=15)1 Abbreviations: MSS-microsatellite stable; CRC-colorectal cancer; NET-neuroend

  32. Slide 32: Treatment Response in Melanoma Patient with a Confirmed RECIST PR

    ©2025 WEREWOLF THERAPEUTICS32 | Treatment Response in Melanoma Patient with a Confirmed RECIST PR 76-year-old woman with a BRAF wild type metastatic in-transit melanoma who progressed while receiving adjuvant pembrolizumab Patient had diffuse RLE cutaneous metastases, a non-healing melanomatous ulce

  33. Slide 33: Evidence of Durable Treatment Effect in Melanoma Patient with Confirmed PR

    ©2025 WEREWOLF THERAPEUTICS33 | Evidence of Durable Treatment Effect in Melanoma Patient with Confirmed PR Pretreatment Post-treatment Medial RLE Lateral RLE At 28 weeks, approximately 12 weeks after discontinuing WTX-330, the patient was noted to have an ongoing response at a subset of lesions (off

  34. Slide 34: WTX-330 Increased Expression of T/NK Cell Activation & Antigen Presentation Genes

    ©2025 WEREWOLF THERAPEUTICS34 | WTX-330 Increased Expression of T/NK Cell Activation & Antigen Presentation Genes NanoString data show evidence of pleotropic IL-12 activities in the tumor microenvironment, including in MSS CRC Abbreviations: IFN-interferon; MSS-microsatellite stable; CRC-colorectal

  35. Slide 35: WTX-330 Increased Intratumoral T and NK Cell Expansion and Activation in MSS CRC

    ©2025 WEREWOLF THERAPEUTICS35 | WTX-330 Increased Intratumoral T and NK Cell Expansion and Activation in MSS CRC Pretreatment On-treatment 102-101 MSS CRC Retroperitoneal lymph node Overall response: SD x 24wks 106-104 MSS CRC Liver metastasis Overall response: PD CD8 GRZB IFNγ NK Abbreviations: NK-

  36. Slide 36: WTX-330 Delivered 22-fold Greater IL-12 to Patients Compared to rhIL-12 Therapy

    ©2025 WEREWOLF THERAPEUTICS36 | WTX-330 Delivered 22-fold Greater IL-12 to Patients Compared to rhIL-12 Therapy PK data account for the improved therapeutic index of WTX-330 compared to rhIL-12 Preliminary PK findings: • WTX-330 dosed at 0.024 mg/kg IV Q2W has a ~22-fold higher Cmax than rhIL-12 at

  37. Slide 37: Decreasing Peripheral IFNγ Levels with WTX-330 Dosing Correlate with Improved Tolerability

    ©2025 WEREWOLF THERAPEUTICS37 | Decreasing Peripheral IFNγ Levels with WTX-330 Dosing Correlate with Improved Tolerability C1D 1 P re C1D 2 C1D 3 C2D 1 C2D 2 C2D 3 0 5000 10000 15000 20000 80000 100000 120000 140000 IFNγ IF N γ (p g/ m L) 0.016 mg/kg 0.032 mg/kg 0.024 mg/kg Analysis of plasma IFNγ l

  38. Slide 38: WTX-330 Phase 1b/2 Clinical Trial (Actively Enrolling)

    ©2025 WEREWOLF THERAPEUTICS38 | WTX-330 Phase 1b/2 Clinical Trial (Actively Enrolling) This clinical trial (WTX-330x2102), is a follow-on to the WTX-330 FIH Phase 1 clinical trial (WTX-330x2101) Trial Details Phase 1 portion to drive choice of optimal regimen Results of the Fixed Dose Finding will i

  39. Slide 39: WTX-330 Clinical Data Summary

    ©2025 WEREWOLF THERAPEUTICS39 | Abbreviations: MTD-maximum tolerated dose; TEAE-treatment-emergent adverse events; AE-adverse event; MSS-microsatellite stable; CRC-colorectal cancer; PR-partial response; TME-tumor microenvironment ©2025 WEREWOLF THERAPEUTICS  First systemically administered IL-12 t

  40. Slide 40: T Cell Engagers

    ©2025 WEREWOLF THERAPEUTICS40 | # ©2025 WEREWOLF THERAPEUTICS T Cell Engagers

  41. Slide 41: INDUCER Molecules Employ Werewolf's PREDATOR Platform for TCE Design

    41 | ©2025 WEREWOLF THERAPEUTICS Applying Innovative Protein Therapeutics Design to Inflammatory DiseasesINDUCER Molecules Employ Werewolf’s PREDATOR Platform for TCE Design TCE Challenges • Cytokine Release Syndrome (CRS) and various "on-target, off- tumor" organ adverse effects (dose- limiting tox

  42. Slide 42: Werewolf's Proprietary αCD3 Masking Provides TCEs with Differentiated Silencing

    ©2025 WEREWOLF THERAPEUTICS42 | Werewolf’s Proprietary αCD3 Masking Provides TCEs with Differentiated Silencing In Vivo Cytokine Release Assay (IL-6) Tumor Antigen A Tumor Antigen B Tumor Antigen C In Vitro Cell Killing Assays αCD3 masking prevents cytokine release in mouse models αCD3 masking of T

  43. Slide 43: WTX-712

    ©2025 WEREWOLF THERAPEUTICS43 | # ©2025 WEREWOLF THERAPEUTICS WTX-712

  44. Slide 44: WTX-712: Expanding the Utility of IL-21 Therapy

    ©2025 WEREWOLF THERAPEUTICS44 | WTX-712: Expanding the Utility of IL-21 Therapy Potential WTX-712 Advantages • IL-21 is a differentiated, pleiotropic cytokine that drives effective antitumor response by activating multiple immune cell types • Recombinant IL-21 has shown clinical antitumor activity b

  45. Slide 45: IL-21 Elicits a Highly Effective CD8+ T Cell Response in ICI-Refractory Preclinical Models

    ©2025 WEREWOLF THERAPEUTICS45 | IL-21 Elicits a Highly Effective CD8+ T Cell Response in ICI-Refractory Preclinical Models Sullivan JM et al., AACR 2024 Poster: WTX-712, a Conditionally Active IL-21 INDUKINETM Molecule, Induces a Strong antitumor Phenotype Through a Differentiated Mechanism Abbrevia

  46. Slide 46: WTX-712 Tumor Selective Activity Results in Robust Antitumor Immune Activation

    ©2025 WEREWOLF THERAPEUTICS46 | WTX-712 Tumor Selective Activity Results in Robust Antitumor Immune Activation in Preclinical Models Sullivan JM et al., AACR 2023 Poster: Generation of IL-21 INDUKINETM Molecules for the Treatment of Cancer Sullivan JM et al., SITC 2023 Poster: Development of WTX-712

  47. Slide 47: WTX-518

    ©2025 WEREWOLF THERAPEUTICS47 | # ©2025 WEREWOLF THERAPEUTICS WTX-518

  48. Slide 48: WTX-518: Regulating Multiple Immune Cell Types to Drive Antitumor Immunity

    ©2025 WEREWOLF THERAPEUTICS48 | WTX-518: Regulating Multiple Immune Cell Types to Drive Antitumor Immunity Potential WTX-518 Advantages • IL-18 elicits an antitumor immune response by promoting the collaboration of multiple immune cell types and increasing stem-like CD8+ T cells • WTX-518 is designe

  49. Slide 49: WTX-518 is Resistant to IL-18 Binding Protein with Improved Antitumor Activity

    ©2025 WEREWOLF THERAPEUTICS49 | WTX-518 is Resistant to IL-18 Binding Protein with Improved Antitumor Activity Abbreviations: BPR-binding protein resistant; TME-tumor microenvironment WTX-518 retains potency while preventing binding to IL-18BP BPR mIL-18 INDUKINE provides greater efficacy than wild-

  50. Slide 50: BPR mIL-18 INDUKINE Treatment Promotes Robust Effector Activation and Immune Cell Interactions

    ©2025 WEREWOLF THERAPEUTICS50 | Veh icl e BPR IL -18 IN DUKINE 0 20 40 60 80 100 Polyfunctional NK Cells N K C el l % P ro du ci ng ≥ 3 Ef fe ct or C yt ok in es ✱✱✱✱ BPR mIL-18 INDUKINE increases density of polyfunctional effector cells Veh icl e BPR m IL-18 IN DUKINE 0 500 1000 1500 Polyfunctional

  51. Slide 51: WTX-921

    ©2025 WEREWOLF THERAPEUTICS51 | # ©2025 WEREWOLF THERAPEUTICS WTX-921

  52. Slide 52: WTX-921: IL-10 INDUKINE Therapy for Inflammatory Bowel Disease

    ©2025 WEREWOLF THERAPEUTICS52 | WTX-921: IL-10 INDUKINE Therapy for Inflammatory Bowel Disease Potential WTX-921 Advantages • Selective delivery of IL-10 to inflamed tissues to minimize systemic toxicity • Multipronged effect by inhibiting disease driving innate and adaptive immune cell populations

  53. Slide 53: WTX-921 Treatment Inhibits Disease in Mouse ACT Model of IBD

    ©2025 WEREWOLF THERAPEUTICS53 | WTX-921 Treatment Inhibits Disease in Mouse ACT Model of IBD Abbreviations: ACT-adoptive cell transfer; IBD-inflammatory bowel disease IL-10 INDUKINE treatment blocks disease as measured by multiple metrics 0 5 10 15 20 25 30 35 40 80 90 100 110 120 Weight Change Days

  54. Slide 54: WTX-921 Treatment Inhibited Disease in Mouse ACT Model of IBD

    ©2025 WEREWOLF THERAPEUTICS54 | WTX-921 Treatment Inhibited Disease in Mouse ACT Model of IBD IL-10 INDUKINE treatment prevents immune cell expansion/activation and tissue destruction Abbreviations: ACT-adoptive cell transfer; IBD-inflammatory bowel disease; H&E-hematoxylin and eosin; IF-immunofluor

  55. Slide 55: Shifting the Balance in Cytokine Therapeutics

    ©2025 WEREWOLF THERAPEUTICS55 | Shifting the Balance in Cytokine Therapeutics PREDATOR Platform: Value Creation Engine Our protein engineering technology optimizes the design of conditionally activated cytokine therapeutics (INDUKINE molecules) to diseased tissues. Opportunity to pursue other modali

  56. Slide 56: Experienced Leadership

    ©2025 WEREWOLF THERAPEUTICS56 | Experienced Leadership Daniel J. Hicklin, PhD President and CEO Randi E. Isaacs, MD Chief Medical Officer Steven Bloom Chief Business Officer Tim Trost, CPA Chief Financial Officer Chulani Karunatilake, PhD Chief Technology Officer William Winston, PhD Senior Vice Pre

  57. Slide 57: Thank you!

    ©2025 WEREWOLF THERAPEUTICS57 | Thank you!

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