Werewolf Therapeutics, Inc. · NASDAQ:HOWL
Werewolf Therapeutics — Investor Presentation (November 2024)
53 slides from Werewolf Therapeutics's investor presentation, Nov 12, 2024
Slide 1: Delivering the Power of Immunotherapy
Exhibit 99.1 Delivering the Power of Immunotherapy CORPORATE PRESENTATION | November 2024 1 | ©2024 WEREWOLF THERAPEUTICS
Slide 2: Cautionary Statements
Cautionary Statements This presentation contains forward-looking statements that involve substantial risks and uncertainties inherent in the development of product candidates, including the conduct uncertainties. All statements, other than statements of historical facts, contained in this of researc
Slide 3: Who we are
Who we are Our mission is to unlock the promise of cytokines as effective immunotherapies Werewolf is developing next generation cytokine therapies designed to harness their innate immunological potential to transform the lives of patients with cancer and other serious diseases. 3 | 3 | © ©2024 2024
Slide 4: Clinical-Stage Biopharma Company – Next Generation Conditionally Activated Therapies
Clinical-Stage Biopharma Company – Next Generation Conditionally Activated Therapies Strong Foundation Robust Discovery Engine Clinical Focus PREDATOR® Platform TM Disciplined & Experienced Novel INDUKINE molecules High-Value Opportunities Validated & Differentiated Tunable, tissue-targeted INDUKINE
Slide 5: Overcoming Off-Target Toxicity has been a Key Challenge for Cytokine Therapy
Overcoming Off-Target Toxicity has been a Key Challenge for Cytokine Therapy The Challenge: Our Solution: Off-Tumor Cytokine Toxicity Limits Conditionally Activated Therapeutic Index Immunotherapy Suboptimal Pharmaceutical Properties With Optimized Therapeutic Index Tumor Activated cytokine INDUKINE
Slide 6: PREDATOR Platform
PREDATOR Exposure Platform Half-life extension Selectivity Tumor activation Tunable, Tissue-targeted Therapeutics for Cancer Potency Native Cytokine and other Diseases INDUKINE molecules contain multiple Safety domains, each with a unique function that Peripheral inactivation can be ‘tuned’ for spec
Slide 7: A Portfolio of Novel Clinical and Preclinical Drug Candidates
A Portfolio of Novel Clinical and Preclinical Drug Candidates ANTICIPATED PROGRAM INDICATIONS DISCOVERY IND-ENABLING PHASE 1 PHASE 2 MILESTONES Advanced or Metastatic Solid Tumors Initial data readout from WTX-124 monotherapy expansion Monotherapy and in combination IL-2 INDUKINE Molecule expected i
Slide 8: WTX-124
# WTX-124 8 8 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Slide 9: WTX-124: Improving the Efficacy and Tolerability of IL-2
WTX-124: Improving the Efficacy and Tolerability of IL-2 THE CHALLENGE Approved high-dose IL-2 therapy (HD IL-2) with aldesleukin (Proleukin®) produces durable responses in patients with cutaneous melanoma and renal cell carcinoma, but its use is limited by severe toxicity Unique Advantages of WTX-1
Slide 10: Goal to Significantly Expand Patient Populations Who Might Benefit from IL-2
Goal to Significantly Expand Patient Populations Who Might Benefit from IL-2 But most patients don’t receive HD IL-2 has potential for profound HD IL-2 due to toxicity patient benefit Malignant Malignant Renal 10% Complete Response Melanoma Cell Carcinoma 9% Partial Response 8% 7% 6% 5% 80+ Months 5
Slide 11: WTX-124 Delivers IL-2 Selectively to Tumors in Preclinical Models
WTX-124 Delivers IL-2 Selectively to Tumors in Preclinical Models Released IL-2 expands and activates antitumor CD8+ T effector cells preferentially over Tregs Plasma Tumor WTX-124 INDUKINE IL-2 MC38 mice WTX-124 dosed on Day 1 and 4 (50 µg) Vehicle WTX-124 Abbreviation: TIL-tumor infiltrating lymph
Slide 12: INDUKINE Molecule Strategy Markedly Improves the Therapeutic Window for IL-2
INDUKINE Molecule Strategy Markedly Improves the Therapeutic Window for IL-2 Incorporation of wild type IL-2 in WTX-124 is required for complete tumor regressions and immune memory formation WTX-124 activates long-term antitumor immune memory Improved therapeutic window compared to recombinant IL-2
Slide 13: Data from Ongoing WTX-124 Phase 1/1b Study in ICI-treated Patient Population
Data from Ongoing WTX-124 Phase 1/1b Study in ICI-treated Patient Population Safety Clinical Activity • Generally well tolerated in the outpatient setting • Objective responses at WTX-124 doses ≥12 mg • No evidence of vascular leak syndrome, cytokine Ø Confirmed, durable CR in patient with CSCC rele
Slide 14: WTX-124 Monotherapy and Combination Expansion Arms are Open and Enrolling
WTX-124 Monotherapy and Combination Expansion Arms are Open and Enrolling 67 patients have received at least one dose of WTX-124 (n=47 monotherapy, n=20 combination therapy)* Monotherapy/Combination Dose Expansion MONOTHERAPY DOSE ESCALATION Advanced or metastatic (to be Determination 28 mg of WTX-1
Slide 15: WTX-124 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting
WTX-124 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting Key Safety Findings: Frequency of related TEAEs • Most frequent related TEAEs occurring in were arthralgia, fatigue, pruritis more than and eosinophilia one patient • Majority of related TEAEs were Grade 1 and 2, Grade 3
Slide 16: WTX-124 Monotherapy Induced Rapid, Durable Regressions of Target Lesions
WTX-124 Monotherapy Induced Rapid, Durable Regressions of Target Lesions All three objective responses to WTX-124 monotherapy occurred within two cycles (~8 weeks) Gastroesophageal junction * tumor (18 mg) Cutaneous squamous cell Melanoma (12 mg) carcinoma (12 mg) * Three patients had objective resp
Slide 17: Complete Response Ongoing at 12+ Months in a Patient with ICI-Refractory Cutaneous SCC
June 2023: PET-CT at time of September 2023: Baseline CT Complete Response (CR) Ongoing at 12+ Months in a progression on cemiplimab performed at study entry Patient with ICI-Refractory Cutaneous SCC T NT 72-year-old man with metastatic cutaneous SCC who progressed on RT/cetuximab and had no respons
Slide 18: WTX-124 in Combination with Pembrolizumab Demonstrates Durable Responses
WTX-124 in Combination with Pembrolizumab Demonstrates Durable Responses in ICI-treated Patients Dose Indication Prior therapies Response Status Response DL Tumor Type Prior Therapies Dose Duration • 3w: Increased T cell activation (biopsy) • 8w: 28.7% ↓ of both TLs • Treatment ongoing >7m 1. Pembro
Slide 19: INDUKINE Strategy Successfully Delivers IL-2 to the TME with Low Plasma Exposures
INDUKINE Strategy Successfully Delivers IL-2 to the TME with Low Plasma Exposures Data support the improved therapeutic index and safety profile 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 free IL-2 exposure
Slide 20: WTX-124 Caused Dose Dependent Increases in Intratumoral T-cell Activation
WTX-124 Caused Dose Dependent Increases in Intratumoral T-cell Activation by NanoString Top 40 Key insights from tumor upregulated biomarkers: T-cell activation genes across all • Largest changes seen at 18 mg monotherapy (monotherapy) and 12 mg dose levels (combination) • Upregulation of GRZB and I
Slide 21: Preliminary WTX-124 Clinical Data Demonstrate Potential for Best-in-Class IL-2 Therapy
Preliminary WTX-124 Clinical Data Demonstrate Potential for Best-in-Class IL-2 Therapy Key Takeaways ü Monotherapy activity and an improved tolerability profile demonstrated in heavily pretreated patients refractory to all SOC therapies, including immune checkpoint inhibitors ü Combinations with ICI
Slide 22: Development Strategy Designed to Realize WTX-124 Commercial Opportunity
Development Strategy Designed to Realize WTX-124 Commercial Opportunity Priority Indications: Engaging with FDA on potential registrational path Fast to Market for monotherapy expansion indications in 2L+ melanoma, RCC, CSCC Other IO-Sensitive Tumors: Indication Expansion Development in additional i
Slide 23: WTX-330
# WTX-330 23 23 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Slide 24: WTX-330: Leveraging the Potential of IL-12 Therapy to Address IO Resistance
WTX-330: Leveraging the Potential of IL-12 Therapy to Address IO Resistance THE CHALLENGE IL-12 is a potent, pleiotropic cytokine that could address a substantial unmet medical need for patients who are resistant to SOC immunotherapies. Unfortunately, systemic administration of recombinant human IL-
Slide 25: INDUKINE Delivers IL-12 Selectively to Tumor Tissue with an Improved Therapeutic Index
INDUKINE Delivers IL-12 Selectively to Tumor Tissue with an Improved Therapeutic Index Activation of antitumor CD8+ T effector cells & pleiotropic immune activation in the TME in preclinical models MC38 tumor model Vehicle mWTX-330 Vehicle WTX-124 mWTX-330 Therapeutic Window WTX-124 Differential Gen
Slide 26: WTX-330 FIH study: Study Design and Status Update
WTX-330 FIH study: Study Design and Status Update Twenty-five patients have received at least one dose of WTX-330 to date (n=11 in escalation, n=14 in expansion) Monotherapy Dose Escalation Dose Expansion Patients with solid tumors relapsed/refractory to all SOC ARM A: Patients with IO-sensitive sol
Slide 27: WTX-330 FIH Patient Population was Heterogeneous and Heavily Pretreated
WTX-330 FIH Patient Population was Heterogeneous and Heavily Pretreated Demographics Tumor Types Prior Therapies 1 Prior lines for metastatic disease Eligible patients had relapsed solid n (%) tumors refractory to all SOC AGE (years) Mean (SD) 64.4 (9.4) 0 3 (12.0%) n (%) 1 3 (12.0%) Median 64.0 CRC
Slide 28: WTX-330 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting
WTX-330 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting Key safety findings: Frequency of related TEAEs • Most frequent related TEAEs were 1 occurring in CRS , pyrexia, chills, fatigue, and elevated liver function test more than abnormalities one patient • Gr3 and Gr4 related
Slide 29: Decreasing Peripheral IFNγ Levels with WTX-330 Dosing Correlate with Improved Tolerability
Decreasing Peripheral IFNγ Levels with WTX-330 Dosing Correlate with Improved Tolerability Analysis of plasma IFNγ levels after IFNγ WTX-330 dosing showed: 0.016 mg/kg 0.024 mg/kg • Dose-related IL-12 induction of IFNγ after 140000 the first dose 0.032 mg/kg 120000 • IFNγ “tachyphylaxis” beyond the
Slide 30: Early Signs of Clinical Antitumor Activity Across Solid Tumor Indications
Early Signs of Clinical Antitumor Activity Across Solid Tumor Indications Metastatic cutaneous melanoma Microsatellite-stable colorectal cancer (MSS CRC) and other GI malignancies • 76-year-old woman with diffuse melanoma in- transit metastases who had progressed on adjuvant • 50-year-old man who ha
Slide 31: WTX-330 Demonstrated Monotherapy Clinical Activity Across Diverse Tumor Types
WTX-330 Demonstrated Monotherapy Clinical Activity Across Diverse Tumor Types 1 One patient with a confirmed PR (RECIST 1.1) and an additional seven patients with stable target lesions (n=15) Abbreviations: MSS-microsatellite stable; CRC-colorectal cancer; NET-neuroendocrine tumor; SCC-squamous cell
Slide 32: Treatment Response in Melanoma Patient with a Confirmed RECIST PR
Treatment Response in Melanoma Patient with a Confirmed RECIST PR March 2024 (pretreatment): May 2024: After three doses of 76 76- -ye yea ar r- -o old ld w wo om ma an with a n with a B BRA RAF F wild ty wild type pe m me et ta as st ta atic tic in in- -tr tra ans nsiit t Patient progressing at mel
Slide 33: Evidence of Durable Treatment Effect in Melanoma Patient with Confirmed PR
Evidence of Durable Treatment Effect in Melanoma Patient with Confirmed PR Pretreatment Post-treatment At 28 weeks, approximately 12 weeks after discontinuing WTX-330, the patient was noted to have an ongoing response at a subset of lesions Medial (off all therapy) RLE • Pretreatment (March 2024): P
Slide 34: WTX-330 Increased Expression of T/NK Cell Activation & Antigen Presentation Genes
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 Log2 fold change Changes in gene expression caused by WTX-330 demonstrating IL-12 activity: • Increased e
Slide 35: Additional Evidence of Increased T/NK cell Expansion and Activation in MSS CRC
Additional Evidence of Increased T/NK cell Expansion and Activation in MSS CRC Pretreatment On-treatment CD8+ Cell GrzB+CD8+ Cell GrzB+ NK Cell Density Density Density 102-101 150 8 1.5 1.75X 1.5X MSS CRC 6 100 1.0 Retroperitoneal lymph node 4 50 0.5 2 Overall response: 0 SD x 24wks 0 0.0 SCRN C1D22
Slide 36: WTX-330 Delivered 22-fold > IL-12 Compared to Recombinant Human IL-12 Therapy at its MTD
WTX-330 Delivered 22-fold > IL-12 Compared to Recombinant Human IL-12 Therapy at its MTD PK data account for the improved therapeutic index of WTX-330 compared to rhIL-12 PK profiles for WTX-330 and free IL-12 compared to Preliminary PK findings: rhIL-12 Cmax at its MTD (mean ± SEM) • WTX-330 dosed
Slide 37: WTX-330 is a Potentially First-in-Class Systemically Administered IL-12 Therapy
WTX-330 is a Potentially First-in-Class Systemically Administered IL-12 Therapy Key Takeaways ü First systemically administered IL-12 therapy with monotherapy clinical activity and a generally tolerable safety profile ü Increased therapeutic window: WTX-330 delivered 22-fold more IL-12 on a molar ba
Slide 38: WTX-712
# WTX-712 38 38 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Slide 39: WTX-712: Expanding the Utility of IL-21 Therapy
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 but has not been developed due to
Slide 40: IL-21 Elicits a Highly Effective CD8+ T Cell Response in ICI-Refractory Preclinical Models
IL-21 Elicits a Highly Effective CD8+ T Cell Response in ICI-Refractory Preclinical Models EMT-6 Renca IL-21 is active in several ICI refractory models and can provide greater antitumor activity than IL-2 Induction of effector molecules in CD8+ T cells Increased CD8+ T cell polyfunctionality* IL-21
Slide 41: WTX-712 Tumor Selective Activity Results in Robust Antitumor Immune Activation
WTX-712 Tumor Selective Activity Results in Robust Antitumor Immune Activation in Preclinical Models WTX-712 antitumor activity in MC38 tumor model with an IL-21 INDUKINE treatment transforms the tumor improved therapeutic window compared to IL-21 cytokine microenvironment with robust and rapid effe
Slide 42: WTX-518
# WTX-518 42 42 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Slide 43: WTX-518: Regulating Multiple Immune Cell Types to Drive Antitumor Immunity
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 designed to uniquely eliminate the abil
Slide 44: WTX-518 is Resistant to IL-18 Binding Protein with Improved Antitumor Activity
WTX-518 is Resistant to IL-18 Binding Protein with Improved Antitumor Activity BPR mIL-18 INDUKINE triggers tumor cytotoxicity and transforms the TME WTX-518 retains potency while BPR mIL-18 INDUKINE provides greater efficacy than wild-type IL-18 preventing binding to IL-18BP INDUKINE in the MC38 tu
Slide 45: BPR mIL-18 INDUKINE Treatment Promotes Robust Effector Activation and Immune Cell Interactions
BPR mIL-18 INDUKINE Treatment Promotes Robust Effector Activation and Immune Cell Interactions BPR mIL-18 INDUKINE BPR mIL-18 INDUKINE triggers the formation of immune increases density of cell hubs, including stem-like CD8+ T cells, driving the polyfunctional effector cells regression of establishe
Slide 46: WTX-921
# WTX-921 46 46 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Slide 47: WTX-921: IL-10 INDUKINE Therapy for Inflammatory Bowel Disease
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 • Targeted delivery of IL-10 can
Slide 48: WTX-921 Treatment Inhibits Disease in Mouse ACT Model of IBD
WTX-921 Treatment Inhibits Disease in Mouse ACT Model of IBD IL-10 INDUKINE treatment blocks disease as measured by multiple metrics Disease Activity Index 4 No colitis Vehicle WTX-921 3 Weight Change 2 **** 115 No colitis 1 Vehicle WTX-921 110 0 10 20 30 40 Days post transfer 105 Cytokines in the C
Slide 49: WTX-921 Treatment Inhibited Disease in Mouse ACT Model of IBD
WTX-921 Treatment Inhibited Disease in Mouse ACT Model of IBD IL-10 INDUKINE treatment prevents immune cell expansion/activation and tissue destruction Control-No Colitis Disease Induced-Vehicle Treated Disease Induced-INDUKINE Treated H&E IF DAPI CD45 iNOS MUC2 Abbreviations: ACT-adoptive cell tran
Slide 50: PREDATOR Platform Offers Value Creation through Pipeline Expansion and Partnering
PREDATOR Platform Offers Value Creation through Pipeline Expansion and Partnering Oncology-focused INDUKINE Therapeutics • Additional proinflammatory mechanisms • Cell-based therapies • mRNA therapies Expanding Conditional-Activation Technology to New Modalities • T cell engagers • Antibody drug con
Slide 51: Shifting the Balance in Cytokine Therapeutics
Shifting the Balance in Cytokine Therapeutics PREDATOR Platform: Value Creation Engine WTX-124 WTX-330 Our protein engineering technology optimizes the design Phase 1 of conditionally activated cytokine therapeutics (INDUKINE Phase 1/1b molecules) to diseased tissues. Clinical Trial Clinical Trial i
Slide 52: Experienced Leadership
Experienced Leadership Daniel J. Hicklin, PhD Randi E. Isaacs, MD Chulani Karunatilake, PhD Chief Medical Officer President and CEO Chief Technology Officer Ellen Lubman, MBA Tim Trost, CPA William Winston, PhD Chief Business Officer Chief Financial Officer Senior Vice President, Research 52 | ©2024
Slide 53: Thank you!
Thank you! 53 | ©2024 WEREWOLF THERAPEUTICS
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