Core Viewpoint - Werewolf Therapeutics, Inc. (HOWL) has been upgraded to a Zacks Rank 2 (Buy), indicating a positive outlook based on rising earnings estimates, which significantly influence stock prices [1][3]. Earnings Estimates and Stock Price Movement - The Zacks rating system emphasizes the correlation between changes in earnings estimates and stock price movements, making it a valuable tool for investors [2][4]. - An increase in earnings estimates typically leads to higher fair value calculations by institutional investors, resulting in buying or selling pressure that affects stock prices [4]. Company Performance and Investor Sentiment - The upgrade reflects an improvement in Werewolf Therapeutics' underlying business, which is expected to drive stock appreciation as investors recognize this positive trend [5]. - Over the past three months, the Zacks Consensus Estimate for Werewolf Therapeutics has increased by 6.6%, indicating a positive revision trend [8]. Zacks Rank System - The Zacks Rank system classifies stocks based on earnings estimate revisions, with only the top 20% of stocks receiving a 'Strong Buy' or 'Buy' rating, suggesting a strong potential for market-beating returns [9][10]. - The upgrade of Werewolf Therapeutics to a Zacks Rank 2 places it in the top 20% of Zacks-covered stocks, indicating a favorable position for potential stock price increases in the near term [10].

Core Insights - Werewolf Therapeutics, Inc. is an innovative biopharmaceutical company focused on developing conditionally activated therapeutics to stimulate the immune system for cancer treatment [3] - The company will participate in a fireside chat at the Jefferies Global Healthcare Conference on June 5, 2025, featuring CEO Daniel J. Hicklin and CMO Randi Isaacs [1][2] Company Overview - Werewolf Therapeutics leverages its proprietary PREDATOR® platform to create therapeutics that activate selectively in the tumor microenvironment while remaining inactive in peripheral tissues [3] - The company's advanced clinical candidates include WTX-124 and WTX-330, which are conditionally activated Interleukin-2 (IL-2) and Interleukin-12 (IL-12) molecules, respectively, aimed at treating solid tumors [3] - WTX-124 is being advanced in multiple tumor types both as a single agent and in combination with immune checkpoint inhibitors, while WTX-330 is being explored for various tumor types and Non-Hodgkin Lymphoma [3]

Core Insights - The investigational drug shows promise in treating advanced cutaneous squamous cell carcinoma, with a patient experiencing no detectable cancer after 12 weeks of treatment [1][2][3] - The incidence of cutaneous squamous cell carcinoma has tripled over the past three decades, highlighting the growing burden of this disease [7] Company Insights - HonorHealth Research Institute is conducting a clinical trial for a new drug designed to activate in the tumor microenvironment, offering hope for patients with limited treatment options [1][4][5] - Werewolf Therapeutics is pioneering the development of therapeutics that stimulate the immune system, utilizing its proprietary PREDATOR® platform to create conditionally activated molecules [11] Industry Insights - Approximately 1 million Americans are diagnosed with cutaneous squamous cell carcinoma annually, with nearly 7,000 fatalities occurring when the disease becomes advanced or metastatic [6] - Current treatment options for advanced cases are limited, particularly for patients who do not respond to checkpoint inhibitors [6][9]

Summary of Werewolf Therapeutics Conference Call Company Overview - Werewolf Therapeutics is a clinical stage biopharmaceutical company focused on developing conditionally activated biologics for cancer and other serious diseases. The company has engineered a pipeline of cytokine prodrugs, referred to as endokines, to address therapeutic index challenges associated with potent biologics [2][3] Core Programs - The lead endokine programs include: - WTX-124 (an interleukin-2 endokine) - WTX-330 (an interleukin-12 endokine) - The company has also developed T cell engagers called inducers, designed to address therapeutic index challenges of T cell engagers [3][19] Clinical Data and Efficacy - WTX-124 has completed dose escalation for both monotherapy and combination therapy with pembrolizumab, with a determined dose of 18 mg delivered IV every two weeks [5][6] - Expansion arms are open for indications including: - Cutaneous melanoma - Renal cell carcinoma - Cutaneous squamous cell carcinoma, where a patient achieved a complete response after failing standard treatment [6][7] - The company aims for an overall response rate above 20% for monotherapy and higher for combination therapy, with enrollment progressing well [11][12] Safety Profile - The safety profile of WTX-124 has shown no hallmark toxicities associated with high-dose IL-2, allowing for outpatient delivery to a broad patient population [9][10] Regulatory Pathway - The company plans to present data to the FDA in the coming quarters, seeking insights on both monotherapy and combination data for potential registration [13][14] Future Expectations - The company anticipates presenting updated interim data in Q4 2025, with a focus on both efficacy and safety metrics [9][22] - For WTX-330, the company has completed a first-in-human trial, showing a good safety profile and antitumor activity, with plans for further studies [16][17] Inducers Platform - The inducers platform aims to mask immune cell engagement to reduce cytokine release syndrome, enhancing the therapeutic index of T cell engagers [19][20] - The company plans to announce a development candidate for the inducers platform imminently [22] Conclusion - Werewolf Therapeutics is positioned for significant developments in the coming months, with a robust pipeline and promising clinical data that could lead to regulatory advancements and potential market opportunities [24][25]

Core Insights - Werewolf Therapeutics, Inc. is focused on developing conditionally activated therapeutics to enhance the immune system for cancer treatment and other immune-mediated conditions [1][2] - The company will present data on its IL-2 and IL-12 INDUKINE molecules at the Hanson Wade Cytokine-Based Drug Development Summit, showcasing the validation of its unique immunotherapy approach [2] Company Overview - Werewolf Therapeutics is leveraging its proprietary PREDATOR platform to create therapeutics that stimulate both adaptive and innate immunity, aiming to overcome the limitations of traditional proinflammatory immune therapies [2] - The company's INDUKINE molecules are designed to remain inactive in peripheral tissues and activate selectively within the tumor microenvironment [2] - The most advanced product candidates include WTX-124 and WTX-330, which are conditionally activated IL-2 and IL-12 molecules, respectively, targeting solid tumors and Non-Hodgkin Lymphoma [2] Upcoming Events - Sameer Chopra, M.D., Ph.D., Vice President of Clinical Development, will speak at the summit on May 15, 2025, at 4:15 PM ET, discussing the therapeutic index improvements of proinflammatory cytokines for cancer immunotherapy [2]

Summary of Werewolf Therapeutics Conference Call Company Overview - Werewolf Therapeutics was founded in 2017 with a focus on pro-inflammatory mechanisms, particularly cytokines [4][5] - The company aims to create tolerable drugs from cytokines, which have clinical activity but are associated with toxicity and poor pharmaceutical properties [5][6] - The platform developed is called the "predator platform," which utilizes fully potent wild type cytokines and protease-cleavable linkers to enhance therapeutic index and safety [8][9] Core Product Development - The most advanced product is WTX-124, which is currently in clinical trials with both monotherapy and combination therapy arms [20][21] - A flat dose of 18 mg of WTX-124 has been established for dose expansion arms, with ongoing trials in melanoma, renal cell cancer, and cutaneous squamous cell carcinoma [20][21][22] - Early data shows dramatic activity, including a complete response in a patient who failed standard care [22][23] Clinical Trial Insights - The company has demonstrated early monotherapy activity and dose-dependent biomarker responses, which were not shown by other companies [23][24] - The focus is on both monotherapy and combination therapy, with plans to present data to the FDA for potential accelerated approval [27][34] - Enrollment for the melanoma monotherapy expansion arm is expected to be completed by the end of the current quarter [27] Future Directions - The company is also developing an IL-10 for inflammatory bowel disease (IBD) and a T cell engager (TCE) platform, indicating a diversification beyond oncology [9][42][44] - The IL-12 program aims to tackle cold tumors and has shown promising preclinical results [37][38] - Werewolf is actively seeking partnerships to advance its IBD program and has previously partnered with Jazz Pharmaceuticals for another molecule [48][50] Financial Position - As of March, the company reported a cash position of $92 million, which is expected to last until the fourth quarter of 2026, covering important upcoming events [51]

Financial Performance - Total revenue for the three months ended March 31, 2025 was $0, a decrease from $0.7 million recognized in the same period of 2024 [109]. - Net loss for the three months ended March 31, 2025 was $18.1 million, compared to a net loss of $16.2 million in the same period of 2024 [108]. - Interest income decreased to $1.0 million for the three months ended March 31, 2025, down from $2.0 million in 2024, attributed to lower cash equivalents held [112]. - Interest expense increased to $1.3 million for the three months ended March 31, 2025, compared to $1.0 million in 2024, due to a higher effective interest rate under the K2HV Loan Agreement [113]. - The accumulated deficit as of March 31, 2025 was $432.7 million, with expectations of continued substantial losses in the foreseeable future [115][118]. - Net cash used in operating activities for Q1 2025 was $18.9 million, an increase of $3.7 million compared to $15.3 million in Q1 2024, primarily due to decreased revenue and increased interest expenses [137]. - The company reported a net decrease in cash, cash equivalents, and restricted cash of $18.9 million for the three months ended March 31, 2025 [136]. Research and Development - The company reported external development costs totaling $6,927,000 for the three months ended March 31, 2025, compared to $6,637,000 for the same period in 2024, reflecting an increase in investment in product candidates [98]. - Research and development expenses increased to $13.1 million for the three months ended March 31, 2025, compared to $12.9 million in 2024, primarily due to a $1.0 million increase in clinical trial costs [110]. - Research and development expenses are expected to increase substantially as the company progresses clinical trials and continues preclinical development of multiple product candidates [98]. - WTX-124 is currently in a Phase 1/1b clinical trial, with a recommended dose of 18 mg administered intravenously every two weeks, and interim data is expected to be presented in the second half of 2025 [87]. - WTX-330 completed Phase 1 clinical trials in Q1 2025, with updated safety and efficacy data presented in November 2024, and a Phase 1b/2 trial initiated in Q2 2025 [88]. - The company is developing WTX-712, WTX-518, and WTX-921, with WTX-712 showing a unique mechanism that activates tumor-specific T lymphocytes [89]. - The PREDATOR platform is being utilized to develop conditionally activated immune cell engagers, with the first INDUCER development candidate expected to be nominated in Q2 2025 [92]. Collaboration and Funding - The company has entered into a global collaboration with Jazz Pharmaceuticals for the development of the JZP898 INDUKINE molecule, with Jazz responsible for commercialization activities [93]. - The company has received $20.0 million in payments from Jazz under the Collaboration Agreement and is eligible for up to $1.255 billion in additional milestone payments [130]. - The company anticipates needing substantial additional funding to support ongoing operations and growth strategies [119]. - The company anticipates needing additional funding to complete the development of product candidates WTX-124 and WTX-330, as current cash resources are insufficient [133]. - The K2HV Loan Agreement provides up to $60.0 million in term loans, with $30.0 million received at closing and additional tranches available based on certain milestones [122]. - The term loan matures on May 1, 2028, with an interest rate of at least 10.3% or a variable rate based on the prime rate plus 1.8% [123]. - The company may consider equity or debt financing to fund operations, which could lead to dilution for shareholders or impose operational restrictions [134]. Administrative Expenses - General and administrative expenses decreased to $4.9 million for the three months ended March 31, 2025, down from $5.0 million in 2024, mainly due to a reduction in professional services fees [111]. - The company expects general and administrative expenses to increase as personnel headcount grows to support research and development activities [103]. Operational Outlook - Future revenue generation will depend on achieving various development and regulatory milestones, with potential fluctuations based on product sales and collaborations [96]. - The company’s operating expenditures will depend on the progress and costs associated with clinical trials and product development [132]. - The estimated total base rent payments for the office and laboratory lease expiring in May 2030 are approximately $12.7 million [142]. - The company did not sell any shares under the ATM Offering during the three months ended March 31, 2025, after raising $20.2 million in the previous period [139].

Corporate Overview [Company Highlights](index=3&type=section&id=Company%20Highlights) Werewolf Therapeutics is a clinical-stage biopharmaceutical company developing next-generation, conditionally activated immunotherapies, leveraging its PREDATOR® platform to create INDUKINE™ molecules with an improved therapeutic index, and is well-capitalized with a cash runway into the fourth quarter of 2026 - The company's core technology is the **PREDATOR® platform**, which creates **conditionally activated INDUKINE™ molecules** to deliver potent cytokine payloads with an **improved therapeutic index**[6](index=6&type=chunk)[8](index=8&type=chunk) - Lead clinical programs are **WTX-124 (IL-2)**, a potential **best-in-class** product for immunotherapy-sensitive tumors, and **WTX-330 (IL-12)**, a potential **first-in-class** molecule for poorly immunogenic cancers[6](index=6&type=chunk) - The company has a deep preclinical pipeline including **WTX-712 (IL-21)**, **WTX-518 (IL-18)**, **WTX-921 (IL-10)**, and **IFNα** (licensed to Jazz), as well as **INDUCER™ T cell engagers**[7](index=7&type=chunk) | Financial Metric | Value | | :--- | :--- | | Cash and Cash Equivalents (as of Mar 31, 2025) | $92.0M | | Projected Cash Runway | Into 4Q 2026 | [PREDATOR® Platform Technology](index=4&type=section&id=PREDATOR%20Platform%20Technology) The PREDATOR® platform is designed to overcome the off-target toxicity that has historically limited cytokine therapies by creating conditionally activated immunotherapies selectively delivered and activated within the tumor microenvironment (TME), thereby optimizing the therapeutic index - The platform addresses the key challenge of **systemic cytokine toxicity** by enabling **targeted delivery** to the **tumor microenvironment** and **on-target immune activation**[9](index=9&type=chunk)[13](index=13&type=chunk) - The INDUKINE™ molecule design consists of four key components: - **Blocking Domain:** Ensures peripheral inactivation for safety - **Linker:** Proprietary tumor-activated linker provides selectivity - **Native Cytokine:** Delivers a potent antitumor immune response - **Anti-HSA:** Provides half-life extension for improved exposure[15](index=15&type=chunk) Pipeline and Programs [Pipeline Overview](index=6&type=section&id=Pipeline%20Overview) The company's pipeline includes two clinical-stage assets, WTX-124 (IL-2) and WTX-330 (IL-12), and a diverse preclinical portfolio, with key upcoming milestones including Phase 1/1b data for WTX-124 in 2H25 and the nomination of the first T cell engager development candidate in 2Q25 | Program | Indication | Stage | Anticipated Milestones | | :--- | :--- | :--- | :--- | | **WTX-124 (IL-2)** | Advanced/Metastatic Solid Tumors | **Phase 1/1b** | **P1/1b** mono/combo data in 2H25; Meet with FDA | | **WTX-330 (IL-12)** | Advanced/Metastatic Solid Tumors & Lymphoma | **Phase 1b/2** | Actively enrolling in **P1b/2** clinical trial | | **WTX-712 (IL-21)** | Cancer | IND-enabling | **IND-enabling studies** ongoing | | **WTX-518 (IL-18)** | Cancer | IND-enabling | **IND-enabling studies** ongoing | | **WTX-921 (IL-10)** | Inflammatory Disease (IBD) | Discovery | **Available for partnering** | | **INDUCER Molecules** | Cancer | Discovery | First Development Candidate nomination in **2Q25** | | **JZP898 (IFNα)** | Cancer | **Phase 1** | **Phase 1** FIH study ongoing (Partnered with Jazz) | [WTX-124 (IL-2 INDUKINE Molecule)](index=7&type=section&id=WTX-124%20(IL-2%20INDUKINE%20Molecule)) WTX-124 is a conditionally activated IL-2 prodrug designed to improve upon the efficacy and severe toxicity of high-dose IL-2, with Phase 1/1b data showing it is generally well-tolerated and demonstrates durable monotherapy and combination activity in heavily pretreated, ICI-refractory patients, aiming for a fast-to-market strategy [Rationale and Preclinical Data](index=8&type=section&id=WTX-124_Rationale_and_Preclinical_Data) WTX-124 aims to expand the use of IL-2 therapy to a broader patient population by selectively releasing wild-type IL-2 in the tumor microenvironment, leading to preferential activation of antitumor CD8+ T cells over Tregs, resulting in complete tumor regressions, immune memory, and a significantly improved therapeutic window - The goal is to provide a **safer IL-2 therapy** to patients with **ICI-sensitive tumors** who are ineligible for **high-dose IL-2** due to its **severe toxicity**[21](index=21&type=chunk)[23](index=23&type=chunk)[28](index=28&type=chunk) - Preclinical studies show WTX-124 selectively releases IL-2 in the tumor, leading to a **19.8x higher ratio** of **CD8+ Tetramer+ T cells** to **Tregs** in the tumor-draining lymph node compared to vehicle[29](index=29&type=chunk)[31](index=31&type=chunk) - WTX-124 demonstrated a **therapeutic window (TW) of >20**, a **significant improvement** over recombinant IL-2 which has a **TW of <4** in preclinical models[34](index=34&type=chunk) [Clinical Trial Design and Safety](index=12&type=section&id=WTX-124_Clinical_Trial_and_Safety) The Phase 1/1b trial for WTX-124 has completed dose escalation, establishing **18mg IV Q2W** as the recommended dose for expansion (RDE) for both monotherapy and combination with pembrolizumab, demonstrating general tolerability in the outpatient setting with no evidence of severe toxicities - Dose escalation is complete, with **18mg IV Q2W** selected as the **RDE** for both **monotherapy** and **combination therapy** expansion arms, which are actively enrolling[37](index=37&type=chunk) - WTX-124 was **generally well tolerated**, with **no evidence of vascular leak syndrome (VLS)**, **≥Grade 2 cytokine release syndrome (CRS)**, or infusion reactions. **No new safety signals** were observed in combination with pembrolizumab[40](index=40&type=chunk)[42](index=42&type=chunk) - The **most frequent related TEAEs** were arthralgia, fatigue, pruritus, and eosinophilia, with the majority being **Grade 1-2**[42](index=42&type=chunk) [Clinical Efficacy](index=15&type=section&id=WTX-124_Clinical_Efficacy) WTX-124 has shown compelling antitumor activity, inducing rapid and durable monotherapy responses, including a confirmed complete response (CR) in an ICI-refractory cutaneous squamous cell carcinoma (CSCC) patient ongoing for over 18 months, and producing durable partial and complete responses in melanoma patients in combination with pembrolizumab - Monotherapy induced **objective responses** in **3 out of 16 patients** (**ORR=18.75%**) at potential RDE doses, with responses occurring **within 8 weeks**[45](index=45&type=chunk) - A patient with **ICI-refractory metastatic CSCC** achieved a **confirmed CR** that has been ongoing for **over 18 months**, including **more than a year off therapy**[47](index=47&type=chunk)[49](index=49&type=chunk) | Dose | Tumor Type | Prior Therapies | Response (Combination with Pembrolizumab) | | :--- | :--- | :--- | :--- | | 12mg | Melanoma | Pembrolizumab, Ipilimumab/nivolumab, Nivolumab | Complete Response (CR) at 36 weeks | | 12mg | Melanoma | Pembrolizumab/propranolol, TVEC | Partial Response (PR) ongoing >8 months | [Pharmacokinetics (PK), Pharmacodynamics (PD), and Strategy](index=18&type=section&id=WTX-124_PK_PD_and_Strategy) Pharmacokinetic data confirm WTX-124's improved safety with peak free IL-2 exposure approximately **146-fold lower** than high-dose IL-2, while pharmacodynamic data show dose-dependent increases in intratumoral T-cell activation, supporting a fast-to-market development strategy in priority indications targeting a total market of **~$23 billion** - Peak free IL-2 exposure after an 18mg dose of WTX-124 is **~146-fold lower** than that of high-dose IL-2, while the prodrug Cmax is **~1.5-fold higher**, demonstrating **effective systemic shielding** and **half-life extension**[61](index=61&type=chunk)[62](index=62&type=chunk) - Paired tumor biopsies showed **dose-dependent upregulation** of **T-cell activation genes** (e.g., IL2RA, GZMB, LAG3), with **combination therapy** further enhancing the effect[63](index=63&type=chunk) - The development strategy includes: 1) **Fast to Market** in 2L+ melanoma, RCC, CSCC; 2) **Indication Expansion** to other IO-sensitive tumors; 3) **Moving Upstream** to combine with SOC in earlier lines[68](index=68&type=chunk) - The initial target market size for Melanoma, CSCC, RCC, and PD-L1 ≥1% NSCLC is estimated at **~$23 billion**[70](index=70&type=chunk)[71](index=71&type=chunk) [WTX-330 (IL-12 INDUKINE Molecule)](index=24&type=section&id=WTX-330%20(IL-12%20INDUKINE%20Molecule)) WTX-330 is a conditionally activated IL-12 prodrug designed to unlock the potent effects of IL-12 for treating IO-resistant tumors by overcoming historical toxicity limitations, with Phase 1 data demonstrating a manageable safety profile and monotherapy clinical activity, including a confirmed partial response in melanoma, leading to a follow-on Phase 1b/2 trial to optimize dosing and explore activity in selected tumor types [Rationale and Preclinical Data](index=25&type=section&id=WTX-330_Rationale_and_Preclinical_Data) WTX-330 aims to be the first successful systemically administered IL-12 therapy by addressing severe toxicities, with preclinical data showing selective IL-12 delivery to the tumor, activating antitumor CD8+ T cells and other immune pathways, resulting in a **49-fold improved therapeutic window** - The primary goal is to enable **IL-12 therapy** for patients with **poorly immunogenic** or **IO-resistant tumors** by **improving its tolerability**[77](index=77&type=chunk)[79](index=79&type=chunk) - Preclinically, WTX-330 demonstrated a **49x improved therapeutic window** over a chimeric IL-12 and induced **potent antitumor activity** and **pleiotropic immune activation** in the TME[80](index=80&type=chunk)[81](index=81&type=chunk) [Phase 1 FIH Trial and Safety](index=27&type=section&id=WTX-330_Clinical_Trial_and_Safety) The first-in-human (FIH) Phase 1 trial enrolled **25 patients** with diverse solid tumors, demonstrating that WTX-330 was generally well-tolerated with primarily mild to moderate, manageable, and reversible related TEAEs consistent with IL-12's mechanism of action, leading to an expansion dose set at **0.024 mg/kg** - The **FIH trial** enrolled **25 patients**, with **44%** having received **≥4 prior lines of therapy** for metastatic disease[83](index=83&type=chunk)[86](index=86&type=chunk) - **Most frequent related TEAEs** were CRS, chills, pyrexia, and elevated liver function tests. **Grade 3/4 TEAEs** were **manageable and reversible**[90](index=90&type=chunk) - Expansion arms were opened at **0.024 mg/kg**. **Two dose-limiting toxicities (DLTs)** were observed at the higher **0.032 mg/kg** dose, but a **maximum tolerated dose (MTD) was not reached**[90](index=90&type=chunk) [Clinical Efficacy and Pharmacodynamics (PD)](index=30&type=section&id=WTX-330_Clinical_Efficacy_and_PD) WTX-330 demonstrated monotherapy clinical activity, including a confirmed partial response in a melanoma patient and stable disease in MSS colorectal cancer patients, with pharmacodynamic data from tumor biopsies confirming on-target IL-12 activity through increased expression of T/NK cell activation genes and increased T and NK cell density, even in 'cold' tumors - A **confirmed PR (RECIST 1.1)** was achieved in a **melanoma patient** who had progressed on pembrolizumab. The response lasted **16 weeks**[92](index=92&type=chunk)[96](index=96&type=chunk) - **Stable disease** was observed for **16 and 24 weeks** in **two patients** with **microsatellite-stable colorectal cancer (MSS CRC)**[92](index=92&type=chunk) - NanoString analysis of tumor biopsies showed **increased expression** of **genes related to T-cell activation** (IFNG, CD8A), **cytolytic function** (GRZMB), and **antigen presentation**, confirming **IL-12 activity** in the TME[106](index=106&type=chunk)[109](index=109&type=chunk) - Multiplexed immunofluorescence in MSS CRC patients showed **increased density** of **CD8+ T cells** and **Granzyme B+ NK cells** post-treatment[110](index=110&type=chunk)[111](index=111&type=chunk) [Pharmacokinetics (PK) and Next Steps](index=36&type=section&id=WTX-330_PK_and_Next_Steps) Pharmacokinetic analysis shows WTX-330 delivered **22-fold greater** molar exposure of IL-12 compared to recombinant IL-12's MTD, with **~5-fold lower** peak free IL-12 levels, validating its improved therapeutic index, and a follow-on Phase 1b/2 trial is actively enrolling to optimize dosing and evaluate activity in melanoma, MSS colorectal cancer, and non-Hodgkin's lymphoma - WTX-330 at **0.024 mg/kg** achieved a **~22-fold higher Cmax** than rhIL-12 at its MTD, with **~5-fold lower peak free IL-12 exposure**, demonstrating an **improved therapeutic index**[113](index=113&type=chunk)[115](index=115&type=chunk) - **Peripheral IFNγ levels**, a marker of systemic IL-12 activity and toxicity, showed a **dose-related spike** after the first dose but **decreased with subsequent doses** ('tachyphylaxis'), correlating with **improved tolerability**[116](index=116&type=chunk)[119](index=119&type=chunk) - A new **Phase 1b/2 trial** (WTX-330x2102) is actively enrolling to determine an **optimal regimen** (fixed vs. step-up dosing) and explore expansion cohorts in **melanoma**, **MSS CRC**, and **advanced NHL**[120](index=120&type=chunk)[121](index=121&type=chunk) [Preclinical Pipeline](index=40&type=section&id=Preclinical%20Pipeline) Werewolf has a deep preclinical pipeline leveraging its PREDATOR® platform, including INDUCER™ molecules (conditionally activated T cell engagers), WTX-712 (IL-21), WTX-518 (IL-18), and WTX-921 (IL-10), targeting a range of mechanisms and indications from cancer to inflammatory diseases - **INDUCER™ Molecules (T Cell Engagers):** Applying the **PREDATOR platform** to create masked T cell engagers (TCEs) to mitigate **cytokine release syndrome (CRS)** and **on-target, off-tumor toxicity**. The first development candidate is expected to be nominated in **2Q25**[128](index=128&type=chunk)[18](index=18&type=chunk) - **WTX-712 (IL-21):** An **INDUKINE molecule** designed to deliver IL-21, a pleiotropic cytokine that activates multiple immune cells and shows preclinical activity in **ICI-refractory models**. Currently in **IND-enabling studies**[133](index=133&type=chunk)[137](index=137&type=chunk) - **WTX-518 (IL-18):** An **INDUKINE molecule** designed to be resistant to the natural inhibitor IL-18BP, potentially complementing **WTX-330 (IL-12)** due to known synergy. Currently in **IND-enabling studies**[152](index=152&type=chunk)[155](index=155&type=chunk) - **WTX-921 (IL-10):** An **INDUKINE molecule** for **inflammatory bowel disease (IBD)**, designed to selectively deliver the anti-inflammatory cytokine IL-10 to inflamed tissues. The program is **available for partnership**[167](index=167&type=chunk)[169](index=169&type=chunk) Summary and Outlook [Corporate Summary and Financial Position](index=55&type=section&id=Corporate%20Summary%20and%20Financial%20Position) Werewolf Therapeutics is strategically positioned with two wholly-owned clinical programs, a deep preclinical pipeline, and a validated platform technology, maintaining a strong financial position with **$92.0 million** in cash as of March 31, 2025, providing a cash runway into the fourth quarter of 2026 to support multiple near-term, value-enhancing catalysts - The company has **two lead, wholly-owned clinical programs**: **WTX-124 (Phase 1/1b)** and **WTX-330 (Phase 1b/2)**[178](index=178&type=chunk)[180](index=180&type=chunk) - A **deep preclinical pipeline** includes **INDUKINE molecules** for **IL-21**, **IL-18**, **IL-10**, and **INDUCER T cell engagers**[180](index=180&type=chunk) | Financial Snapshot | Value | | :--- | :--- | | **Cash and Cash Equivalents** (as of Mar 31, 2025) | $92.0M | | **Cash Runway** | Into 4Q 2026 | | **Shares Outstanding** (as of May 2, 2025) | ~44.9M | [Leadership](index=56&type=section&id=Leadership) The company is led by an experienced management team with deep expertise in immunotherapy research and development, business development, and finance - Key executives include: - **Daniel J. Hicklin, PhD** (President and CEO) - **Randi E. Isaacs, MD** (Chief Medical Officer) - **Chulani Karunatilake, PhD** (Chief Technology Officer) - **Steven Bloom** (Chief Business Officer) - **Tim Trost, CPA** (Chief Financial Officer) - **William Winston, PhD** (SVP, Research)[183](index=183&type=chunk)[184](index=184&type=chunk)

Core Insights - Werewolf Therapeutics is advancing its clinical-stage programs, particularly WTX-124 and WTX-330, with significant milestones expected in the second half of 2025 [2][6][4] - The company is also developing proprietary INDUCER T cell engager molecules, with a candidate expected to be nominated by the end of Q2 2025 [2][7] - Financial guidance indicates sufficient cash runway into Q4 2026, with cash and cash equivalents reported at $92.0 million as of March 31, 2025 [11][17] Clinical Development - WTX-124 is a conditionally activated Interleukin-2 (IL-2) molecule being evaluated as a monotherapy and in combination with pembrolizumab for various solid tumors [3][9] - WTX-330, an Interleukin-12 (IL-12) molecule, has initiated patient dosing in a Phase 1b/2 trial to optimize its exposure in the tumor microenvironment [4][6] - The company plans to present interim data from the WTX-124 trial in the second half of 2025, focusing on tolerability and response rates [6] Financial Performance - For Q1 2025, research and development expenses were $13.1 million, slightly up from $12.9 million in Q1 2024 [11][15] - General and administrative expenses decreased to $4.9 million in Q1 2025 from $5.0 million in Q1 2024 [11][15] - The net loss for Q1 2025 was $18.1 million, compared to a net loss of $16.2 million in the same period of 2024 [11][15] Strategic Initiatives - The company is launching an educational campaign in May to raise awareness about skin cancer and the differentiation of its therapeutics [2][6] - Werewolf's proprietary PREDATOR masking technology is designed to enhance the safety and efficacy of its T cell engagers by silencing peripheral activity [2][7]

Core Insights - Werewolf Therapeutics, Inc. announced the efficacy of its IL-10 INDUKINE molecule, WTX-921, in reducing tissue damage and inflammatory cytokine production in a mouse colitis model [1][3] - The findings provide a deeper understanding of WTX-921's anti-inflammatory effects on the immune landscape in the inflamed colon [1] Company Overview - Werewolf Therapeutics is focused on developing conditionally activated therapeutics aimed at stimulating the immune system for cancer and immune-mediated conditions [1][7] - The company utilizes its proprietary PREDATOR platform to design molecules that activate selectively in the tumor microenvironment, addressing limitations of conventional therapies [7] Product Development - WTX-921 is engineered to selectively deliver IL-10 to inflamed tissues, minimizing systemic toxicity while providing therapeutic exposure [6] - The molecule has shown potential in blocking disease-driving effector molecules and cytokines, impacting both innate and adaptive immune responses [6] Clinical Findings - The data presented at the AAI Annual Meeting indicate that WTX-921 effectively masks IL-10, preventing off-tissue effects and demonstrating efficacy in preventing weight loss and reducing Disease Activity Index (DAI) scores in a colitis model over four weeks [4][3] - The treatment resulted in decreased immune cell infiltration and reduced RNA levels of inflammatory cytokines in treated animals [4] Market Context - The CDC estimates that 7 million people worldwide had Inflammatory Bowel Disease (IBD) in 2024, highlighting the need for improved treatment options [3]