Werewolf Therapeutics(HOWL) - 2025 Q1 - Quarterly Results

Corporate Overview Company Highlights 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][8] - 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] - 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] | Financial Metric | Value | | :--- | :--- | | Cash and Cash Equivalents (as of Mar 31, 2025) | $92.0M | | Projected Cash Runway | Into 4Q 2026 | PREDATOR® Platform Technology 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][13] - 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] Pipeline and Programs Pipeline Overview 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) 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 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][23][28] - 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][31] - 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] Clinical Trial Design 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] - 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][42] - The most frequent related TEAEs were arthralgia, fatigue, pruritus, and eosinophilia, with the majority being Grade 1-2[42] 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] - 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][49] | 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 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][62] - 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] - 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] - The initial target market size for Melanoma, CSCC, RCC, and PD-L1 ≥1% NSCLC is estimated at ~$23 billion[70][71] WTX-330 (IL-12 INDUKINE Molecule) 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 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][79] - 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][81] Phase 1 FIH 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][86] - Most frequent related TEAEs were CRS, chills, pyrexia, and elevated liver function tests. Grade 3/4 TEAEs were manageable and reversible[90] - 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] Clinical Efficacy and Pharmacodynamics (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][96] - Stable disease was observed for 16 and 24 weeks in two patients with microsatellite-stable colorectal cancer (MSS CRC)[92] - 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][109] - Multiplexed immunofluorescence in MSS CRC patients showed increased density of CD8+ T cells and Granzyme B+ NK cells post-treatment[110][111] Pharmacokinetics (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][115] - 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][119] - 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][121] Preclinical Pipeline 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][18] - 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][137] - 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][155] - 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][169] Summary and Outlook Corporate Summary and Financial Position 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][180] - A deep preclinical pipeline includes INDUKINE molecules for IL-21, IL-18, IL-10, and INDUCER T cell engagers[180] | 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 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][184]