Werewolf Therapeutics presents preclinical, clinical data on WTX-330

Werewolf Therapeutics (HOWL) shared clinical and preclinical data at the 2024 Society for Immunotherapy of Cancer’s 39th Annual Meeting, taking place November 6-10 in Houston, Texas. WTX-330, a potential first-in-class systemically delivered IL-12 therapy selectively activated in the tumor microenvironment, is currently being evaluated in a Phase 1 clinical trial: NCT05678998. This is Werewolf’s second clinical program to validate the INDUKINE design, delivering potent immune mechanisms to the tumor with improved tolerability and evidence of clinical efficacy. Preliminary clinical findings presented at SITC demonstrate WTX-330’s promising therapeutic potential as a monotherapy, exhibiting a favorable tolerability profile and inducing tumor shrinkage in patients with treatment-resistant solid tumors, including those tumors that are less sensitive to immunotherapy. A Phase 1/2 dose- and regimen-finding clinical trial, designed to optimize WTX-330 exposure in the tumor microenvironment and explore activity in selected indications, is expected to begin enrolling in the first half of 2025. As of October 7, 2024, the study had enrolled twenty-five patients with diverse solid tumors, including microsatellite stable colorectal cancer, cholangiocarcinoma, metastatic cutaneous melanoma, and non-small cell lung cancer, with more than 70% of patients having received at least two prior lines of therapy for metastatic disease. Key findings include: Favorable tolerability profile: Treatment-related adverse events were primarily mild to moderate; severe AEs occurred but were manageable and reversible. Pharmacokinetic improvements over rhIL-12: WTX-330 had 22-fold greater plasma exposure than the reported maximum tolerated dose of rhIL-12 but with low levels of active IL-12. IL-12 activity and tumor immune activation: Evidence of IL-12 activity in the tumor microenvironment with four patients with MSS CRC showing evidence of tumor immune activation in on-treatment tumor biopsies. Antitumor activity: A 76 year old patient with diffuse in-transit metastatic melanoma who had progressed on adjuvant pembrolizumab achieved a Response Evaluation Criteria in Solid Tumors confirmed partial response. Additionally, Werewolf presented preclinical data demonstrating the ability of INDUKINE molecules containing IL-2, IL-12, IL-21, or IL-18 cytokines to generate cytokine-specific antitumor immunity as monotherapy in mice bearing syngeneic tumors. These data revealed unique pharmacological profiles for each cytokine, underscoring the strategic rationale to develop each as an INDUKINE molecule for targeted therapeutic applications.