Werewolf Therapeutics Shares Data at SITC 39th Annual Meeting

Werewolf Therapeutics, Inc., a cutting-edge biopharmaceutical company, has unveiled promising clinical and preclinical data at the 2024 Society for Immunotherapy of Cancer’s (SITC) 39th Annual Meeting. The event is being held from November 6-10 in Houston, Texas. Werewolf shared significant advancements regarding its tumor-activated IL-12 prodrug, WTX-330, and additional preclinical insights into its INDUKINE™ molecules.

WTX-330 is a potential first-in-class therapy being evaluated in a Phase 1 clinical trial (NCT05678998). It is designed to be selectively activated in the tumor microenvironment, delivering potent immune responses while maintaining a favorable tolerability profile. The preliminary findings presented at SITC are promising, indicating that WTX-330 as a monotherapy has induced tumor shrinkage in patients with treatment-resistant solid tumors, which are often less responsive to immunotherapy.

Randi Isaacs, M.D., Chief Medical Officer at Werewolf, emphasized the importance of these early results. "The data from this first-in-human trial of WTX-330, combined with its observed monotherapy activity in both immunotherapy-sensitive and resistant tumors, reinforces our belief in WTX-330's potential to address critical unmet needs in oncology," she stated. Isaacs expressed optimism about advancing this novel therapeutic, aiming to explore its full clinical potential for patient benefit.

As of October 7, 2024, the study had enrolled twenty-five patients with a variety of solid tumors, including microsatellite stable colorectal cancer (MSS CRC), cholangiocarcinoma, metastatic cutaneous melanoma, and non-small cell lung cancer (NSCLC). More than 70% of these patients had undergone at least two prior lines of therapy for metastatic disease. Key findings from the study include:

1. **Favorable Tolerability Profile**: Treatment-related adverse events (AEs) were generally mild to moderate, including common symptoms like fatigue, increased AST/ALT, pyrexia, and neutropenia. Severe AEs were noted but were manageable and reversible.

2. **Pharmacokinetic Improvements**: WTX-330 demonstrated 22-fold greater plasma exposure compared to the reported maximum tolerated dose of rhIL-12, with minimal levels of active IL-12 (<1.6% of the prodrug).

3. **IL-12 Activity and Tumor Immune Activation**: Evidence of IL-12 activity was observed in the tumor microenvironment, with four MSS CRC patients showing signs of tumor immune activation in on-treatment biopsies.

4. **Antitumor Activity**: Notably, a 76-year-old patient with diffuse in-transit metastatic melanoma, who had previously progressed on adjuvant pembrolizumab, achieved a RECIST-confirmed partial response.

In addition to the clinical data, Werewolf presented preclinical findings that showcase the anti-tumor potency of INDUKINE molecules containing various cytokines like IL-2, IL-12, IL-21, and IL-18. These molecules demonstrated cytokine-specific antitumor immunity as monotherapies in mice with syngeneic tumors. Each cytokine exhibited unique pharmacological profiles, highlighting the strategic rationale for their development as targeted therapeutic applications.

WTX-330 was designed to deliver active IL-12 selectively into the tumor microenvironment, enhancing the therapeutic window and promoting localized immune responses against tumors. This approach aims to address the limitations of conventional proinflammatory immune therapies by ensuring that the molecules remain inactive in peripheral tissues and activate only in the tumor microenvironment.

Werewolf Therapeutics, leveraging its proprietary PREDATOR® platform, is at the forefront of developing conditionally activated therapeutics that stimulate the body’s immune system for treating cancer and other immune-mediated conditions. The company's advanced clinical-stage product candidates, WTX-124 and WTX-330, are being developed for the treatment of solid tumors. WTX-124, a conditionally activated IL-2 INDUKINE molecule, is being tested both as a single agent and in combination with an immune checkpoint inhibitor. WTX-330, the conditionally activated IL-12 INDUKINE molecule, is being evaluated as a single agent for various tumor types and Non-Hodgkin Lymphoma.