Werewolf Therapeutics to Present Phase 1/1b Data on WTX-124 Alone and with Pembrolizumab in Solid Tumors

Werewolf Therapeutics, Inc. recently announced significant findings from its Phase 1/1b clinical trial of WTX-124, a conditionally activated Interleukin-2 (IL-2) molecule designed to stimulate the immune system for cancer treatment. This innovative therapy aims to treat patients with locally advanced or metastatic solid tumors who have not responded to prior checkpoint inhibitor therapy. The data, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, reveals encouraging results indicating the potential of WTX-124 as a promising treatment option.

Clinical Activity and Safety
The trial demonstrated that WTX-124 is both clinically active and generally well-tolerated in patients. Notably, three objective responses were observed, including a durable confirmed complete response (CR) and two partial responses (PRs), among patients who were refractory to immune checkpoint inhibitor therapy. These responses were characterized by 100% regression of target lesions, occurring within the first two treatment cycles and maintaining durability at the recommended dose for expansion (RDE).

Monotherapy and Combination Therapy
WTX-124 was evaluated as a monotherapy and in combination with pembrolizumab, an immune checkpoint inhibitor. In monotherapy, doses ranging from 1 mg to 28 mg were administered to 35 patients. The combination therapy involved 12 patients who received WTX-124 doses between 3 mg and 12 mg. The combination therapy was generally well-tolerated and showed enhanced immune activation in tumors, suggesting potential improved antitumor activity when combined with pembrolizumab.

Safety Profile
The treatment-emergent adverse events (TEAEs) reported were mostly mild to moderate in severity, manageable, and reversible. Importantly, no new safety concerns were identified when WTX-124 was combined with pembrolizumab, supporting its potential as a safe treatment option.

Mechanism of Action
Analysis of paired tumor biopsies indicated that WTX-124 robustly activated and expanded effector T cells preferentially over regulatory T cells (Tregs). This preferential activation is crucial for potent antitumor immune responses and suggests that WTX-124 can effectively enhance the immune system's ability to target and destroy cancer cells.

Dosing and Expansion Plans
Based on these promising results, Werewolf Therapeutics has selected an 18 mg dose of WTX-124 administered intravenously every two weeks as the RDE for the Phase 1b dose-expansion portion of the trial. The company has initiated three expansion arms focused on advanced or metastatic renal cell carcinoma, cutaneous melanoma, and cutaneous squamous cell carcinoma. Additionally, the company continues to explore various doses in combination with pembrolizumab and plans to select an RDE for this combination therapy by the third quarter of 2024.

Future Directions
Werewolf Therapeutics is committed to advancing WTX-124 as a potential best-in-class IL-2 therapy. The company plans to engage with regulatory authorities to discuss potential pathways for accelerated approval of WTX-124 as a monotherapy in immune-checkpoint inhibitor relapsed/refractory indications. This strategic approach aims to bring this promising treatment to patients who have limited therapeutic options.

Conclusion
The new clinical data from Werewolf Therapeutics’ Phase 1/1b trial of WTX-124 presents a compelling case for its potential as an effective and well-tolerated cancer treatment. With promising monotherapy and combination therapy results, WTX-124 offers hope for patients with difficult-to-treat tumors, marking a significant step forward in cancer immunotherapy.

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