WTX-124 Earns FDA Fast Track for Refractory Melanoma

The FDA has granted fast track designation to the investigational therapeutic agent WTX-124 for the potential treatment of patients with locally advanced or metastatic cutaneous melanoma that has progressed following standard-of-care immunotherapy, addressing a critical unmet need in the oncology community.¹

WTX-124, an investigational, systemically delivered, conditionally activated pro-drug of recombinant human interleukin-2 (IL-2; aldesleukin), is currently under evaluation in a phase 1/1b open-label, multicenter study (NCT05479812)² in patients with advanced solid tumors.

The FDA's fast track program is specifically intended to expedite the development and review of novel agents that demonstrate the potential to address an unmet medical need for serious or life-threatening conditions.¹ Fast track designation permits more frequent engagement with the FDA, allows for the submission of a biologics license application on a rolling basis, and may qualify the agent for priority review or accelerated approval upon submission.

“At Werewolf, we are focusing on efforts to address the high unmet need of cancer patients, and we believe there is significant opportunity with WTX-124 for the potential treatment of advanced cancers,” said Daniel J. Hicklin, PhD, president and chief executive officer of Werewolf Therapeutics, in a press release. “We are encouraged by this fast track designation as an important milestone for the WTX-124 program and because it underscores the urgent need for patients with relapsed/refractory melanoma where treatment options are limited. In the fourth quarter, we anticipate sharing preliminary data from the ongoing WTX-124 phase 1/1b clinical trial, including in patients with cutaneous melanoma, and engaging with the FDA regarding the potential registration strategy for this agent.”

The fast track designation was predicated on promising data from the ongoing study, which demonstrated clinically meaningful antitumor activity and a tolerable safety profile in the cohort of patients with previously treated cutaneous melanoma. The approval recognizes the significant clinical challenge posed by refractory melanoma, where treatment options are limited following failure of immune checkpoint inhibitors (ICIs).

What is the Mechanism of Conditional Cytokine Activation?

WTX-124 is a conditionally activated cytokine therapeutic engineered using the proprietary INDUKINE™ platform.¹ It functions as a pro-drug designed to remain inactive in the peripheral circulation and systemic tissues, thereby mitigating the severe, dose-limiting toxicities traditionally associated with high-dose recombinant human IL-2, such as vascular leak syndrome and lymphopenia.

This conditionally active design involves a masking moiety that prevents the agent from binding to the IL-2 receptor complexes in the systemic environment. The drug is selectively cleaved and activated by proteases highly expressed within the tumor microenvironment (TME). Upon activation, the unmasked IL-2 moiety can bind to the intermediate-affinity and high-affinity IL-2 receptors on local immune effector cells, predominantly CD8-positive T cells and natural killer (NK) cells. This mechanism is intended to locally stimulate a potent antitumor immune response while maintaining a favorable systemic safety profile. In melanoma, which is often considered immunogenic, the ability to concentrate IL-2 activity within the TME without inducing substantial systemic cytokine-related toxicities represents a potentially significant therapeutic advantage.

The phase 1/1b clinical trial is evaluating WTX-124 across multiple advanced solid tumors, including melanoma.² The trial design includes both single-agent arms and combination arms investigating the agent in conjunction with the PD-1 inhibitor pembrolizumab (Keytruda).

The patient population for the fast track designation—those with locally advanced or metastatic cutaneous melanoma after prior ICI therapy—represents a disease state with a poor prognosis.¹ Standard first-line treatment for metastatic melanoma often includes anti–PD-1 agents such as pembrolizumab or nivolumab (Opdivo), or a combination of anti–CTLA-4 and anti–PD-1 agents. However, a large percentage of patients develop resistance or suffer disease progression. For this refractory population, high-dose aldesleukin, despite its known toxicities, has historically been one of the few approved treatment options, underscoring the high therapeutic hurdle that WTX-124 seeks to clear with an improved safety profile.

The rationale for combining WTX-124 with an agent like pembrolizumab is rooted in the synergistic potential of local T-cell proliferation and activation provided by the pro-drug IL-2, combined with the immune-stimulatory effects of PD-1 blockade. By locally increasing T-cell density and effector function within the tumor bed, WTX-124 may potentially enhance the efficacy of checkpoint inhibition in previously nonresponsive or refractory lesions.

REFERENCES:

1. Werewolf Therapeutics, Inc. Werewolf Therapeutics Receives Fast Track Designation from the U.S. FDA for WTX-124, an Investigational Therapy for the Treatment of Cancer. News release. Werewolf Therapeutics. Published October 8, 2025. Accessed October 9, 2025. https://tinyurl.com/bdfprvuu

2. Dose Escalation and Expansion Study of WTX-124 as Monotherapy and in Combination With Pembrolizumab (Pembro) in Patients With Selected Advanced or Metastatic Solid Tumors. ClinicalTrials.gov. Updated July 28, 2025. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT05479812