FDA Grants Orphan Drug Designation to IFx-2.0 for Advanced Melanoma

The FDA has granted orphan drug designation (ODD) to IFx-2.0 for the treatment of stage IIB to stage IV cutaneous melanoma based on data showing safety and clinical benefit in patients who received prior PD-1 inhibitor.¹

IFx-2.0, an innate immune agonist designed to overcome resistance to immune checkpoint inhibitors (ICIs), was previously being investigated in Merkel cell carcinoma. The ODD reflects the urgent clinical need for innovative therapies capable of overcoming resistance to current standards of care in melanoma.

“Our current focus with IFx-2.0 is targeting completion of enrollment in our phase 3 study of IFx-2.0 in combination with [pembrolizumab (Keytruda)] for the first-line treatment of advanced or metastatic Merkel cell carcinoma,” said James Bianco, MD, president and CEO of TuHURA Biosciences, in a news release. “We believe receiving ODD in advanced cutaneous melanoma demonstrates not only the significant need for new treatments in skin cancer but also highlights IFx-2.0 as a potential new therapeutic approach in this patient population.”

The Challenge of PD-1 Resistance

Despite the success of ICIs in cutaneous melanoma, a substantial portion of patients either fail to respond or eventually experience progression after an initial response. Subsequent treatment options often yield diminishing returns and lower durable response rates. Delivered by intralesional injection, IFx-2.0 uses a plasmid DNA delivery system to encode Emm51, a highly immunogenic bacterial protein on the surface of the patient’s own tumor cells to act as an antigen to bring immune response to the tumor.²

Clinical Evidence and Orphan Drug Status

The FDA’s decision was informed by data from a phase 1 first-in-human study (NCT03655756) published in Molecular Cancer Therapeutics by lead investigator Joseph Markowitz, MD, of the Moffitt Cancer Center in Tampa, Florida.² Patients received at least 1 injection and could receive continued dosing every 3 weeks if they tolerated IFx-2.0. Patients were permitted to receive subsequent therapy at their physician’s discretion and responses to the next line of therapy were monitored clinically.

The trial demonstrated that IFx-2.0 was safe and well tolerated, with no dose-limiting toxicities and only grade 1 or 2 treatment-related adverse events in 6 treated patients with stage III or IV unresectable melanoma. Both adaptive and innate immune responses were detected in the injected lesions. Crucially, the study highlighted that in 3 of 4 patients refractory to anti–PD-1 therapy, clinical benefit was achieved when IFx-2.0 was followed by subsequent anti–PD-1 treatment, with some patients able to receive surgical resection and maintain progression-free survival.

The ODD provides TuHURA with several incentives, including 7 years of market exclusivity upon approval, tax credits for clinical trials, and waivers for FDA user fees.¹ This regulatory support is vital for accelerating the development of therapies targeting rare but life-threatening conditions like advanced melanoma.

Future Directions and Clinical Impact

TuHURA is currently focusing on its phase 3 registration trial (NCT06947928), which is evaluating IFx-2.0 in combination with pembrolizumab for Merkel cell carcinoma. This study randomly assigned patients to receive the injection plus pembrolizumab vs pembrolizumab plus placebo with a primary end point of overall response rate. However, the ODD for cutaneous melanoma signals a broadening of the drug's potential application.

The investigators in the phase 1 trial suggested that continued research in the cutaneous melanoma space could investigate synergy between PD-1 and IFx-2.0 in conjunction rather than subsequently, as is being done in the Merkel cell carcinoma trial.² 

The post–PD-1 landscape remains one of the most critical frontiers in oncology. Priming the immune system to overcome resistance to anti–PD-1 therapy is a promising treatment approach to open up more ways to maximize the efficacy of immune checkpoint inhibitors.

References

1. TuHURA Biosciences received FDA Orphan Drug Designation for IFx-2.0 for the treatment of stage IIB to stage IV cutaneous melanoma. News release. TuHURA Biosciences. February 2, 2026. Accessed February 2, 2026.

2. Markowitz J, Shamblott M, Brohl AS, et al. First-in-human stage III/IV melanoma clinical trial of immune priming agent IFx-Hu2.0. Mol Cancer Ther. 2024;23(8):1139-1143. doi:10.1158/1535-7163.MCT-23-0652