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The FDA approved denileukin diftitox (Lymphir), the first novel targeted systemic therapy approved for relapsed/refractory (r/r) cutaneous T-cell lymphoma (CTCL) since 2018, Citius Pharmaceuticals .

The approval stipulates use in patients who have received at least one prior systemic therapy for CTCL. A novel immunotherapeutic agent, denileukin diftitox targets the interleukin (IL)-2 receptor on malignant T cells and T regulatory (Treg) cells. The therapy has a direct cytotoxic effect on tumor cells that express IL-2 receptors and depletes host Tregs to enhance immune response.

"As a treating oncologist, I have seen the profound negative effect on the quality of life in patients with r/r CTCL," said Francine Foss, MD, of the Yale Cancer Center in New Haven, Connecticut, in the company statement. "Given the long-term nature of the disease, pruritus, ulceration of the tumors, and secondary pyogenic skin infection, it is vital to get this skin involvement under control.

"Lymphir is the first therapeutic option in many years to offer hope of reducing skin disease, bringing us one step closer to filling the need for CTCL patients, particularly those that are not able to complete or continue prior therapies."

A rare type of non-Hodgkin lymphoma, CTCL is diagnosed in an estimated 2,500-3,000 patients each year, and an estimated 40,000 are living with the chronic condition. and account for a majority of cases.

Support for the approval came from the phase III , an open-label, single-arm, multicenter trial involving 112 patients with stage I-IV r/r CTCL, previously treated with a median of four prior regimens. The primary endpoint was objective response rate, and data analysis included 69 evaluable patients. The results showed an ORR of 36.2% (25/69). Additionally, 54 of 64 (84.4%) skin-evaluable patients had a decrease in skin tumor burden, including eight of 64 (12.5%) who had complete clearance. Median time to response was 1.41 months, and a majority of responses began within one or two cycles of treatment.

Among 119 patients treated in three clinical studies, the most common (≥20%) adverse events were increased transaminases, decreased albumin, nausea, edema, decreased hemoglobin, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome (CLS). The FDA required a boxed warning about the risk of CLS.

The approval continues a history of denileukin diftitox that . Initially approved for r/r CTCL in 1999 under the trade name Ontak, the original version of the therapy was marketed with that name until 2014, when U.S. sales were discontinued. Evidence linking the drug to vision loss prompted the FDA to require a boxed warning in 2006.

The therapy underwent modifications to improve purity, during which it was called E7777. The FDA considered E7777 a new drug that required regulatory approval.

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