FDA Issues Complete Response Letter to BLA of Denileukin Diftitox for CTCL


Although no safety or efficacy issues were reported in the biologics license application for denileukin diftitox for cutaneous T-cell lymphoma, a complete response letter has been issued.

  • A complete response letter issued by the FDA requires Citius Pharmaceuticals, Inc., to incorporate enhanced product testing for denileukin diftitox (Lymphir).

  • Denileukin diftitox did not produce any safety or efficacy issues in the biologics application (BLA) submitted for patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL).

  • Two trials continue to evaluate denileukin diftitox for patients with recurrent or metastatic solid tumors and relapsed/refractory B-cell lymphomas.

The FDA has issued a complete response letter to the BLA seeking approval for denileukin diftitox for the treatment of patients with relapsed or refractory CTCL after at least 1 prior systemic therapy.1

Under the complete response letter, the FDA has required Citius to incorporate enhanced product testing, and additional controls agreed to with the FDA during the market application review.

Importantly, there were no clinical safety or efficacy issues raised with the product or the proposed prescribing information.

"We appreciate the FDA's expeditious review of our application. We intend to provide additional data and remain fully engaged with the FDA as we continue to work toward approval. We remain confident in the potential of [denileukin diftitox] to become an important addition to the treatment landscape for patients with relapsed or refractory CTCL and make a meaningful difference in their lives," said Leonard Mazur, chairman and chief executive officer of Citius Pharmaceuticals, Inc., in a press release.

Denileukin diftitox is an engineered interleukin-2 (IL-2)-diphtheria toxin fusion protein that binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. In preclinical studies, denileukin diftitox showed the ability to deplete murine Tregs in vivo and human Tregs ex vivo. In combination with anti-m-PD1, denileukin diftitox led to improved tumor response and significant improvements in survival.

In 2011 and 2013, the FDA granted an orphan drug designation to denileukin diftitox for the treatment of patients with PTCL and CTCL, respectively. In 2021, denileukin diftitox also received regulatory approval in Japan for the treatment of CTCL and peripheral T-cell lymphoma (PTCL), and an exclusive license with rights to develop and commercialize the agent in all markets, excluding Japan and certain parts of Asia, was granted to the company.

Citius continues to work toward the approval of denileukin diftitox for this patient population.

Two investigator-initiated trials are underway to evaluate the potential safety and efficacy of denileukin diftitox.2 In the first, denileukin diftitox will be investigated in combination with pembrolizumab (Keytruda) in patients with recurrent or metastatic solid tumors (NCT05200559). The second trial is assessing denileukin diftitox given prior to lymphodepletion chemotherapy and chimeric antigen receptor T-cell therapies for the treatment of patients with relapsed/refractory B-cell lymphomas who are at a high risk for failure from tisagenlecleucel (Kymriah) alone (NCT04855253).

Results from these preclinical trials will determine whether regulatory approval for denileukin diftitox should be sought for the treatment of rare forms of cancer.

  1. Citius Pharmaceuticals, Inc. receives a complete response letter from the U.S. Food and Drug Administration (FDA) for Lymphir™ (denileukin diftitox) for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. July 29, 2023. Accessed July 31, 2023. https://tinyurl.com/54nsnu5k
  2. Pipeline. Citius Pharmaceuticals, Inc. Accessed July 31, 2023. https://citiuspharma.com/pipeline/I-ONTAK/default.aspx
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