Denileukin Diftitox BLA Resubmitted for CTCL After Addressing FDA Concerns

• The resubmission follows ongoing engagement as Citius Pharmaceuticals, Inc. has addressed the issues noted in the complete response letter (CRL).

• FDA acceptance of the resubmission package and issuance of a Prescription Drug User Fee Act (PDUFA) date is expected within 30 days.

• Denileukin diftitox (Lymphir) is an interleukin-2 (IL-2)-based immunotherapy with orphan drug designations for peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). It was approved in Japan in 2021.

The biologics license application (BLA) for denileukin diftitox has been resubmitted to the FDA for the treatment of patients with relapsed/refractory CTCL after at least 1 prior systemic therapy.¹

Previously in July 2023, a complete response letter (CRL) was issued to the BLA, citing the need for additional manufacturing controls and enhanced product testing. In September 2023, the FDA addressed the CRL and gave Citius Pharmaceuticals, Inc. the necessary actions required to support the resubmission of the BLA.

The resubmission now follows ongoing engagement as Citius has addressed the issues noted in the letter. Of note, no safety or efficacy issues were cited in the CRL and there is no need for any additional trials.

FDA acceptance of the completed resubmission package and issuance of a PDUFA date is expected within 30 days of resubmission.

Lymphomas: © David A Litman - stock.adobe.com

Denileukin diftitox is an IL-2-based immunotherapy. The engineered recombinant fusion protein combines the IL-2 receptor binding domain with diphtheria toxin fragments, which then, by specifically binding to IL-2 receptors on the cell surface, causes diphtheria toxin fragments in cells to inhibit protein synthesis.

Two orphan drug designations were granted to denileukin diftitox by the FDA in 2011 and 2013 for the treatment of patients with PTCL and CTCL. In 2021, denileukin diftitox was approved in Japan for the treatment of CTCL and PTCL. An exclusive license with rights to develop and commercialize the agent was acquired by the company in all markets except for Japan and certain parts of Asia.

There are currently 2 investigator-initiated trials ongoing to assess the safety and efficacy of denileukin diftitox: a trial combining the agent with pembrolizumab (Keytruda) for the treatment of patients with recurrent or metastatic solid tumors (NCT05200559), and a trial of denileukin diftitox given before lymphodepletion chemotherapy and chimeric antigen receptor T-cell therapies for patients with relapsed/refractory B-cell lymphomas who are at a high risk for failure from tisagenlecleucel (Kymriah) alone (NCT04855253).^2,3

REFERENCES:

1. Citius Pharmaceuticals resubmits the biologics license application of LYMPHIR™ (denileukin diftitox) for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. February 14, 2024. Accessed February 14, 2024. http://tinyurl.com/4edfmhnn

2. T-regulatory cell depletion with E7777 combined with pembrolizumab in recurrent or metastatic solid tumors. ClinicalTrials.gov. Updated November 9, 2023. Accessed February 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05200559

3. Study of E7777 prior to kymriah for R/R DLBCL. ClinicalTrials.gov. Updated July 7, 2023. Accessed February 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04855253