FDA Accepts BLA for Cutaneous T-Cell Lymphoma Therapy


I/Ontak is an engineered IL-2-diphtheria toxin fusion protein. The PDUFA target action date is Sept. 28, 2023.

The FDA has accepted Citius Pharmaceuticals’ biologics license application (BLA) for I/Ontak (denileukin diftitox) to treat patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL). The Prescription Drug User Fee Act (PDUFA) target action date is Sept. 28, 2023.

Cutaneous T-cell lymphoma is a type of cutaneous non-Hodgkin lymphoma (NHL) that comes in a variety of forms and is the most common type of cutaneous lymphoma. In CTCL, T-cells, a type of lymphocyte that plays a role in the immune system, become cancerous and develop into skin lesions.

I/Ontak is an engineered IL-2-diphtheria toxin fusion protein. I/Ontak specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. It is a purified and more bioactive formulation than the previously FDA-approved Ontak.

Ontak was marketed in the United States from 1999 to 2014, when it was voluntarily withdrawn from the market because of production issues related to the E. coli expression system and purification challenges. Company officials said manufacturing improvements resulted in a new formulation that maintains the same amino acid sequence but features improved purity and bioactivity.

The BLA is supported by a pivotal phase 3 study. Topline results released in April 2022 showed that I/Ontak demonstrated anti-tumor activity in the treatment of persistent or recurrent CTCL. I/Ontak provided disease control without cumulative toxicity and has an average time to response within one to two cycles of treatment in patients that have failed multiple prior therapies. The primary outcome measure was objective response rate (ORR), defined as the proportion of subjects with a significant reduction in tumor size that can be classified as achieving either a partial response or a complete response.

An independent review committee determined the study achieved an objective response rate of 36.2% and an investigator efficacy analysis determined that the study achieved an objective response rate of 42.3%. Overall rates of adverse events and serious adverse events were consistent with published data of previously approved Ontak. Most common adverse events included: nausea, fatigue, increased alanine aminotransferase, chills and peripheral oedema. No new safety concerns were identified.

Myron Czuczman, M.D.

Myron Czuczman, M.D.

“I/Ontak has a unique dual mechanism of action that exerts both direct tumor cell killing and transient elimination of immunosuppressive Tregs within the tumor microenvironment. If approved, we believe this biologic with its observed efficacy and safety data would arm oncologists in the United State with an important additional treatment option for this devastating orphan disease,” Myron Czuczman, M.D., chief medical officer of Citius, said in a press release in April.

In September, the company announced it is beginning research to evaluate I/Ontak in combination with Keytruda (pembrolizumab) to treat patients with recurrent or metastatic solid tumors. The University of Pittsburgh will be conducting a dose-ranging study. Additionally, Citius is collaborating with the University of Minnesota for a dose-finding study to evaluate I/Ontak before (Kymriah) tisagenleucel CAR-T therapy in patients with diffuse large B-cell lymphoma. The trial enrolled its first patient in May 2021.

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