FDA Accepts BLA of Denileukin Diftitox Reformulation for Persistent or Recurrent Cutaneous T-cell Lymphoma

The FDA has accepted a biologics license application seeking the approval of a reformulation of denileukin diftitox for use as a potential therapeutic option in patients with persistent or recurrent cutaneous T-cell lymphoma.

The FDA has accepted a biologics license application (BLA) seeking the approval of a reformulation of denileukin diftitox (I/ONTAK; E7777) for use as a potential therapeutic option in patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL).1

The BLA was supported by data from the phase 3 Study 302 trial (E777-G000-302; NCT01871727), where I/ONTAK demonstrated an objective response rate (ORR) of 36.2% (95% CI, 25.0%-48.7%) per independent review committee (IRC) assessment in the 69 patients who comprised the primary efficacy analysis set.2 In this group, the median duration of response (DOR) was 6.5 months (range, 3.0+ to 23.5+), with a median time to response (TTR) of 1.41 months. The clinical benefit rate (CBR) was 49.3% (95% CI, 37.0%-61.6%).

Per investigator assessment, I/ONTAK elicited an ORR of 42.3% (95% CI, 30.6%-54.6%) in the 71 patients who comprised the efficacy analysis set. In this group, the median DOR was 5.7 months (range, 0.7+ to 26.1+), the median TTR was 1.41 months, and the CBR was 53.5% (95% CI, 41.3%-65.5%).

The Prescription Drug User Fee Act date is set for September 28, 2023.

"The acceptance of the previously announced BLA submission for I/ONTAK is another important regulatory milestone for our oncology program…We look forward to the potential approval of this therapeutic for patients with persistent or recurrent cutaneous T-cell lymphoma, a rare disease for which patients with advanced disease have limited treatment options," Leonard Mazur, chairman and chief executive officer of Citius Pharmaceuticals, Inc. stated in a press release.

I/ONTAK is a recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis.

I/ONTAK is a purified version of denileukin diftitox and a reformulation of ONTAK, which was granted a full approval from the FDA in October 2008 for use in this CTCL patient population.3 The original formulation was voluntarily withdrawn from the United States market in 2014.

The multicenter, open-label, single-arm Study 302 enrolled patients who were at least 18 years of age who had a histopathologic diagnosis of CTCL and CD25 positivity.4 Patients were required to receive prior treatment for their disease and have a washout period of at least weeks 4 before starting treatment on Study 302. Other eligibility criteria included an ECOG performance status of 0 to 2 for the lead-in portion of the research, and 0 or 1 in the main study; acceptable bone marrow function; and a life expectancy of at least 3 months.

The lead-in portion of the trial aimed to identify the optimal dose of I/ONTAK in 21 patients. Patients were administered I/ONTAK at daily doses ranging from 6 µg/kg to 15 µg/kg. A dose of 9 µg/kg daily was determined to be used for the main study by the trial’s Protocol Steering Committee.

In the second part of the study, 91 patients with stage I to IV CTCL received I/ONTAK at a daily dose of 9 µg/kg via intravenous infusion over the course of 1 hour for 5 consecutive days every 21-day cycle.

The trial’s primary end point was ORR based on the global response score. Per trial protocol, if the lower limit of the 2-sided 95% confidence interval of the observed ORR exceeded 25% per IRC assessment, the study drug would be determined to be efficacious and have clinical benefit in this population.

Secondary and exploratory end points included progression-free survival, DOR, TTR, ORR, and safety.

Safety findings were consistent with previously reported data for the original formulation of denileukin diftitox. The most common adverse effects included nausea, fatigue, increased alanine aminotransferase, chills, and peripheral edema. No new safety signals were observed.


  1. Citius Pharmaceuticals, Inc. announces U.S. Food and Drug Administration acceptance of biologics license application of denileukin diftitox for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. December 1, 2022. Accessed December 1, 2022. https://bit.ly/3XLMnqh
  2. Citius Pharmaceuticals reports topline data from the pivotal phase 3 study of cancer immunotherapy I/ONTAK (E7777) for the treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL) in support of BLA submission. News release. Citius Pharmaceuticals, Inc. April 6, 2022. Accessed December 1, 2022. https://prn.to/3SNgnis
  3. FDA grants full approval to Ontak (denileukin diftitox) for use in patients with cutaneous T-cell lymphoma (CTCL). News release. Eisai Corporation of North America. October 16, 2008. Accessed December 1, 2022. https://bit.ly/3C8TSgR
  4. A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma. ClinicalTrials.gov. Updated January 25, 2022. Accessed December 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01871727
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