Engineered IL-2-diphtheria toxin fusion protein denileukin diftitox for the treatment of rare forms of cancer

I/ONTAK (E7777), is a purified reformulation of denileukin diftitox (ONTAK®), a previously FDA-approved cancer immunotherapy for the treatment of persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare form of non-Hodgkin lymphoma. Improvements to the original formulation resulted in a therapy that maintains the same amino acid sequence, but features greater purity and bioactivity. 
We believe I/ONTAK is a novel targeted oncology asset with an attractive near-term revenue opportunity and a substantially de-risked path to support commercial success. Patient enrollment in a global, multicenter, open-label, single-arm Pivotal Phase 3 study of I/ONTAK in participants with persistent or recurrent CTCL was completed in December 2021. I/ONTAK is a clinical phase product candidate for which we have applied but not received regulatory approval.

Citius plans to further explore the potential of I/ONTAK to treat larger patient populations with additional indications in peripheral T-cell lymphoma (PTCL) and immuno-oncology.  I/ONTAK has been granted orphan drug designation (ODD) by the FDA for the treatment of CTCL and PTCL.

E7777 received regulatory approval in Japan for the treatment of CTCL and PTCL in 2021. Citius’s exclusive license include rights to develop and commercialize I/ONTAK (E7777) in all markets except for Japan and certain parts of Asia.

Program Highlights

  • Phase 3 Pivotal trial completed December 2021; top line results are consistent with the prior formulation
  • Biologics license application (BLA) for an initial indication in CTCL submitted Q3 2022 
  • Considered a new biologic by the FDA, I/ONTAK would potentially be eligible for 12 years of exclusivity, if approved

How It Works

I/ONTAK is a recombinant engineered fusion protein that combines interleukin-2 and diphtheria toxin. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis.  Its unique mechanism of action targets both malignant T-cells and immunosuppressive regulatory T-cells (Tregs). Transiently eliminating Tregs has the potential of unleashing potent immune responses by the patient’s immune system against their tumors.  

In recent preclinical studies, denileukin diftitox has demonstrated the ability to deplete murine Tregs in-vivo and human Tregs ex vivo. In addition, the combination of denileukin diftitox with anti-m-PD1 showed improved tumor response and very significant improvement in survival in the combination groups relative to either therapy alone in a syngeneic mouse solid tumor model. 

Based on these data, two investigator-initiated trials are underway to evaluate the potential safety and efficacy of: 1) I/ONTAK in combination with Pembrolizumab (anti-PD 1) in patients with recurrent or metastatic solid tumors (Title: The efficacy of T-regulatory cell depletion with E7777 combined with immune checkpoint inhibitor, pembrolizumab, in recurrent or metastatic solid tumors: Phase I/II Study. IND #157242); and 2) I/ONTAK given prior to lymphodepletion (LD) chemotherapy and KYMRIAH® (tisagenlecleucel) CAR T-cell therapy for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) considered at a high risk for failure from KYMRIAH® alone (Title: Phase I/II Trial Using E7777 to Enhance Regulatory T-Cell Depletion Prior to Tisagenlecleucel (Kymriah) Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL). IND #153242). These are pre-clinical trials, the results of which will determine whether we seek regulatory approval for the respective product candidate and indication.

I/ONTAK exerts cytotoxic action by IL-2R binding, internalization and cellular toxicity

I/ONTAK unleashes potent immune responses against the tumors by transiently eliminating Treg cells