23 May 2022 - - US-based immunotherapy company ImmunityBio, Inc. (NASDAQ: IBRX) has submitted a Biologics License Application to the US Food and Drug Administration for N-803, a first-in-class IL-15 superagonist, plus Bacillus Calmette-Guérin for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ with or without Ta or T1 disease, the company said.

The BLA is supported by the results of ImmunityBio's studies in bladder cancer including the pivotal QUILT 3032 study (NCT03022825), where 71% of patients who had failed on previous therapies showed an over 50% increase in both response and median duration compared to the FDA-approved alternatives Valrubicin and Pembrolizumab, a systemic checkpoint inhibitor therapy for this indication.

The FDA previously granted N-803 Breakthrough Therapy and Fast Track designations when used in combination with Bacillus Calmette-Guerin for the treatment of BCG-unresponsive NMIBC CIS.

If approved by the FDA, N-803 plus BCG would be the first new immunotherapy for this indication in 23 years that can be delivered directly to the bladder (intravesically) to induce natural killer cells and T cells, providing a new treatment option for patients with this form of bladder cancer.

The results of the pivotal Phase 2/3 clinical trial demonstrated the therapeutic combination gives patients a greater chance to avoid removal of the bladder itself--a surgical procedure referred to as radical cystectomy.

This surgery is one of the last remaining options for many patients that do not respond to other therapies, but is costly to the healthcare system and comes with a high risk of mortality and complications that affect patient quality of life.

The BLA submission for BCG-unresponsive NMIBC is based on data from 171 subjects from Phase I and 2 trials in bladder cancer and on 84 subjects treated in ImmunityBio's Pivotal Phase 2/3 QUILT 3032 study of the combination of N-803 and BCG.

The combination had a well-tolerated profile and the full results of this study will be presented at an oral presentation at the 2022 American Society of Clinical Oncology Annual meeting to be held June 3-7 in Chicago.

The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of the natural killer and T cells.

N-803 is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein.

Its mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation.

N-803 has improved pharmacokinetic properties, longer persistence in lymphoid tissues and enhanced anti-tumor activity compared to native, non-complexed IL-15 in vivo.

N-803 is currently being evaluated for adult patients in two clinical NMIBC trials. QUILT 2005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT 3032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC CIS and Papillary Disease.

Trained immunity is a recently discovered immune system response triggered by BCG. Natural Killer and T cells are activated by BCG resulting in bladder cancer cell death.

When an appropriate secondary stimulus is administered along with BCG, that trained immune response is enhanced to induce immune memory resulting in a prolonged duration of immunological response.

N-803, an IL-15 superagonist which proliferates NK and T cells, serves as this enhancing secondary boost and augments the immunological response when given in combination with BCG.

ImmunityBio said it believes this mechanism of action of inducing trained innate immune memory, through the combination of N-803 and BCG, contributes to the high complete response rate and prolonged 24-month durable complete response reported in this trial.

ImmunityBio is a clinical-stage biotechnology company developing next-generation therapies and vaccines that bolster the natural immune system to defeat cancers and infectious diseases.

The company's range of immunotherapy and cell therapy platforms, alone and together, act to drive and sustain an immune response with the goal of creating durable and safe protection against disease.

These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases.

ImmunityBio's clinical pipeline consists of 27 clinical trials--18 of which are in Phase 2 or 3 development--across 13 indications in liquid and solid tumors (including bladder, pancreatic, and lung cancers) and infectious diseases (including SARS-CoV-2 and HIV).

Anktiva, ImmunityBio's lead cytokine fusion protein, is a novel interleukin-15 (IL-15) superagonist complex and has received Breakthrough Therapy and Fast Track Designations from the US Food and Drug Administration for BCG-unresponsive CIS non-muscle invasive bladder cancer (NMIBC).

The company has established GMP manufacturing capacity at scale with cutting-edge cell manufacturing expertise and ready-to-scale facilities, as well as extensive and seasoned R and D, clinical trial, and regulatory operations, and development teams.