On July 28, 2022 ImmunityBio, Inc reported that The FDA accepted for review a Biologics License Application (BLA) for its antibody cytokine fusion protein as a treatment for patients with BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ (CIS) with or without Ta or T1 disease. ImmunityBio, a leading clinical-stage immunotherapy company, filed the BLA based on positive results from a series of studies of the investigational treatment, including the ongoing QUILT 3.032 trial. The Prescription Drug User Fee Act (PDUFA) target action date is May 23, 2023.

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This combination of N-803 with BCG is ImmunityBio’s first BLA to reach this stage of FDA acceptance for review. This marks an important milestone in the pursuit of ImmunityBio’s vision of transforming how cancer patients are treated without high-dose chemotherapy, but instead by activating the patient’s innate immune system. If approved, N-803 plus BCG would be the first immunotherapy combination for this indication in 23 years that can be delivered directly to the bladder (intravesically) to induce natural killer cells and T cells. It represents an essential step in the clinical demonstration of the Nant Cancer Vaccine hypothesis proposed by ImmunityBio’s founder, Patrick Soon-Shiong, M.D. of "Quantum oncotherapeutics: a longitudinal spatiotemporal orchestration towards immunogenic cell death".

N-803 has a unique mechanism of action that leads to the proliferation of NK and T cells that are cells of the adaptive and innate immune system. Through this action, N-803 provides a secondary boost to the immunological response generated by BCG for bladder cancer, or by a checkpoint inhibitor for other indications. In the QUILT 3.032 study, 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.

"This BLA acceptance brings us a very important step closer to being able to offer this promising combination therapeutic to more people living with NMIBC and, ultimately, reduce the incidence of cystectomies," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. "This is a compelling example of the power of inducing trained innate immune memory to potentially provide long-term, durable effects against serious, life-threatening diseases."

"We are pleased the FDA has begun its review, and ImmunityBio is prepared to move rapidly to manufacturing and marketing should the Agency approve our therapeutic for this indication," said Richard Adcock, President and CEO of ImmunityBio.

The BLA submission is supported by the results from ImmunityBio’s bladder cancer trials including QUILT 3.032, an open-label, three cohort, multicenter Phase 2/3 study of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) that was opened in 2017. The primary endpoint for Cohort A of this Phase 2/3 study is incidence of complete response (CR) of CIS at any time. Results of this trial were presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO 2022). See link here to video presentation on UroToday.

ImmunityBio’s IL-15 superagonist N-803

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 (NK) 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 has been studied in more than 700 patients in multiple Phase 1 and 2 trials in both liquid and solid tumors. It is currently being studied in trials for non-muscle-invasive bladder cancer, pancreatic cancer, non-small-cell lung cancer, non-Hodgkin’s lymphoma, and HIV.

N-803 has received both Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC CIS, as well as Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS. However, it is important to note such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that a product candidate will receive approval. Seminal patents covering intravesical administration of BCG and N-803 were issued (US 11,173,191 B2 and US 9,925,247 B2) providing term coverage until 2035.