On October 23, 2023 ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, reported it has completed the resubmission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for N-803 (Anktiva), a first-in-class IL-15 superagonist, plus Bacillus Calmette-Guérin (BCG) for the treatment of BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ (CIS) with or without Ta or T1 disease (Press release, ImmunityBio, OCT 23, 2023, View Source [SID1234638824]).

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The BLA is supported by the results of ImmunityBio’s studies in bladder cancer including the pivotal QUILT-3.032 study (NCT03022825), published in NEJM Evidence1 in November 2022. An update of the duration of response regarding the responders identified by the FDA in the efficacy population for BCG unresponsive subjects with high-risk CIS disease was provided in the BLA resubmission. This update demonstrated a prolonged duration of remission in responding subjects, with a median duration of CR not yet reached with a follow-up in responders exceeding 28 months, and a safety profile as reported previously. The updated duration of CR in these responding BCG-unresponsive subjects showed that the probability of maintaining a CR for ≥ 24 months was 60%, with a cystectomy free rate at ≥ 24 months of over 90%.

In addition, ImmunityBio provided an update on the long-term follow-up (QUILT-205) of subjects receiving N-803 plus BCG for CIS ± Ta/T1 in the Phase 1b (QUILT-2.005) trial, examining the survival of the nine subjects entering the trial since 2014. All 9 subjects (100%) achieved a complete remission and the results are published in Oncoimmunology2-5. Of the nine subjects, two were deceased from causes other than bladder cancer and one was lost to follow-up. Of the 6 subjects available for follow-up (QUILT-205), 6 out of 6 subjects (100%) demonstrated long-term complete remission with bladder preservation over a median survival period of 8.8 years and all 6 subjects have avoided a cystectomy to date.

ImmunityBio’s IL-15 superagonist N-803 (Anktiva)
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 investigational IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) bound to an IL-15 receptor α/IgG1 Fc fusion protein. Its proposed mechanism of action is direct specific stimulation of CD8+ T cells and NK cells through beta gamma T-cell receptor binding with generation of memory T-cells while avoiding T-reg stimulation. N-803 is designed to have 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 in adult patients in two clinical NMIBC trials. QUILT-2.005 is investigating use of N-803 in combination with BCG for patients with BCG-naïve NMIBC; QUILT-3.032 is studying N-803 in combination with BCG in patients with BCG-unresponsive NMIBC CIS and Papillary Disease.

N-803 is investigational. Safety and efficacy have not been established by any Health Authority or Agency, including the FDA.

Selected Publications:

Chamie, K., Chang, S. S., Kramolowsky, E., Gonzalgo, M. L., Agarwal, P. K., Bassett, J. C., Bjurlin, M., Cher, M. L., Clark, W., Cowan, B. E., David, R., Goldfischer, E., Guru, K., Jalkut, M. W., Kaffenberger, S. D., Kaminetsky, J., Katz, A. E., Koo, A. S., Sexton, W. J., … Soon-Shiong, P. (2023). IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. In NEJM Evidence (Vol. 2, Issue 1). Massachusetts Medical Society. View Source
Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, Soon-Shiong P. Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021 May 3;10(1):1912885. doi: 10.1080/2162402X.2021.1912885. PMID: 33996264; PMCID: PMC8096327.
Chamie K, Chang SS, Gonzalgo M, Kramolowsky EV, Sexton WJ, Bhar P, et al.. Final clinical Results of Pivotal Trial of IL-15rαfc Superagonist N-803 with BCG in BCG-Unresponsive CIS and Papillary Non-Muscle Invasive Bladder Cancer (NMIBC). J Clin Oncol (2022) 40(16_suppl):4508. doi: 10.1200/JCO.2022.40.16_suppl.4508
Chamie K, Chang SS, Gonzalgo M, Kramolowsky EV, Sexton WJ, Bhar P, et al.. Phase II/III Clinical Results of IL-15rαfc Superagonist N-803 with BCG in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) Carcinoma in Situ (CIS) Patients. J Clin Oncol (2021) 39(suppl 6):510. doi: 10.1200/JCO.2021.39.6_suppl.510
Huang J, Shiao SL, Furuya H, Rosser CJ. Immunogenomic Analysis of Exceptional Responder to ALT-803 (IL-15 Analogue) in BCG Unresponsive Nonmuscle Invasive Bladder Cancer: A Case Series and Review of the Literature. J Immunother. 2019 Nov/Dec;42(9):354-358. doi: 10.1097/CJI.0000000000000269. PMID: 31107371; PMCID: PMC6783344.