Anktiva™ N-803 plus BCG Cancer Vaccine
ImmunityBio's IL-15 Superagonist Anktiva™ N-803 Plus BCG is a therapy to treat adults with non-muscle-invasive Bladder Cancer (NMIBC) carcinoma in situ (CIS) with or without Ta/T1 papillary disease. N-803 (generic name nogapendekin alfa in Aricept ((NAI)) 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 Natural Killer (NK) cells through beta gamma T-cell receptor binding (not alpha) while avoiding T-reg stimulation.
The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the NK and T cells' development, maintenance, and function. The IL-15 superagonist N-803 acts synergistically with Bacille Calmette-Guerin (BCG). As a result, 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.
The superagonist N-803 has been studied in more than 700 patients in multiple phases 1 and 2 clinical trials in liquid and solid tumors. In addition to the study in NMIBC, it is currently being studied in trials for pancreatic cancer, non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, and HIV. On November 10, 2022, the journal NEJM Evidence published its conclusion from a phase 2/3 study: In patients with BCG-unresponsive bladder carcinoma in situ and papillary NMIBC treated with BCG and the novel agent NAI, CRs were achieved with the persistence of effect, cystectomy avoidance, and 100% bladder cancer–specificity survival at 24 months. The U.S. Food and Drug Administration (FDA) approved the TICE® BCG vaccine from Merck, which is used in this therapy.
"The peer review and publication of data in NEJM Evidence highlight the significance of the positive results of the QUILT 3.032 trial in patients with BCG-unresponsive NMIBC," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio, in a press release on November 10, 2022. "These data further our understanding of N-803's unique role in potentially boosting the proliferation of natural killer and T cells while synergistically enhancing BCG efficacy."
On December 27, 2022, an editorial from urological cancer experts from Memorial Sloan Kettering Cancer Center stated: "The efficacy and minimal toxicity of this combination represents a major advance for the care of patients with BCG-unresponsive NMIBC, and the authors should be congratulated. In addition, this promising combination offers a potential alternative to cystectomy and may allow us to move beyond single-arm studies toward randomized phase 3 trials against other novel therapies."
On October 23, 2023, ImmunityBio announced it completed the resubmission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for N-803 (Anktiva®). A PDUFA date of April 23, 2024, has been communicated by the FDA, Recent study results support the BLA, including the pivotal Phase II/III, open-label, single-arm, multicenter QUILT-3.032 clinical study published in NEJM Evidence in November 2022. No health authority or agency, including the FDA, has established N-803's safety and efficacy.
Based in Culver City, CA, ImmunityBio is a vertically integrated, clinical-stage biotechnology company developing next-generation therapies and vaccines that bolster the natural immune system to defeat cancers and infectious diseases. ImmunityBio's clinical pipeline consists of 27 clinical trials—18 in phase 2 or 3 development. On September 11, 2023, the Company announced $470 Million in Equity and Debt Financing From Founder Dr. Patrick Soon-Shiong and Nant Entities.
U.S. FDA Review Anktiva N-803 Plus BCG
In a complete response letter issued in May 2023, the FDA indicated it could not approve the biologics license application for Anktiva. Deficiencies were identified during an inspection of production facilities operated by ImmunityBio's contract manufacturing partners for the drug, according to a filing with the U.S. Securities & Exchange Commission. On October 23, 2023, the Company announced the resubmission for N-803 in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer Carcinoma-In-Situ and provided updated data on prolonged duration of complete response in BCG-Unresponsive and BCG-Naïve NMIBC patients.
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.
Anktiva N-803 plus BCG Therapy Indication
The Company stated while BCG is an effective treatment for many patients, it doesn't work for an estimated 40% of NMIBC cases. Patients with intermediate or high-risk NMIBC typically receive a treatment of transurethral resection of the bladder tumor (TURBT) followed by BCG intravesical instillation. However, cancer will recur in 30% to 40% of patients with NMIBC despite adequate treatment with BCG. Moreover, even among those in whom a complete response is achieved with BCG, up to 50% see their cancer return.
Tri-Ad5 Vaccine Combination With N-803
On April 25, 2023, ImmunityBio, Inc. announced the opening of a phase 2b clinical trial to study its investigational Tri-Ad5 vaccine combination (Adenovirus 5 CEA/MUC1/brachyury) together with its IL-15 superagonist N-803 for people with a hereditary condition known as Lynch syndrome to prevent colorectal and other cancers in study participants.
Anktiva N-803 plus BCG Therapy News
October 26, 2023 - "We are pleased that the FDA has accepted ImmunityBio's resubmission of the BLA as a complete response, following our productive interactions leading up to the resubmission. We look forward to working closely with the Agency to finalize the review and bringing this important immune-enhancing therapeutic to bladder cancer patients," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio.
September 11, 2023 - Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer of ImmunityBio, commented in a press release, "As a scientist and physician, I believe in the science behind our therapeutics and look forward to continuing to work with our team members through this critical stage in our Company's evolution. ImmunityBio has taken on the enormous challenge of transforming the current approaches to cancer care and even preventing the onset of cancer by activating the patient's immune system and developing a NANT cancer vaccine. The Company is unique in that it owns the multiple immunotherapy platforms needed to orchestrate the trifecta approach (NK, T cell, and Dendritic cell activation) to accomplish this vaccine and that these unencumbered molecules and cell therapies are all at various stages of clinical trials. We recognize the enormity of such a challenge, and this investment will enable the scientists and physicians to pursue the goal of potentially curing cancer in our lifetime."
May 11, 2023 - Reuters reported that a letter to the Company by a health regulator said it could not approve the application in its present form. The deficiencies are related to the FDA's pre-license inspection of the Company's third-party contract manufacturing firms.
April 25, 2023 - "We are excited to partner with the NCI on this important cancer vaccine study to potentially prevent or delay the onset of cancer for people who carry the gene associated with Lynch syndrome," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio, in a press release.
February 16, 2023 - ImmunityBio, Inc. announced that it had executed financing expected to result in gross proceeds at closing of approximately $50 million before deducting any offering-related expenses, subject to customary closing conditions. The warrants could result in additional gross proceeds of up to $60 million if fully exercised.
November 10, 2022 - NEJM Evidence has published results from the QUILT 3.032 phase 2/3 clinical trial studying N-803 plus BCG in adults with NMIBC CIS with or without Ta/T1 papillary disease.
July 28, 2022 - The U.S. FDA accepted a BLA from ImmunityBio, Inc. for review.
May 23, 2022 - ImmunityBio, Inc. announced it had submitted a BLA to the U.S. FDA for N-803.
February 2022 - Data presented at the ASCO® Genitourinary Cancers Symposium showed a complete response in 59 of 83 patients 7 with a 1% CR rate (95% CI: 60.1, 80.5) and a median duration of CR of 24.1 months. In patients who responded to the investigational therapeutic, the probability of avoiding bladder cancer and cystectomy progress at 24 months exceeded 90%. In addition, the combination of Anktiva and BCG had a well-tolerated profile with 0% treatment-related serious adverse events (SAEs), 0% immune-related AEs, and 100% bladder cancer-specific overall survival at 24 months.
January 2019 - ScienceDirect published a Brief Correspondence: Prognostic Implication of the U.S. FDA-defined BCG-unresponsive Disease.
N-803 plus BCG Clinical Trials
N-803 is currently being evaluated in adult patients in two clinical NMIBC trials. QUILT-2.005 is investigating the 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. QUILT 3.032 Registrational Trial of IL-15 Superagonist N-803 Plus BCG in Patients with Bladder Cancer - results presentation.
