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Anktiva N-803 plus BCG Vaccine

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February 21, 2024
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Anktiva™ N-803 plus BCG Cancer Vaccine 2024

ImmunityBio's 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. Given the observed strong efficacy and favorable AE profile and mode of administration, N-803 represents a significant advance in the treatment option compared to existing therapies for BCG unresponsive CIS and Papillary NMIBC, as these researchers wrote in 2022. 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 a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for N-803 (Anktiva®). The FDA communicated a Prescription Drug User Fee Act (PDUFA) date of April 23, 2024. 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. On February 5, 2024, the Company announced that the journal Urology Practice published findings from Patient-Reported Outcomes (PROs) of participants in the phase 2/3 QUILT 3.032 study. These PROs support the positive interim results from the study published in NEJM Evidence, wherein 71% of patients in cohort A with CIS with or without Ta/T1 disease achieved a complete response. The finding of the relative stability of global health and physical function during the study is similar to that reported by others for BCG monotherapy, suggesting the novel combination is as tolerable as treatment with BCG alone.

As of February 2024, no health authority or agency, including the FDA, has established N-803's safety and efficacy. The U.S. FDA has approved Merck's TICE® BCG vaccine for use in the U.S., which is used in this therapy.

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. The Company's pipeline is based on broad immunotherapy and cell therapy platforms designed to attack cancer and infectious pathogens by activating the innate and adaptive branches of the immune system in an orchestrated manner. ImmunityBio's clinical pipeline consists of 27 clinical trials—18 in phase 2 or 3 development. On January 2, 2024, the Company announced an aggregate of $850 million in capital raised in 2023, with $320 million from institutional investors and $530 million from the founder, Dr. Patrick Soon-Shiong.

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-. It provided updated data on the 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 vaccination 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

February 5, 2024 - "Many current therapies for bladder cancer slow disease progression but can cause debilitating side effects," commented Principal Investigator Karim Chamie, M.D., Associate Professor of Urology at UCLA, in a press release. "The QUILT 3.032 Quality of Life study data suggest that many patients not only have a durable response but also report no decline in physical function, which is very important for these patients."

January 2, 2024 - "This transaction raises significant capital for the Company to support important growth plans, yet with limited equity dilution and with a cap on total payments tied to the initial investment," said Richard Adcock, Chief Executive Officer and President of ImmunityBio. "Besides providing a capital source at a key inflection point for ImmunityBio, this investment demonstrates strong confidence by Oberland Capital in our future, and in particular in the potential value of Anktiva in bladder cancer, as well as the direction of our clinical pipeline."

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 Vaccine 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.

In February 2024 - The ongoing phase 2/3 open-label multicenter registrational study QUILT 3.032 (NCT03022825) is evaluating the safety and efficacy of the investigational interleukin-15 superagonist N-803 (also known as Anktiva® and nogapendekin alfa inbakicept, NAI) in combination with a standard therapy for NMIBC, bacillus Calmette-Guerin (BCG), in patients who failed or in whom cancer returned after BCG monotherapy, and thus were diagnosed as BCG-unresponsive. Durability, cystectomy avoidance, progression-free survival, disease-specific survival (DSS), and overall survival are secondary endpoints for cohort A. Cohort C was discontinued due to a low response rate with N-803 monotherapy, per study design.

In 2022 - An open-label, multicenter Phase 3 study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) with CIS and Papillary disease is reported. Results: Cohort A (CIS) Efficacy: Fully enrolled n = 81 with a 20.9-month median follow-up. CR rate 72% (95% CI: 60.5%, 81.1%) with a median duration for 3-month responders of 24.1 months and a 60% probability of maintaining this CR for ≥ 18 months (95% CI: 43.1%, 73.5%). The 12-month cystectomy-free rate is 89% (95% CI: 80.1%, 94.6%), with a 100% cancer-specific survival rate at 24 months. Cohort B (Papillary) Efficacy: To date, 73 patients have enrolled with a median follow-up of 17.3 months. The primary endpoint was met with a disease-free rate at 12 months is 57% (95% CI: 43.7%, 68.5%) and at 18 months, 53% (95% CI: 38.8%, 64.8%). The 12-month cystectomy-free rate is 95% (95% CI: 84.7%, 98.3%), with a 98% cancer-specific survival rate at 24 months. Combined Efficacy: In the combined group (n = 154) of BCG unresponsive NMIBC, with a 19.3 months median follow-up, the 12-month cystectomy-free rate was 92% (95% CI: 85.5%, 95.3%), and the 24 months OS is 94% (95% CI: 86.9%, 97.1%) with 99.5% cancer-specific overall survival. Combined Safety: There were 0% treatment-related SAE's and 0% immune-related SAEs, with 4/ 154 (3%) ≥ TR Grade 3 AEs. 0% treatment-related deaths have occurred as of Sept 2021 analysis date.

Clinical Trials