Anktiva® (N-803) IL-15 Superagonist Vaccine Availability, Clinical Trials, Dosage, Side Effects
ImmunityBio, Inc. (Altor BioScience, LLC) intravesical therapy Anktiva® (N-803) (nogapendekin alfa) is a first-in-class interleukin-15 agonist IgG1 fusion complex consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. The fusion complex of ANKTIVA mimics the natural biological properties of the membrane-bound IL-15 receptor alpha, delivering IL-15 by dendritic cells and driving the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. The proliferation of the trifecta of these immune-killing cells and the activation of trained immune memory results in immunogenic cell death, inducing a state of equilibrium with durable, complete responses. ANKTIVA has improved pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity compared to native, non-complexed IL-15 in-vivo.
The Company's Cancer Moonshot program (QUILT clinical trials) launched in January 2016. Anktiva is the backbone of ImmunityBio's Quantum Oncotherapeutics immunotherapy-based vaccine approach for treating multiple tumor types. Anktiva's triangle offense against cancer includes natural killer cells, T cells, and memory T cells. "We hypothesized that activation and proliferation of natural killer cells through IL-15 stimulation could rescue T cells after checkpoint failure, regardless of tumor type or location. As with non-muscle invasive bladder cancer, we believe that ANKTIVA enhanced the NK and T cell activity critical for targeting and killing cancer cells which have entered the phase of tumor evasion and resistance," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio, in a press release on April 25, 2024. The Company is applying its science and platforms to treating cancers, including developing potential cancer vaccines and developing immunotherapies and cell therapies that we believe sharply reduce or eliminate the need for standard high-dose chemotherapy.
On April 22, 2024, ImmunityBio announced that the U.S. Food and Drug Administration (FDA) had approved (BLA 761336) ANKTIVA plus BCG for treating patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors. The U.S. FDA has approved Merck's TICE® BCG vaccine for this therapy. The Bacillus Calmette-Guérin (BCG) vaccine is an approved combination therapy to treat adults with unresponsive non-muscle-invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta/T1 papillary disease.
On July 2, 2024, a Plain Language Review was published by Taylor and Francis Online. It reported that N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants in NCT02138734 (Phase 1/2 study) and NCT03022825 (Phase 2/3 study), and the effects were long-lasting. Participants remained NMIBC-free for a range of 8.3 to 9.2 years.
ImmunityBio is a vertically integrated biotechnology company based in Culver City, CA. It is 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. On April 25, 2024, the Company confirmed $100 million in non-dilutive cash infusion with Anktiva's FDA approval, bringing cash-on-hand to approximately $240 million for the launch of ANKTIVA in NMIBC.
Anktiva plus BCG Vaccine Availability
In September 2024, ImmunityBio announced that more than 100 million medical lives are being covered by medical reimbursement policies that include eligibility for ANKTIVA reimbursement. In May 2024, it was added to the National Comprehensive Cancer Network guidelines. On June 20, 2024, ImmunityBio, Inc. announced the initial treatment of multiple patients in the U.S. to receive therapy with ANKTIVA. According to an X post by @DrPatSoonShiong, the initial 1,000 doses of ANKTIVA shipped on May 1, 2024. The Company previously announced that ANKTIVA® Drug Substance was completed and released with two-year storage stability data sufficient for 170,000 doses.
ANKTIVA Availability in the European Union, United Kingdom
ImmunityBio confirmed on August 12, 2024, that it has begun the filing process for obtaining regulatory approval for ANKTIVA in the European Union (EU) and the United Kingdom. The filing will include 30 countries, including 27 in the EU and three in the European Economic Area. The Company anticipates completing the submission of the initial EMA filing in Q4 2024.
Anktiva plus BCG Vaccine Price
In 2024, Anktiva will be priced at $35,800 per dose.
Anktiva plus BCG Vaccine Payment Options
The ImmunityBio CARE™ program is designed to help patients access ImmunityBio’s innovative treatment.
Anktiva Access to BCG Vaccines
On May 2, 2024, ImmunityBio, Inc. announced an exclusive arrangement with the Serum Institute of India (SII) to supply the Company with BCG vaccines. The agreement covers the manufacturing of standard BCG (sBCG) currently approved for use outside the U.S. and a next-generation recombinant BCG (iBCG) undergoing testing. Two gene modifications have been implemented in BCG to improve its immunogenicity and safety, leading to iBCG. It is intended for use with Anktiva for currently approved and potential future indications, subject to regulatory approvals. The companies plan to accelerate the ongoing Phase 2 clinical trials of iBCG in Europe, which has demonstrated safety advantages over sBCG and enhanced immunogenicity in driving both CD8+ and CD4 T cells. ImmunityBio plans to submit this protocol to the U.S. FDA and global regulatory bodies in mid-2024.
Bladder Cancer Patient Treatment Costs
The annual projected cost of bladder cancer treatment is over $2 billion. The cost profile differs substantially among the stages of the disease. The average price per patient varied from $19,521 (stage 0a) to $169,533 (metastatic disease).
Anktiva plus BCG Therapy Bladder Cancer Indication
Bladder cancer is the 9th most commonly diagnosed cancer in 2022. In the U.S., the American Cancer Society estimates there will be 83,190 new cases and 16,840 deaths from bladder cancer in 2024. 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.
Anktiva plus BCG Therapy Non-Small Cell Lung Cancer (NSCLC) Indication
On September 9, 2024, the phase 2b study of ANKTIVA in combination with checkpoint inhibitors KEYTRUDA or OPDIVO in multiple tumor types, including NSCLC who failed CPI, showed long-term overall survival of 57% (49/86) and 34% (29/86) at 12 and 18 months respectively, exceeding the current standard of care. Based on the results of the QUILT 3.055 study and other trials involving ANKTIVA with checkpoint inhibitors, ImmunityBio is opening Phase 3 trials of ANKTIVA plus KEYTRUDA or OPDIVO in 1st and 2nd line NSCLC.
On April 25, 2024, ImmunityBio announced positive overall survival results in the QUILT 3.055 study of 2nd- and 3rd-line Non-small cell lung cancer (NSCLC) patients who progressed after checkpoint inhibitor therapy (pembrolizumab, nivolumab, or atezolizumab) and standard-of-care chemotherapy. The study's results reinforce ImmunityBio's belief in the unique mechanism of action of ANKTIVA (N-803, or nogapendekin alfa inbakicept-pmln) and its potential efficacy as a next-generation immunotherapy across multiple solid and liquid tumor types.
Anktiva Endometrial Cancer Indication
ImmunityBio, Inc. announced on August 6, 2024, the opening of the QUILT 502 clinical trial to study ANKTIVA® together with the investigational AdHER2DC vaccine (autologous dendritic cells transduced with HER2 expressing adenovirus) in individuals with HER2-expressing endometrial cancer. This trial will evaluate ANKTIVA as an agent to replace the short-term activity of checkpoint inhibitor immunotherapies with long-term effectiveness. The Phase1/2 interventional study will enroll 60 participants with HER2-positive endometrial cancer, who will also receive pembrolizumab and lenvatinib, two FDA-approved drugs for endometrial cancer. The study is expected to be completed in 2026.
Anktiva Lynch Syndrome Indication
ImmunityBio partnered with the NCI in February 2024 to study the use of ANKTIVA in cases of Lynch syndrome. This genetic condition is linked with a significantly increased incidence of cancers, particularly colon cancer.
Anktiva plus BCG Vaccine Mechanism of Action
Anktiva's mechanism of action is direct specific stimulation of CD8+ T cells and Natural Killer (NK) through beta gamma T-cell receptor binding, generating 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. 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 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.
Anktiva Plus BCG Vaccine Dosage
For dosage induction, 400 mcg of Anktiva with BCG vaccine is administered intravesically once a week for six weeks. A second induction course may be administered if the complete response is not achieved at month 3. For maintenance, 400 mcg of Antiva is administered intravesically with BCG once a week for three weeks at months 4, 7, 10, 13, and 19. Additional maintenance instillations with BCG may be required for patients with an ongoing complete response at month 25 and later.
U.S. FDA Review Anktiva Plus BCG Vaccine
The U.S. FDA approved Anktiva on April 22, 2024. On October 23, 2023, ImmunityBio announced it completed the resubmission of a Biologics License Application (BLA) to the U.S. FDA for N-803 (Anktiva®). 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. N-803 has received both FDA Breakthrough Therapy and Fast Track designated treatment of BCG-unresponsive NMIBC CIS and Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC CIS.
BCG Naïve Trial Global Expansion
ImmunityBio continues to add U.S. sites to the BCG naïve trial (QUILT-2.005) and enroll patients in the study. Further, the company has received regulatory approval to begin patient enrollment in QUILT-2.005 in India. Additionally, the company plans to submit an application to the South African regulatory authorities in Q3 2024 to initiate the QUILT-2.005 trial in that country.
Anktiva plus BCG Therapy Side Effects
Anktiva's most common (≥15%) adverse reactions, including laboratory test abnormalities, are increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills, and pyrexia. Pregnancy: May cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
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 plus BCG Therapy News
September 9, 2024 - Patrick Soon-Shiong, M.D., Executive Chairman, Founder, and Global Chief Scientific and Medical Officer at ImmunityBio, commented, “Based on this study, the ResQ studies have been activated as randomized Phase 3 trials in both 1st. and 2nd line NSCLC by combining ANKTIVA with pembrolizumab or nivolumab versus standard of care. The current results presented at the World Congress on Lung Cancer confirm that by activating the body’s natural immune system and proliferating natural killer cells, killer T cells, and memory T cells, this IL-15 superagonist boosts, or rescues, the checkpoint inhibitor likely by reactivating MHC1 expression on the tumor. We are excited at the potential of converting a MHC-ve cold tumor to a MHC+ve hot tumor and evolving the field of immunotherapy beyond T cells.”
September 8, 2024 - John Wrangle, M.D., MPH, Associate Professor, Medical University of South Carolina, presented an oral presentation of the data at the World Congress on Lung Cancer in San Diego in the session titled “Novel Immunotherapy Strategies and Combinations.”
August 12, 2024 - “We are encouraged by the keen interest that physicians are showing in ANKTIVA as a treatment option for their patients with non-muscle invasive bladder cancer with carcinoma in situ (CIS), as well as by our conversations with payers as we see them adding our approved product into their policies,” said Richard Adcock, President and CEO of ImmunityBio.
June 20, 2024 - Richard Adcock, President and CEO of ImmunityBio, stated, “We look forward to ANKTIVA reaching more and more eligible NMIBC patients and for our science to deliver even more therapies from our pipeline.”
May 2, 2024 - "We are pleased to partner with the Serum Institute of India so that the power of its large-scale, world-class GMP manufacturing capacity can be used to address the issue of BCG shortage, which affects thousands of bladder cancer patients annually," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio.
April 25, 2024 - The company announced positive overall survival results of ANKTIVA combined with checkpoint inhibitors in NSCLC from the completed QUILT 3.055 trial.
April 22, 2024 - "The FDA's approval of ANKTIVA marks our launch of a next-generation immunotherapy beyond checkpoint inhibitors," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio.
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.
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," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio.
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.
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 severe 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
As of August 12, 2024, ImmunityBio continues to add U.S. sites to the BCG naïve trial (QUILT-2.005) and enroll patients in the study. Further, the company has received regulatory approval to begin patient enrollment in QUILT-2.005 in India, and the necessary medicines have been successfully imported into the country for use in the trial. Additionally, the company plans to submit an application to the South African regulatory authorities in Q3 2024 to initiate the QUILT-2.005 trial in that country.
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 in Aricept, NAI) in combination with 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.
