Valrubicin

Patient Reported Outcomes (PROs) based on a May 16, 2022 data cutoff in the QUILT 3.032 trial indicate stability of physical function and global health in patients who completed PRO questionnaires and reached month 24 on-study Overall, participants with complete responses (CRs) to combination therapy with the novel interleukin-15 (IL-15) superagonist N-803 and bacillus Calmette-Guerin (BCG) reported better physical function than those who did not achieve a CR at month 6 Stability of these PROs supports the safety and tolerability of the potential new treatment combination Taken together with the positive durable 71% response and 89.2% cystectomy avoidance rates in cohort A and a favorable safety pro the May 16, 2022 data cutoff, along with the available PROs, support a favorable risk-benefit ratio for N-803 plus BCG in this patient population The Food and Drug Administration (FDA) is currently reviewing the Biologics License Application (BLA) for N-803 plus BCG for the treatment of NMIBC CIS with a Prescription Drug User Fee Act (PDUFA) date of April 23, 2024 CULVER CITY, Calif.--(BUSINESS WIRE)-- ImmunityBio, Inc. (NASDAQ: IBRX), a clinical-stage immunotherapy company, today announced that findings from Patient-Reported Outcomes (PROs) of participants in the phase 2/3 QUILT 3.032 study of N-803 plus BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) were published by the peer-reviewed journal Urology Practice. 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 published PROs based on a May 16, 2022 data cutoff indicate that both physical function and global health as self-reported by QUILT 3.032 participants with BCG-unresponsive NMIBC CIS (cohort A) or papillary disease (cohort B), remained stable over the 2-year course of the study for patients who completed the PRO questionnaires and reached 24 months on-study. In addition, overall both cohort A and B participants who reached month 24 on-study and also completed an NMIBC-specific questionnaire focusing on the challenges of bladder cancer, also reported no decline of their health or urinary tract-related symptoms while in the study. Overall, participants who achieved a complete response with the novel combination therapy reported better physical function by month six of the study than those who did not achieve a complete response. “The self-reported stability of health and physical function over the course of the study by the participants reflect another aspect of safety and tolerability of this new combination therapy,” said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. “Taken together with the positive response rate in cohort A of over 70%, the persistence of responses and cystectomy avoidance, these QoL findings suggest a favorable risk-benefit ratio for this potential new therapeutic option for patients with BCG-unresponsive bladder cancer.” The finding of relative stability of global health and physical function during the course of the study is similar to that reported by others for BCG monotherapy, suggesting the novel combination is as tolerable as treatment with BCG alone. “Many current therapies for bladder cancer slow disease progression but can cause debilitating side effects,” said Principal Investigator Karim Chamie, M.D., Associate Professor of Urology at UCLA. “The data from the QUILT 3.032 Quality of Life study 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.” QUILT 3.032 Study Details 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. The study comprises three cohorts, with cohort A enrolling patients with carcinoma in situ (CIS) with or without Ta/T1 disease and cohort B enrolling patients with high grade Ta/T1 papillary disease. Both cohorts A and B received combination N-803 plus BCG therapy. Cohort C patients, with CIS +/- Ta/T1 disease received N-803 monotherapy. The primary end point is the incidence of CR at the 3- or 6-month assessment visit for cohorts A and C, and the disease-free survival (DFS) rate at 12 months for cohort B. Durability, cystectomy avoidance, progression-free survival, disease-specific survival (DSS), and overall survival are secondary end points for cohort A. Cohort C was discontinued due to a low response rate with N-803 monotherapy, per study design. The FDA has accepted for review ImmunityBio’s resubmission of its biologics license application (BLA) for N-803 plus BCG for the treatment of BCG-unresponsive NMIBC CIS with or without Ta or T1 disease, and has set a user fee goal date (PDUFA date) of April 23, 2024. Bladder cancer is the 10th most-commonly diagnosed cancer, with approximately 80% of newly diagnosed cases being NMIBC. Intravesical (directly to the bladder) instillation of BCG after removal of cancer tissue from the lining of the bladder (transurethral resection of the bladder tumor; TURBT) is Standard-of-Care (SoC) for intermediate and high-risk NMIBC patients, but up to 40% of patients will fail BCG therapy and ~50% will relapse after an initial response and given a diagnosis of being BCG-unresponsive. Therapies approved by the FDA for this indication include pembrolizumab, nadofaragene, combined gemcitabine and docetaxel, and valrubicin. Radical cystectomy – surgical removal of the bladder - is also an option for these patients. QUILT 3.032 is being conducted to address the need for a safe, effective therapeutic option for BCG-unresponsive NMIBC patients that provides an opportunity for avoidance of radical cystectomy. N-803 is investigational. Safety and efficacy have not been established by any Health Authority or Agency, including the FDA. About ImmunityBio 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 range of immunotherapy and cell therapy platforms, alone and together, act to drive and sustain an immune response with the goal of creating durable and safe protection against disease. ImmunityBio is applying its science and platforms to treating cancers, including the development of potential cancer vaccines, as well as developing immunotherapies and cell therapies that ImmunityBio believes sharply reduce or eliminates the need for standard high-dose chemotherapy. These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases. For more information, please visit Immunitybio.com. 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Dr. Patrick Soon-Shiong, M.D./Courtesy of ImmunityBio Three decades after first writing about how natural killer cells (NK) functioned, Dr. Patrick Soon-Shiong, M.D., and his company, ImmunityBio, Inc. are on the final leg of what they hope will be U.S. Food and Drug Administration approval of their drug, N-803 (anktiva), for the treatment of bladder cancer. In the late 1980s, Soon-Shiong was a professor and surgeon at the UCLA School of Medicine specializing in pancreatic cancer and transplants of the organ. But he had a dilemma dealing with the body’s immune system that both hindered and helped what he was trying to accomplish. NK cells were responsible for causing organ rejection while those same cells killed the cancer in the pancreas. Continuing on the earlier efforts of Dr. Anthony M. Sun, M.D. of Connaught Laboratories in Toronto, who was experimenting on rats to reverse diabetes, Soon-Shiong enhanced Sun’s encapsulation method for islets made from a gel that came from seaweed. He devised a purified formula that improved how islets pass insulin, glucagon, oxygen and hormones while blocking antibodies and T cells in the immune system which would otherwise destroy the islets. “I’ve been pursuing that for the rest of my career, trying to figure out how to orchestrate NK cells and T cells,” Soon-Shiong told BioSpace. What followed was Soon-Shiong performing the world’s first encapsulated human islet transplant, the first engineered islet cell transplant and the first pig to man islet cell transplant in a diabetic patient. Besides trying to orchestrate cells, Soon-Shiong was also choreographing business deals to advance his research. His business acumen generated the revenue that led to his most successful medical achievement to date, Abraxane (paclitaxel), which is helping to finance his future endeavors, including anktiva. But it hasn't been without family turmoil. In 1991, along with his brother, Soon-Shiong co-founded VivoRx, which was followed by a second startup called VivoRx Pharmaceuticals. A legal fight between the brothers forced Soon-Shiong out of VivoRX. He left with VivoRx Pharmaceuticals and changed its name to American Bioscience. Soon-Shiong also founded a second company called American Pharmaceutical Partners and acquired two money-losing factories for it. He was soon able to turn those businesses into money makers. Soon-Shiong used the income for research and development into improving the generic chemotherapy drug paclitaxel. He called his re-worked version of paclitaxel Abraxane, and it performed better in clinical trials and was less likely to cause allergic reactions. Abraxane is an albumin-bound form of paclitaxel, now indicated for the treatment of breast cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer, cancer of the fallopian tubes and primary peritoneal cancer. In 2005, the FDA approved Abraxane and American Pharmaceutical shares jumped 47%. A short time after the FDA’s decision, Soon-Shiong announced he would combine his publicly traded American Pharmaceutical with privately held American BioScience, of which he owned 80%. To do this, American Pharmaceutical would issue 86 million new shares to American BioSience. The wheeling and dealing added about $2.5 billion to Soon-Shiong’s wealth while smaller investors questioned the ethics of the transaction. Fifteen months after merging the companies, Soon-Shiong split them into two new businesses, APP Pharmaceuticals and Abraxis, which held the rights to Abraxane. In 2008 and 2010 Soon-Shiong sold his two companies for a total of $9.1 billion. The poor kid from South Africa had obtained the American dream. Besides his work in the life sciences industry, the eclectic Soon-Shiong has used his wealth for some of his other interests. A self-proclaimed news junkie, he bought the Los Angeles Times and San Diego Union-Tribune. As a big fan of basketball, he purchased a minority position in the Los Angeles Lakers by taking over the ownership stake of team legend Ervin “Magic” Johnson and got courtside seats for their games. But medical science is Soon-Shiong’s primary focus, which brings us to the here and now. Soon-Shiong’s clinical-stage immunotherapy company, ImmunityBio, which he founded in 2014, had already received Breakthrough Therapy and Fast Track designations from the FDA for N-803, when in May the company submitted a Biologics License Application. N-803 is a first-in-class IL-15 superagonist, plus Bacillus Calmette-Guérin (BCG) intended for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without Ta or T1 disease. If N-803 receives approval, it will be the first FDA-approved immunotherapy since BCG in 1990 that can be delivered directly to the bladder to induce natural killer cells and T cells. It will also be the Culver City, California company’s first FDA-sanctioned product. “It’s one of the first opportunities to show that N-803 actually activates and proliferates NK cells and T cells and drives memory T cells for your innate immune system to treat cancer and infectious diseases,” Soon-Shiong, who turns 70 in July, said. What are the challenges in developing N-803? “It’s a biologic,” Soon-Shiong said. “It's really a paradigm shift in the sense that we want to preserve your immune system. So, the challenge is, how do we break the 40-year current standard of care where we give high-dose chemotherapy and high-dose radiation, which counterintuitively wipes out your NK cells and T cells. So, we needed to find ways to address this and in 2017, I'm pleased to say that the Oncology Center of Excellence under (director) Dr. (Richard) Pazdur, gave us the opportunity to launch this under the QUILT trial program.” The goal of N-803 is to reduce the chances a patient will need surgery and its tremendous cost. “Patients who are BCG unresponsive face the surgical procedure called radical cystectomy,” Soon-Shiong said. “Unfortunately, it’s fraught with a 9% mortality, a 60% morbidity, high cost, terrible quality of life, losing a bladder in elderly patients, nephritis infection, visits to the hospital, and it’s one of the costliest procedures in healthcare for cancer. So, there was a great unmet need of avoiding radical cystectomy and we followed that [FDA] guidance in the trial design.” The BLA submission for BCG-unresponsive NMIBC is based on data from 171 subjects from Phase I and II trials in bladder cancer and 84 subjects treated in ImmunityBio’s Pivotal Phase II/III QUILT 3032 study of the combination of N-803 and BCG. There was a 71% complete remission rate according to the study’s data. Patients who had failed on previous therapies showed an over 50% increase in both response and median duration compared to the FDA-approved alternatives, Endo’s Valstar (valrubicin) and Merkc's Keytruda (pembrolizumab), a systemic checkpoint inhibitor therapy for this indication. “You could see a 26.6-months median duration of response and significant reduction of cystectomy with a very, very tolerable profile. [It] validates this hypothesis by harnessing the natural killer cells and T cells. You can get durable memory,” Soon-Shiong said. Data presented from the QUILT 3032 study by the company at the American Society of Oncology’s annual meeting also showed that at 24 months there was a 96% avoidance of bladder cancer progression, patients had a cystectomy avoidance rate of 91% and there was 100% overall survival for bladder cancer in responders. Additionally, N-803 showed promise in treating pancreatic cancer. In a Phase II QUILT 88 clinical trial, patients with advanced pancreatic cancer who were treated with the Nant Cancer Vaccine, N-803 and off-the-shelf PDL1-targeted high-affinity NK cell infusion showed more than double the median overall survival rate compared to historical survival data. Median overall survival for patients with third- to sixth-line pancreatic cancer was 6.2 months. Soon-Shiong holds over 200 patents and ImmunityBio is currently working on 27 clinical trials. To keep the research going, Soon-Shiong is spending his own money to support those projects. “I've personally made a significant investment and I'll continue to do so. We need to, but I'm confident that the data and the results will generate the appropriate resources needed for us to pursue what we’re doing,” Soon-Shiong said. One group that needs convincing that ImmunityBio is on the right track is Wall Street. The company’s stock has dropped about 90% over the past 14 months. But Soon-Shiong isn’t concerned. “Wall Street follows rather than leads and we need to lead,” he said. “We do care about the shareholders, but what we need to do is generate organic value. Abraxane was proof of that when we were developing a vaccine and went public in 2001. “If you go back and look at the history of American Pharmaceutical Partners, it followed the exact same strategy where the stock fell down to single digits and nobody would believe this drug would get approved and it's now at a billion dollars in sales. So, I think you just have to have complete belief in the science, which we do, and the validity of each application.” Soon-Shiong’s work on N-803 could have additional benefits, like fighting COVID-19. In 2020, he was selected by the federal government to participate in “Operation Warp Speed,” which was established to accelerate the development of vaccines. “I've said since 2020 when COVID broke out that unless we generated a vaccine that is not just antibody-based but T cell and NK cell-based, we will never stop transmission. More importantly, an antibody-based vaccine will actually enhance the mutational evolution of this virus and create what we now see facing us today," Soon-Shiong said. If anktiva is approved by the FDA, what will it mean personally for Soon-Shiong? “This would be the first validation, all the way to the FDA if it were approved, that indeed, you do not need chemotherapy,” he said. “If you can take a patient's own immune system and activate it, you can get a complete remission.” A final decision by the FDA on N-803 is expected in 2023.