On April 22, 2024, ImmunityBio's IL-15 superagonist N-803 was approved for marketing by the FDA, in combination with BCG.（BCG）Combined useFor the treatment of high-risk non-muscle invasive bladder cancer (CIS, papillary lesions) patients who do not respond to BCG, the trade name is Anktiva.The approval of N-803 marks the first new therapy for this type of patient in 24 years.This method has significantly reduced the rate of bladder removal. Affected by this, ImmunityBio's stock price increased by 20% after hours.
Delayed Due to CMC DefectsN-803 is an IL-15 superagonist composed of an IL-15 mutant (IL-15 N72D), the IL-15 receptor α chain, and the Fc receptor. On one hand, ImmunityBio incorporates the Fc fragment to extend its half-life, and on the other hand, introduces a mutation at the IL-15 N72D site to enhance its biological activity. Compared to using IL-15 alone, N-803 is more stable, has a longer survival time in the body, and can better stimulate the immune system for an extended period.The success of N-803 is a significant breakthrough for this patient population, with up to 40% of NMIBC patients being unresponsive to BCG. The efficacy of N-803 in this group is particularly remarkable.Based on the Phase I/II data from 171 subjects and the pivotal clinical study QUILT3032 enrolling 84 subjects, N-803 was first submitted to the FDA for a BLA in May 2022. In this clinical study, compared with the existing therapies approved by the FDA, 71% of patients who previously failed BCG treatment responded to N-803+BCG, with a median duration of response exceeding 50%.However, in May 2023, the FDA rejected its marketing application due to deficiencies with the third-party contract manufacturer. In the CRL, the FDA provided recommendations to address the CMC issues and requested the submission of "duration of response and safety data." However, no new preclinical or Phase III clinical safety or efficacy studies were required.This setback comes at a tough time for the company, with a net loss of $117 million in Q1 2023 and a cash balance of $91.26 million.As a result, ImmunityBio's stock price also plummeted by 55%.Although CMC issues are not fatal and approval can still be obtained after the problems are resolved, the delay in the marketing process will still cause visible and invisible losses to pharmaceutical manufacturers.After Rejection, ImmunityBio Updates QUILT 3.032 ResponseDuration data and resubmitted the listing application, In October 2023, the re-submitted listing application was approvedThe FDA has accepted the application, with the PDUFA date set for April 23, 2024.In the updated data, the duration of response for patients who previously responded to N-803 has been extended.，The probability of CR lasting ≥24 months is 60%.，The rate of no cystectomy exceeds 90% at ≥24 months.N-803 shows promising efficacyThis also provided the company with a crucial injection of funds. In January 2024, Oberland Capital andImmunityBio, Inc.Signed a cooperation agreement worth up to 320 million US dollars, toAccelerate the commercialization and clinical trial development of N-803.The agreement includes an immediate investment of $210 million, as well asN-803An additional $100 million in funding after receiving FDA approval.ImmunityBio is also developing N-803 for non-small cell lung cancer, which is currently in Phase II clinical trials. The ORR of N-803 combined with PD-1 monoclonal antibody is 38%.Among 15 patients with high PD-L1 expression)，mOS 17 months.IL-15Discovered in 1994.Published in 2008On NCI"Twelve immunotherapy drugs that could cure cancers" lists IL-15 as one of the potential tumor immunotherapy approaches.IL-15 is a pleiotropic cytokine,Plays a central role in the development, survival, and activation of NK, T, and B cells. IL-15 not only increases the number of NK cells and T cells but also activates NK cells and cytotoxic CD8+ T cells, thereby exerting tumor-killing and pathogen-fighting effects. Within the tumor microenvironment, IL-15 has the potential to promote lymphocyte proliferation and transform "cold tumors," which are unresponsive to commonly used immunosuppressants like anti-PD-1 antibodies, into responsive "hot tumors."In the development of IL-15, there were quite a few familiar companies, such asHengrui Bio,Boji Bio, Bioniz Therapeutics, etc.But except forImmunityBioBeyond that, almost no progress has been made.Hengrui'sSHR-150 has been out of touch for many years,Boji Biotech has gone bankrupt and is under liquidation.Natural IL-15 has a short half-life and low monomer bioactivity, making it difficult to develop clinically.Progress is slow. In October last year, SOTIO's IL-15 superagonist Nanrilkefusp alfa was discontinued due to insufficient efficacy. The recent breakthrough in efficacy and regulatory approval of N-803 signifies the significant auxiliary role and clinical value of cytokines in cancer treatment.https://firstwordpharma.com/story/5738548
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