Protecting the bladder is definitely a topic worth paying attention to for pharmaceutical companies. The core reason is that there are many patients who face the decision of whether to keep their bladders. Bladder cancer is the tenth most common cancer in the world, with more than 614,000 new cases of bladder cancer in 2022. About 70% of patients are initially diagnosed with non-muscle invasive bladder cancer (NMIBC), corresponding to a population of more than 400,000. According to the severity, NMIBC can be divided into carcinoma in situ (CIS) that only exists on the surface of the bladder, non-invasive papillary carcinoma (Ta), and tumors that invade the lamina propria (T1).

Fortunately, bladder cancer has obvious early symptoms, which facilitates early detection and early treatment. In the past few decades, the standard treatment for NMIBC has been transurethral resection of bladder tumors (TURBT) plus postoperative adjuvant intravesical instillation of BCG. Unfortunately, bladder tumors are like leeks, which grow again after being cut, and even grow taller. There is a high recurrence rate and progression rate after TURBT. Research data show that even for low-risk NMIBC patients, despite a very low progression rate, the risk of recurrence within 5 years is about 40-50%. For high-risk disease, even if up to 80% of patients have an initial response to intravesical BCG, the overall high recurrence or progression rate is about 50%. For T1 disease, especially when re-resected, the progression rate is close to 80%. For cases that do not respond to initial intravesical treatment, the success rate of secondary bladder preservation treatment is in the range of 20-40%.

Ultimately, for NMIBC patients who do not respond to BCG, if the disease progresses further, they will face radical cystectomy (RC), which is the removal of the bladder and surrounding organs. This is not a good choice. On the one hand, fragile tumor patients are prone to losing their lives due to infection and other problems. Data show that the 90-day mortality and morbidity of postoperative patients are 3-6% and 28-64% respectively; on the other hand, even if they survive successfully, patients must carry urine bags for life, and their quality of life declines. Survival is important, but living with dignity is a higher pursuit. This is also one of the reasons why many patients refuse RC and look forward to alternatives that can preserve the bladder. Based on this unmet clinical need, the FDA pointed out in the guidelines released in 2018 that the treatment goal for NMIBC patients who are unresponsive to BCG is to avoid RC.

At this time, NMIBC drug development is critical. The birth of any new drug is a very difficult process. The pathogenesis and biological characteristics of NMIBC are not yet clear, and the large heterogeneity makes it difficult to find therapeutic targets and verification. The high recurrence and progression rates require new drugs to not only effectively control tumors, but also reduce the risk of recurrence and progression to muscle-invasive bladder cancer (MIBC). The road is long and difficult. But biopharmaceuticals have always been like this. Where there is market demand, pharmaceutical companies will rush to develop research and development. Only with competition will better drugs be available, bringing patients greater hope for disease cure.

2024 can be said to be a year of accelerated breakthroughs in the field of NMIBC treatment. As mentioned above, in April, Anktiva was approved by the FDA as the first IL-15-based immunotherapy launched by ImmunityBio to treat NMIBC. IL-15 has a wide range of immunomodulatory activities, can promote the proliferation and activation of CD8+ cytotoxic T cells and NK cells, and is considered one of the most promising targets in cancer immunotherapy. Natural IL-15 has a short half-life, so the balance between safety and efficacy needs to be considered in drug development. Anktiva is an IL-15 superagonist complex, which is composed of a fusion of an IL-15 mutant and an IL-15 receptor α chain. Compared with natural IL-15, Anktiva has better pharmacokinetic properties, longer lymphoid tissue persistence, and enhanced anti-tumor activity, providing patients with another option to avoid radical cystectomy (RC).

Of course, Anktiva is not the first non-surgical alternative therapy for NMIBC. In early 2020, Keytruda was approved by the FDA as a monotherapy for high-risk non-muscle invasive bladder carcinoma in situ (CIS) who cannot or are unwilling to undergo surgery and are ineffective for BCG treatment. In 2022, the adenovirus-based gene therapy Adstiladrin was approved for marketing, providing patients with a new treatment option. However, Anktiva has potential advantages in efficacy.

Data from the KEYNOTE-057 trial showed that the 3-month complete remission (CR) rate of CIS patients who were unresponsive to BCG was 41%, and the median duration of remission (DoR) was 16.2 months; Adstiladrin targeted the same population, with a 3-month CR rate of 51% and a DoR of 9.7 months. The results of Anktiva's registration clinical trial QUILT-3.032 showed that with a follow-up time of 23.9 months, the CR rate of BCG-unresponsive CIS patients with or without Ta/T1-like lesions was 71%, and the median DoR was 26.6 months. Although these trials are not head-to-head comparisons and the data are not completely comparable, the DoR of up to 26.6 months is undoubtedly a significant advantage of Anktiva. The International Bladder Cancer Group (IBCG) has set a clinically significant DoR of 24 months for the treatment of NMIBC, and the target patients for this type of drug are those who want to control the progression of the disease and avoid surgery.

In November 2023, updated follow-up data further confirmed the efficacy of Anktiva. The results showed that the CR rate still reached 61%, and the longest DoR has exceeded 47 months and may be further extended. Of course, Anktiva is not without competition, and its strong enemies are still behind. The outcome of the competition between Anktiva and K drug and Adstiladrin is uncertain, and new competitors have unexpectedly emerged. Oncolytic virus therapy has always been highly anticipated in various tumor treatments due to its high selectivity and lethality to tumor cells. CG Oncology has taken the lead in making a wonderful debut in the field of oncolytic virus therapy for NMIBC.

Since its inception, CG Oncology has focused on developing anti-cancer oncolytic immunotherapy, and Cretostimogene is its masterpiece. As an adenovirus oncolytic virus, Cretostimogene can specifically recognize tumor cells and replicate in them. While directly lysing tumor cells, it releases tumor antigens and transgenic granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce immune response. This two-pronged strategy of using poison to fight poison has enabled Cretostimogene to show strong anti-tumor potential.

More directly, according to the latest Phase III clinical data released by CG Oncology, the CR rate of NMIBC patients who were unresponsive to BCG was as high as 75.2%. As of the data collection deadline, more than half of the subjects were still in remission, and the median DoR had not been reached but exceeded 9 months. At the deadline, the cystectomy-free survival rate (CFS) reached 92.4%, and the CFS of CR patients was 100%. For NMIBC patients, preserving the bladder as much as possible is undoubtedly the good news they want to hear most.

Based on Cretostimogene's excellent clinical data, CG Oncology plans to submit a new drug application to the FDA in the second half of 2025. At the same time, the company also plans to combine Cretostimogene with drug K, which has been recognized as a breakthrough therapy by the FDA in May 2023. Phase II clinical data of the combination therapy also showed great potential for bladder preservation therapy: the overall CR rate reached 83%, the CR rate at 12 months was 57%, and the CR rate at 24 months was 54%, of which 95% of patients maintained CR from 12 months to 24 months. The median DoR has not yet been reached, but it has exceeded 21 months. The 24-month CFS was 80%, and 100% of CR patients also did not need to receive RC.

Whether it is monotherapy or combination therapy, whether it is clinical data performance or indications, Cretostimogene has shown strong competitiveness. In this battle to protect the bladder, Cretostimogene has great potential. The clinical needs of NMIBC are large enough and unmet. Global pharmaceutical companies such as Johnson & Johnson and UroGen Pharma are accelerating pipeline research and development, and Chinese pharmaceutical companies are also actively exploring new therapies. For example, Rongchang Biopharma's HER2 ADC drug vedicizumab is making a breakthrough, and Lepu Biopharma directly owns the domestic rights of Cretostimogene. There are more and more treatment options for NMIBC, bringing hope to patients. Who can win in the NMIBC race depends on who can better protect the patient's bladder.

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