FDA Approves First Gene Therapy for Bladder Cancer

SUMMARY: The FDA on December 16, 2022, approved ADSTILADRIN® (Nadofaragene firadenovec-vncg) for adult patients with high-risk Bacillus Calmette-Guérin (BCG) unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS) with or without papillary tumors. According to the American Cancer Society, 81,180 new cases of bladder cancer were diagnosed in 2022 and 17,100 died of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. The current standard intervention for superficial bladder cancers-Non-Muscle Invasive Bladder Cancer (NMIBC) involves removing the bladder tumor and intravesical treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, for patients with high-risk Non-Muscle Invasive Bladder Cancer, including those with Carcinoma in Situ, High Grade T1, or large-volume or recurrent Ta tumors, to reduce the risk of recurrence. Although 80% of patients have an initial complete response to BCG, more than half of patients have recurrence and progression within the first year, and develop resistance to BCG. These patients are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes. The development of a safe, effective and durable intravesical treatment remains a critical unmet need for patients who want to avoid radical cystectomy or systemic immunotherapy.

ADSTILADRIN® (Nadofaragene firadenovec-vncg) is a nonreplicating recombinant adenovirus vector-based gene therapy, that delivers a copy of the human Interferon alfa-2b gene to the patient’s bladder urothelial cells. This novel gene therapy approach provides a longer duration of exposure of the urothelium to Interferon alfa-2b, by allowing the urothelial cells to produce Interferon on an ongoing basis. The safety and efficacy of intravesical ADSTILADRIN® for patients with BCG-refractory and relapsing non-muscle-invasive bladder cancer, was demonstrated in Phase I and Phase II clinical trials. The present study was conducted to evaluate the efficacy and safety of intravesical ADSTILADRIN® in a larger population of patients with BCG-unresponsive Non-Muscle Invasive Bladder Cancer.

This Phase III multicenter, open-label, single-arm trial enrolled 157 patients with high-risk Non-Muscle Invasive Bladder Cancer, 98 of whom had BCG-unresponsive Carcinoma in Situ, evaluable for response. A single-arm design was adopted as there is no standard treatment for this patient population. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following BCG. Patients received ADSTILADRIN® 75 mL intravesical instillation (3 x 1011 viral particles/mL) once every three months up to 12 months, unacceptable toxicity, or recurrent high-grade NMIBC. Patients without high-grade recurrence were allowed to continue ADSTILADRIN® every three months. The major efficacy outcome measures were Complete Response (CR) at any time and Duration of Response (DoR). CR was defined as negative cystoscopy with applicable TransUrethral Resection of Bladder Tumor (TURBT) and biopsies, and urine cytology. Random bladder biopsies of five sites were conducted in patients remaining in CR at 12 months.

The Complete Response Rate was 51%, the median Duration of Response was 9.7 months and 46% of responding patients remained in Complete Response for at least one year. The most common grade 3 adverse reaction was micturition urgency (1%). Most of patients experienced Grade 1 Adverse Events which included mild fatigue and bladder spasms. The most common Grade 3 toxicity was urinary urgency noted in 1% of patients.

This study has demonstrated that Intravesical delivery of the adenoviral vector containing the human recombinant Interferon alfa-2b gene was associated with promising efficacy outcomes, with an acceptable safety profile. ADSTILADRIN® is a novel treatment option and alternative to chemotherapy and systemic therapies and is the first FDA-approved gene therapy for bladder cancer.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin