Nadofaragene Firadenovec NDA Accepted for Review in Japan for BCG-Unresponsive NMIBC

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The Pharmaceuticals and Medical Devices Agency of Japan accepted for review the new drug application (NDA) seeking the approval of nadofaragene firadenovec in patients with Bacillus Calmette–Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC).1

The NDA is supported by data from a phase 3 trial conducted in Japan, which were shared during the 2025 Japanese Urological Association Annual Meeting. A single quarterly administration of nadofaragene firadenovec led to a complete response (CR) rate of 75% at 3 months in Japanese patients with high-risk, BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without concomitant high-grade Ta or T1 papillary lesions (n = 20).2

Moreover, treatment-related adverse effects (AEs; n = 76) were observed in 80% of safety evaluable patients (n = 16); 64 of these AEs were grade 1 and occurred in 84.2% of patients and 12 of these AEs were grade 2 and occurred in 15.8% of patients. The toxicity profile was determined to be tolerable, with no grade 3 to 5 AEs reported.

“Nadofaragene firadenovec represents an option for those who failed NMIBC treatment,” Professor Keiji Inoue, MD, PhD, of the Department of Urology at Kochi Medical School, stated in a news release.1 “As the first choice after BCG failure, this bladder-sparing gene therapy offers patients a non-chemotherapy option that transforms their own bladder cells into interferon-producing factories. The 75% CR rate achieved with convenient quarterly dosing provides hope for patients who previously faced limited treatment options.”

What Was the Design of the Japanese Study?

The open-label, phase 3 study plans to enroll a total of 25 patients with high-risk BCG-unresponsive NMIBC with CIS only, Ta/T1 high-grade disease with concomitant CIS, or Ta/T1 high-grade disease without concomitant CIS.3 This included patients who

  • Did not respond to BCG treatment and experienced persistent high-grade recurrence within 1 year after initiation of BCG
  • Those with CIS who relapsed within 12 months of their last intravesical treatment despite achieving an initial CR, and
  • Those with high-grade Ta/T1 NMIBC who relapsed within 6 months of their last intravesical treatment

Additional eligibility criteria include life expectancy longer than 2 years, an ECOG performance status of 0 to 2. Upon enrollment, patients receive 75 mL of intravesical nadofaragene firadenovec once every 3 months via a urinary catheter without reinduction. Those who responded at the 3-month assessment will continue this dosing schedule until disease recurrence.2 The primary end point is CR rate at any time following the first dose.3 Secondary end points include duration of response (DOR), duration of event-free survival, time to cystectomy, overall survival (OS), and safety.

What Is Nadofaragene Firadenovec, and What Data Have Previously Been Reported?

The intravesical non-replicating gene therapy leverages a non-replicating adenovirus vector–based therapy containing the interferon alfa-2b gene. The product is administered via catheter directly into the bladder once every 3 months only. The approach leads to high and transient local expression of interferon alfa-2b protein, which strengthens the body’s natural capabilities to fight cancer.

Previously, data from the single-arm phase 3 Study CS-003 (NCT02773849) showed that the therapy elicited a 51% CR rate at 3 months in evaluable patients with high-risk BCG-unresponsive NMIBC with CIS with or without concomitant high-grade Ta or T1 disease (n = 98).4,5 The median DOR was 9.7 months (range, 3-52+). Notably, 46% of those who experienced an initial CR (n = 23) continued to be free of high-grade recurrence at 1 year. These data led to the December 2022 FDA approval of nadofaragene firadenovec-vncg (Adstiladrin) in adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.

At a median follow-up of 50.8 months (interquartile range, 39.1-60.0), 5.8% (95% CI, 2.2%-12.2%) of patients with CIS ± Ta/T1 (CIS; n = 106) were high grade recurrence free (HGRF) at 57 months; this was true for 15% (95% CI, 6.1%-27.8%) of those with Ta/T1 without CIS (Ta/T1; n = 50) at that time point.6 In the respective cohorts, the 57-month Kaplan-Meier–estimated HGRF survival rates were 13% (95% CI, 6.9%-12.5%) and 33% (95% CI, 19.5%-46.6%), respectively. Additionally, the 60-month cystectomy-free survival rate in the CIS cohort was 49% (95% CI, 40.0%-57.1%); in the Ta/T1 cohort, this was 59% (95% CI, 43.1%-71.4%). The 60-month OS rate was 80% (95% CI, 71.0%-86.0%) overall; in the CIS and Ta/T1 cohorts, the respective rates were 76% (95% CI, 64.6%-84.5%) and 86% (95% CI, 70.9%-93.5%).

The data from the Japanese trial were consistent with US real-world data shared by the Mayo Clinic, which showed that nadofaragene firadenovec elicited a CR rate of 79% in patients with BCG-unresponsive NMIBC (n = 29).1,7 At a median follow-up of 8.2 months, 72% of patients had a CR or were free from high-grade recurrence at 3 months and more than half (62%) maintained response at 6 months. Moreover, 94% of patients avoided cystectomy and all were alive at 6 months.

References

  1. Ferring Japan announces PMDA acceptance of NDA filing for nadofaragene firadenovec. News release. Ferring Pharmaceuticals Co., Ltd. September 11, 2025. Accessed September 11, 2025. https://www.businesswire.com/news/home/20250911332715/en/Ferring-Japan-announces-PMDA-Acceptance-of-NDA-Filing-for-nadofaragene-firadenovec
  2. Ferring announces initial data from phase 3 trial in Japanese patients demonstrating 75% complete response rate at 3 months with (nadofaragene firadenovec) in BCG-unresponsive NMIBC patients. News release. Ferring Pharmaceuticals. April 21, 2025. Accessed September 11, 2025. https://www.businesswire.com/news/home/20250421675994/en/Ferring-Announces-Initial-Data-from-Phase-3-Trial-in-Japanese-Patients-Demonstrating-75-Complete-Response-Rate-at-3-Months-with-nadofaragene-firadenovec-in-BCG-unresponsive-NMIBC-Patients1
  3. Safety and efficacy of FE 999326 administered intravesically to Japanese subjects with high-grade, BCG unresponsive, non-muscle invasive bladder cancer (NMIBC). ClinicalTrials.gov. Last updated February 13, 2025. Accessed September 11 ,2025. https://clinicaltrials.gov/study/NCT05704244
  4. FDA approves first gene therapy for the treatment of high-risk, non-muscle-invasive bladder cancer. News release. FDA. December 16, 2022. Accessed September 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin
  5. Nadofaragene firadenovec-vncg (Adstiladrin). Prescribing information; Ferring Pharmaceuticals; 2022. Accessed September 11, 2025. https://www.ferringusa.com/wp-content/uploads/sites/12/2022/12/ADSTILADRIN_pi.pdf
  6. Narayan VM, Boorjian SA, Alemozaffar M, et al. Efficacy of intravesical nadofaragene firadenovec for patients with BCG-unresponsive non-muscle invasive bladder cancer: 5-year follow-up from a phase 3 trial. J Urol. 2024;212(1):74-86. doi:10.1097/JU.0000000000004020
  7. Moyer J, Durant A, Nguyen M, et al. Real-world outcomes of nadofaragene firadenovec in BCG-unresponsive non-muscle invasive bladder cancer. J Clin Oncol. 2025;43(suppl 5):716. doi:10.1200/JCO.2025.43.5_suppl.716

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