What Is Nadofaragene Firadenovec?
Nadofaragene Firadenovec is an FDA-approved medication for the treatment of Non-Muscle Invasive Bladder Cancer (NMIBC). It is a vector-based gene therapy designed to deliver a specific gene into bladder cells. This gene encodes for human interferon (IFN) alfa-2b, which helps to amplify the body's immune response against cancer cells. The therapy utilizes a non-replicating recombinant adenovirus serotype 5 vector to carry the IFN-α2b gene directly to the affected area, aiming to potentiate durable therapeutic responses.
Beyond its approved use for NMIBC, nadofaragene firadenovec is currently being investigated in clinical trials for other forms of bladder cancer. These include muscle invasive bladder urothelial carcinoma, carcinoma in situ (CIS), and low-grade upper tract urothelial carcinoma. Studies are exploring its potential effectiveness in combination with other treatments, such as chemotherapy and immunotherapy, or as a standalone therapy for various stages of bladder cancer, including Stage II and Stage IIIA bladder cancer.
Uses and Conditions Under Study
Nadofaragene firadenovec is primarily studied for various forms of bladder cancer. The drug is FDA-approved for Non-Muscle Invasive Bladder Cancer (NMIBC), a type of cancer that is confined to the lining of the bladder and has not spread into the muscle layer. For patients with NMIBC, nadofaragene firadenovec is believed to help by stimulating an immune response within the bladder, potentially leading to more lasting therapeutic effects. This condition is a focus in at least one trial, which compares its effectiveness to other standard treatments.
The medication is also being investigated for other specific types and stages of bladder cancer. These include Muscle Invasive Bladder Urothelial Carcinoma, where it is being tested in combination with other drugs before radical cystectomy. Carcinoma in Situ (CIS), a high-grade form of NMIBC, is another condition under study, where the gene therapy aims to induce a strong local immune reaction. Low-grade Upper Tract Urothelial Carcinoma is also being explored, with trials investigating its safety and efficacy when instilled into the renal pelvis.
Additionally, nadofaragene firadenovec is being studied for specific staging classifications of bladder cancer, such as Stage II Bladder Cancer AJCC v8 and Stage IIIA Bladder Cancer AJCC v8, and for tumors classified as Ta/T1. In total, nadofaragene firadenovec is being studied across six trials involving 882 participants, with four trials currently recruiting. These trials are sponsored by entities such as Ferring Pharmaceuticals, Memorial Sloan Kettering Cancer Center, and the University of Washington.
Conditions under study include:
- Bladder Cancer
- CIS
- Intermediate Risk Non-Muscle Invasive Bladder Cancer
- Low-grade Upper Tract Urothelial Carcinoma
- Muscle Invasive Bladder Urothelial Carcinoma
- Non-Muscle Invasive Bladder Cancer
- Non-muscle Invasive Bladder Cancer With Carcinoma in Situ
- Stage II Bladder Cancer AJCC v8
- Stage IIIA Bladder Cancer AJCC v8
- Ta/T1
Dosing
Nadofaragene firadenovec is administered as an intravesical instillation, meaning it is delivered directly into the bladder using a catheter. It is also being investigated for instillation into the renal pelvis for certain conditions like low-grade upper tract urothelial carcinoma. The investigational medicinal product dose, concentration, and assessments are aligned with the US prescribing information for nadofaragene firadenovec, indicating a standardized approach to its use.
For patients randomized to receive nadofaragene firadenovec, a common regimen involves instilling the medication intravesically every 3 months for up to 12 months. Specific dosage forms studied in trials include nadofaragene firadenovec as a standalone treatment, and in combination with other therapies. These combinations include nadofaragene firadenovec with gemcitabine and docetaxel, or with pembrolizumab. One phase II trial is testing nadofaragene firadenovec in combination with gemcitabine, cisplatin, and durvalumab before radical cystectomy for muscle invasive bladder cancer.
The drug is studied in various treatment arms, such as "Arm 1 Nadofaragene Firadenovec" and "Arm 2 - Observation," to compare its effectiveness against no treatment or best usual care. The trials do not specify different pediatric doses, focusing on adult administration for bladder cancer conditions.
Side Effects
The most common side effects experienced by patients taking Nadofaragene Firadenovec were related to the bladder and urinary tract. In clinical trials, 21% of patients receiving Nadofaragene Firadenovec experienced bladder spasm, compared to 10% of patients on placebo. Other common side effects included:
- Micturition urgency (an urgent need to urinate): 19% of patients taking Nadofaragene Firadenovec experienced this, compared to 10% on placebo.
- Dysuria (painful urination): 14% of patients taking Nadofaragene Firadenovec experienced this, compared to 7% on placebo.
- Hematuria (blood in urine): 14% of patients taking Nadofaragene Firadenovec experienced this, compared to 9% on placebo.
- Chills: 11% of patients taking Nadofaragene Firadenovec experienced this, compared to 3% on placebo.
- Fatigue: 11% of patients taking Nadofaragene Firadenovec experienced this, compared to 5% on placebo.
- Nausea: 10% of patients taking Nadofaragene Firadenovec experienced this, compared to 5% on placebo.
- Pyrexia (fever): 10% of patients taking Nadofaragene Firadenovec experienced this, compared to 3% on placebo.
Clinical Trial Results
Treatment for High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC)
The effectiveness of Nadofaragene Firadenovec was evaluated in a Phase 3, single-arm, open-label clinical trial (NCT02564722). This study included 151 adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) that included carcinoma in situ (CIS), with or without accompanying papillary tumors. These patients had previously received BCG treatment, a common immunotherapy for bladder cancer, but their cancer either did not respond to the treatment or returned. For such patients, treatment options can be limited, making new therapies particularly important. The trial aimed to assess how well Nadofaragene Firadenovec could achieve a complete response and prevent cancer recurrence.
The primary goal of the study was to determine the rate of complete response (CR) at 3 months. A complete response means that all signs of cancer have disappeared. Key findings from this trial include:
- Complete Response at 3 Months: 48.3% (73 out of 151) of patients treated with Nadofaragene Firadenovec achieved a complete response at 3 months after starting treatment.
- Duration of Complete Response: Among those who achieved a complete response, 46% maintained their response for at least 12 months. The median duration of complete response was 9.7 months, meaning half of the responders maintained their response for at least 9.7 months.
- Recurrence-Free Survival: For patients with carcinoma in situ (CIS) with or without papillary tumors, the 12-month recurrence-free survival rate was 43.7%. This means that nearly 44% of these patients were free from cancer recurrence for at least 12 months. For the subgroup of patients with papillary tumors only, the 12-month recurrence-free survival rate was 30.6%.
The trial demonstrated that Nadofaragene Firadenovec can lead to complete responses and sustained periods without cancer recurrence in patients with high-risk BCG-unresponsive NMIBC.
Currently Recruiting Trials
Nadofaragene firadenovec is currently being investigated in several clinical trials for various forms of bladder cancer. These studies aim to further understand its safety and effectiveness, offering opportunities for patients to contribute to medical research and potentially benefit from new treatments.
One ongoing study, NCT06668493, is a Phase 1/Phase 2 trial evaluating Nadofaragene Firadenovec in individuals with Low-grade Upper Tract Urothelial Carcinoma (LG-UTUC). This study focuses on the safety and tolerability of the treatment when administered to the renal pelvis. It plans to enroll 20 participants to assess complete response at 3 or 6 months.
Another Phase 3 study, NCT06929286, is comparing Nadofaragene Firadenovec to standard treatments for Non-Muscle Invasive Bladder Cancer (NMIBC). This trial, sponsored by Memorial Sloan Kettering Cancer Center, aims to enroll 125 participants to compare the effectiveness of Nadofaragene Firadenovec against other NCCN-recommended standard treatments, such as gemcitabine.
Ferring Pharmaceuticals is sponsoring NCT06510374, a Phase 3 randomized, controlled trial. This study is comparing Nadofaragene Firadenovec against observation in participants with Intermediate Risk Non-Muscle Invasive Bladder Cancer. It seeks to enroll 454 individuals to evaluate the treatment's impact.
Additionally, NCT06545955 is a Phase 3 trial investigating Nadofaragene Firadenovec alone or in combination with chemotherapy (gemcitabine and docetaxel) or immunotherapy (Pembrolizumab). This study focuses on participants with High-grade BCG Unresponsive Non-muscle Invasive Bladder Cancer with Carcinoma in Situ. It aims to enroll 250 participants, building on previous research where 53.4% of subjects achieved a complete response at 3 months in a pivotal trial.
Where to Participate
Clinical trials for Nadofaragene Firadenovec are widely accessible across the United States, with studies actively recruiting at 76 sites in 64 cities across 29 states. This broad reach helps ensure that many patients have the opportunity to participate in these important research efforts.
Top recruiting locations include:
- New York, New York (6 sites)
- Houston, Texas (5 sites)
- Atlanta, Georgia (3 sites)
- Philadelphia, Pennsylvania (3 sites)
- Los Angeles, California (3 sites)
- Dallas, Texas (3 sites)
To be eligible for participation, individuals must generally be between 18 to 21 years of age or older, depending on the specific trial. All genders are welcome, but these studies do not recruit healthy volunteers or children.
Development Timeline
The journey of Nadofaragene Firadenovec in clinical development began in 2024, with the first trial initiated on April 30th. Since then, the development program has steadily expanded, primarily driven by Ferring Pharmaceuticals, which sponsors the majority of the studies. Memorial Sloan Kettering Cancer Center and the University of Washington have also contributed to the research efforts.
Initially, the drug was explored for conditions such as IBS-C and hyperphosphatemia. However, the focus quickly shifted and broadened to address various forms of bladder cancer. The pipeline now includes studies for Intermediate Risk Non-Muscle Invasive Bladder Cancer, Low-grade Upper Tract Urothelial Carcinoma, Muscle Invasive Bladder Urothelial Carcinoma, Non-Muscle Invasive Bladder Cancer, Non-muscle Invasive Bladder Cancer With Carcinoma in Situ, Stage II Bladder Cancer AJCC v8, Stage IIIA Bladder Cancer AJCC v8, and Ta/T1 bladder cancer.
To date, a total of six clinical trials have been initiated, with a combined enrollment target of 882 participants. The development has progressed significantly, with three studies currently in Phase 3, one in Phase 1/Phase 2, one in Phase 2, and one in Phase 4, reflecting a robust and ongoing commitment to understanding Nadofaragene Firadenovec's potential.