First Gene Therapy Receives FDA Approval for Bladder Cancer

On 16 December 2022, the US Food and Drug Administration (FDA) approved Adstiladrin (nadofaragene firadenovec-vncg), a gene therapy for bladder cancer. Recommended for adults with high-risk, non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin (BCG), it is an adenoviral vector-based gene therapy that does not replicate in human cells.

Most bladder cancers are diagnosed early, but the risks of recurrence and spread are high.

Bladder cancer is common and usually begins in the bladder’s inner lining. Over time, cancer cells may metastasise, or spread. Around 75%-80% of newly diagnosed cases are early stage and have not invaded the bladder muscle. This is called non-muscle-invasive bladder cancer (NMIBC). It carries a high recurrence risk, around 30%-80%, as well as a risk of metastasis.

Treatment for high-risk non-muscle-invasive bladder cancer, including carcinoma in situ (CIS), usually involves scraping out the tumour through transurethral resection, known as TUR-M, and BCG. Few effective options are available for BCG-unresponsive patients.

Without treatment, these cancers may invade muscle and then spread to lymph nodes and other tissues or organs. In the United States, around 57 thousand men and 18 thousand women are diagnosed annually, while approximately 12 thousand men and 4.7 thousand women die from the disease. Türkiye Cancer Statistics 2020 reported 12.2 thousand new bladder cancer cases in 1 year and 3.7 thousand annual deaths in Türkiye.

How Does Nadofaragene Firadenovec-vncg Work?

Adstiladrin, whose active molecule is nadofaragene firadenovec-vncg, uses a non-replicating adenoviral vector containing the interferon alpha-2b gene. The modified virus enters cells in the bladder lining and releases the active gene. These cells then produce large amounts of interferon alpha-2b, a protein the body naturally uses in the immune response against cancer. This approach turns patients’ bladder wall cells into interferon microfactories and strengthens the anticancer immune response. Adstiladrin can therefore also be regarded as a form of immunotherapy.

The Study Leading to FDA Approval of Nadofaragene Firadenovec-vncg

Safety and effectiveness were assessed in a multicentre study of 157 patients with high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer. Of these, 98 had BCG-unresponsive carcinoma in situ, with or without papillary tumours.

Patients received Adstiladrin every three months for up to 12 months, until unacceptable toxicity or cancer recurrence.

• Overall, 51% of enrolled patients receiving Adstiladrin achieved a complete response.

Complete response meant disappearance of all cancer signs on cystoscopy, biopsied tissue examination and urine testing.

• Median response duration was 9.7 months. Among responders, 46% maintained a complete response for at least one year.

Adstiladrin is delivered into the bladder through a urinary catheter every three months. The most common adverse effects include bladder discharge, fatigue, bladder spasms, urinary urgency, haematuria, chills, fever and painful urination. The reported US cost for 1 year of treatment was around 200 thousand dollars per patient. It should not be administered to people who are immunosuppressed or immunodeficient.