Nadofaragene firadenovec API Manufacturers

General Description:

Nadofaragene firadenovec, identified by CAS number 1823059-12-6, is a notable compound with significant therapeutic applications. Nadofaragene firadenovec (nadofaragene firadenovec-vncg) is a recombinant non-replicating adenovirus serotype 5 vector containing a transgene encoding human interferon alfa-2b (IFNα2b). It was approved by the FDA on December 2022 for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma _in situ_ (CIS) with or without papillary tumors. It is the first gene therapy approved by the FDA for the treatment of bladder cancer. BCG-unresponsive NMIBC has a high recurrence and is notably difficult to treat. Most patients with this condition undergo radical cystectomy since other non-surgical treatments are far less effective. The use of nadofaragene firadenovec provides a therapeutic alternative to patients seeking non-surgical alternatives for the treatment of BCG-unresponsive NMIBC. Nadofaragene firadenovec is formulated with an excipient (Syn-3) that facilitates gene transfer across the urothelium and promotes the transduction of IFNα2b. The localized expression of this gene induces anti-tumor effects. Nadofaragene firadenovec also has a manageable adverse event profile. Compared to , a smaller proportion of patients experienced grade 3-4 adverse events (4% vs 12.7%).

Indications:

This drug is primarily indicated for: Nadofaragene firadenovec is indicated for the treatment of adult patients with high-risk Bacillus CalmetteGuérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma _in situ_ (CIS) with or without papillary tumors. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Nadofaragene firadenovec undergoes metabolic processing primarily in: As a gene therapy medicinal product, nadofaragene firadenovec is expected to be metabolized by nucleases throughout the body. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Nadofaragene firadenovec are crucial for its therapeutic efficacy: The biodistribution of nadofaragene firadenovec was evaluated in two clinical studies. One of the patients given a second dose of nadofaragene firadenovec at 3 x 10¹¹ vp/mL (2.25 x 10¹³ vp) had measurable vector DNA in blood. The rest of the patients did not have measurable vector DNA in blood one hour after nadofaragene firadenovec administration. In a phase 1 study, one out of 4 patients given 3 x 10¹¹ vp/mL (2.25 x 10¹³ vp) of nadofaragene firadenovec had detectable levels of vector DNA at Day 14. In a phase 2 study, 16 out of 19 patients had detectable levels of vector DNA at Day 12. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Route of Elimination:

The elimination of Nadofaragene firadenovec from the body primarily occurs through: Nadofaragene firadenovec can be detected in urine. The frequency of detection of urine samples positive for vector-derived DNA and persistence of vector-derived DNA is correlated with the dose level. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Pharmacodynamics:

Nadofaragene firadenovec exerts its therapeutic effects through: The safety, tolerability, and maximum tolerated dose (MTD) of nadofaragene firadenovec were evaluated in a phase 1 first-in-human study that enrolled patients (n=17) with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Patients were given five different dose levels in a dose volume of 75 ml: 3 x 10⁹ vp/mL, 1 x 10¹⁰ vp/mL, 3 x 10¹⁰ vp/mL, 1 x 10¹¹ vp/mL, and 3 x 10¹¹ vp/mL; and human interferon alfa-2b (IFNα2b) protein was used as a pharmacodynamic marker. Except for two patients given the lowest nadofaragene firadenovec dose, IFNα2b protein was detected in the urine of all patients. IFNα2b protein was detected up to 10 days after nadofaragene firadenovec administration, suggesting that IFNα2b is expressed in the bladder. Following nadofaragene firadenovec administration, measurable concentrations of IFNα2b protein were detected in urine up to day 12 post-dose, and this was more common in patients at the high dose level. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Nadofaragene firadenovec functions by: Non-muscle invasive bladder cancer (NMIBC) that is unresponsive to Bacillus Calmette-Guérin (BCG) therapy is a type of cancer that is highly difficult to treat. Patients with BCG-unresponsive NMIBC usually undergo radical cystectomy; however, a surgical procedure may not be possible in all patients. For these patients, gene therapies such as nadofaragene firadenovec can be used as an alternative. Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy carrying a copy of a human interferon-alfa 2b (IFNα2b) gene combined with Syn-3, a polyamide surfactant that facilitates gene transfer across the urothelium and enhances viral transduction. The local expression of IFNα2b in the urothelium has pleiotropic anti-tumor effects. Preclinical studies showed that IFNα induced apoptosis in human BCG-unresponsive bladder cancer (BLCA) cells via the induction of autocrine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) production. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Nadofaragene firadenovec is categorized under the following therapeutic classes: Adeno-associated Viral Vector Therapies, Antineoplastic Agents, Cellular and Gene Therapy, Genetic Therapy, Recombinant Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.