Nadofaragene firadenovec

Nadofaragene firadenovec is a non-replicating recombinant type 5 adenovirus vector-based gene therapy containing the human IFNα2b transgene. Intravesical administration of nadofaragene firadenovec results in the entry of viral particles into the tumour cells and the urothelium that make up the luminal surface of the bladder, leading to the expression of IFNα2b protein by those cells. In the transduced cells, the viral DNA does not integrate into the genome. Treatment with nadofaragene firadenovec has shown anti-tumour effects in mice with bladder (cancer cell) xenografts.

The pharmacodynamic marker IFNα2b was present in urine from all patients in the phase 1 and 2 studies except for two patients at the lowest dose level in the phase 1 study (3 × 10⁹ vp/mL). Urine IFNα2b protein was detected up to Day 12 post-dose.

Quantifiable levels of IFNα2b protein in serum were detected in a subset of patients (4 out of 17) in the phase 1 study. The extent of exposure was low and transient with a maximum of a 96-hour duration of exposure post-dose. In the phase 2 study, 12 out of 40 patients had measurable serum IFNα2b protein at month 1 day 2 and 2 out of 40 patients by day 12.

There was no detectable systemic exposure of vector-derived DNA in patients in the phase 1 and 2 studies, except for in 1 out of 40 patients in the phase 2 study.

Vector-specific DNA was present in the urine of most of the patients in the phase 1 study and all patients in the phase 2 study. Presence was correlated to the dose level. The vector-specific DNA persisted for at least 14 days in the phase 1 study and at least 12 days in the phase 2 study. 3 out of 23 (13%) patients in the phase 2 study were positive for vector-specific DNA prior to the second dose.

The excipient Syn3NODA enhances an efficient entry of the adenovirus into the urothelial cells. Systemic exposure of Syn3NODA was assessed in the phase 1 study and was found to be transient with a mean elimination t½ of 8.4 hours with no evidence of retention.

In a repeat-dose toxicity study in monkeys, intravesical nadofaragene firadenovec caused mild to moderate urinary tract inflammation, including chronic inflammation in the tunica muscularis, ulceration, and tissue changes (urothelial hyperplasia and cytoplasmic vacuolation) after the first and second doses. Following a 2-month recovery period after the second dose, partial resolution was observed, with minimal urothelial inflammation and fibrosis in the lamina propria of the bladder remaining in a few animals.

Carcinogenicity studies have not been conducted with nadofaragene firadenovec.

Reproductive toxicity studies have not been conducted with nadofaragene firadenovec. The excipient Syn3NODA distributed to the ovary and uterus in female rats and to the testes and prostate in male rabbits after intravesical dosing. Nadofaragene firadenovec distributed to ovary in female monkeys and testes in male monkeys after intravesical dosing. In repeat-dose toxicity studies with Syn3NODA, there were no treatment-related macroscopic or histopathologic findings in reproductive tissues of rats (IV study, Syn3NODA only) or cynomolgus monkeys (intravesical study) at exposures up to 143-fold and 124-fold, 47-fold and 57-fold the clinical systemic AUC in female and male monkeys, female rats and male rats, respectively. In a repeat-dose toxicity study with nadofaragene firadenovec, there were no treatment-related macroscopic or histopathologic findings in reproductive tissues of cynomolgus monkeys at exposures up to 11-fold the clinical systemic dose.

Syn3NODA has been demonstrated to be non-genotoxic both in in vitro assays (bacterial mutagenicity and chromosome aberration in human lymphocytes) and in an in vivo rat micronucleus study.