Nadofaragene firadenovec

Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy designed to deliver a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to the bladder urothelium. Intravesical instillation of nadofaragene firadenovec results in cell transduction and transient local expression of the IFNα2b protein that is anticipated to have anti-tumor effects.

A Phase 1 first-in-human study was performed to determine the safety, tolerability, and maximum tolerated dose (MTD) of nadofaragene firadenovec in 17 patients with BCG-unresponsive NMIBC. Five dose levels (3 × 10⁹ vp/mL, 1 × 10¹⁰ vp/mL, 3 × 10¹⁰ vp/mL, 1 × 10¹¹ vp/mL, and 3 × 10¹¹ vp/mL; all in a dose volume of 75 mL) of nadofaragene firadenovec were tested and quantifiable concentrations of the pharmacodynamic marker IFNα2b protein were detected in the urine of all patients, with the exception of two patients at the lowest dose level. Measurable concentrations of urine IFNα2b protein up to Day 10 post-dose suggested expression of IFNα2b in the bladder. In a Phase 2 study, all patients had quantifiable concentrations of IFNα2b protein in the urine at Day 2 after dosing with nadofaragene firadenovec at two different dose levels (1 × 10¹¹ vp/mL and 3 × 10¹¹ vp/mL). Measurable concentrations of urine IFNα2b protein was detected up to Day 12 post-dose. This was more common in patients at the high dose level.

Generally, higher IFNα2b concentrations and exposure were observed with increasing doses of nadofaragene firadenovec.

Nonclinical data

Human IFN protein in urine, and vector-specific DNA in blood and tissue samples, were detectable following nadofaragene firadenovec dosing in monkeys, with higher levels at higher doses. All monkeys had vector-specific DNA in the bladder tissue at necropsy on Days 8 and 98 (i.e., seven days after the first and second dose, respectively). Vector-specific DNA was also detected in a limited number of monkeys in the liver, kidney and gonad. At Day 148, only one animal showed vector-specific DNA in one tissue (kidney).

Clinical data

Nadofaragene firadenovec biodistribution and shedding were investigated in two clinical studies. Only a single patient receiving a second dose in one study (Phase 2 study) at dose level of 3 × 10¹¹ vp/mL (2.25 × 10¹³ vp) had measurable vector DNA in blood; no other patients in either study had measurable vector DNA at one hour post-dosing in blood. In urine, measurable vector DNA was detected in both studies. Generally, a higher frequency of detection of urine samples positive for vector-derived DNA, and persistence of vector-derived DNA, correlated with increasing dose level.

At the dose level of 3 × 10¹¹ vp/mL (2.25 × 10¹³ vp), one patient (out of 4 enrolled) had detectable levels of vector DNA at Day 14 in the Phase 1 study and 16 subjects (out of 19 at visit) had detectable levels of vector DNA at Day 12 in the Phase 2 study.