ADSTILADRIN Suspension for intravesical instillation Ref.[107265] Active ingredients: Nadofaragene firadenovec

A Phase 1 first-in-human study was performed to determine the safety, tolerability, and maximum tolerated dose (MTD) of ADSTILADRIN 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 ADSTILADRIN 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 ADSTILADRIN 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 ADSTILADRIN.

Nonclinical data

Human IFN protein in urine, and vector-specific DNA in blood and tissue samples, were detectable following ADSTILADRIN 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

ADSTILADRIN 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.

No animal studies have been conducted to evaluate the effects of ADSTILADRIN on carcinogenesis, mutagenesis, or impairment of fertility.

In cynomolgus monkeys, two repeat intravesical administrations of ADSTILADRIN of either 2.5 × 10 ¹¹ or 1.25 × 10¹³ viral particles (1 × 10¹¹ or 5 × 10¹¹ viral particles/mL, 90 days apart) were associated with inflammation, urothelial hyperplasia, cytoplasmic vacuolation, and focal/multifocal ulceration in the urinary bladder and irritation in the ureter and urethra at necropsy 7 days after the first and second doses. Near complete resolution of these findings was observed following the 57-day recovery period after the second administration, with minimal fibrosis in the lamina propria of the bladder in a limited number of monkeys. Both dose level groups developed antibodies to the adenovirus and human interferon protein.

The efficacy of ADSTILADRIN was evaluated in CS-003 (NCT02773849), an open-label, multicenter, single-arm trial in 103 adults with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors following transurethral resection, of whom 98 were considered evaluable for response. BCG-unresponsive high-risk NMIBC was defined as persistent disease following adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG was defined as the administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with extra-vesical (i.e., urethra, ureter, or renal pelvis), muscle invasive (T2-T4), or metastatic urothelial carcinoma.

Patients received ADSTILADRIN 75 mL intravesical instillation (3 × 10¹¹ vp) once every three months for up to 12 months (four doses) or until unacceptable toxicity or recurrent high-grade (HG) NMIBC. Patients without evidence of HG recurrence were allowed to continue ADSTILADRIN treatment every three months.

The major efficacy outcome measures were complete response (CR) at any time (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable] and urine cytology) and duration of response. Low-grade (Ta) papillary disease was not considered a recurrence for the purposes of evaluating CR. CR was assessed at 3, 6, 9, and 12 months by cystoscopy and cytology. Random bladder biopsy of five sites was conducted in patients remaining in CR at Month 12. Assessment of durability of CR subsequent to these evaluations was performed per local standards of care.

The evaluable CIS study population characteristics were median age of 70 (range 44-89) with 32% >75 years of age; 88% male, 92% White. Tumor pattern at study entry was CIS with T1 (5%), CIS with high-grade Ta (19%), and CIS (76%). The median number of instillations of prior BCG was 12 (range 8 to 18).

Efficacy results are summarized in Table 3.

Table 3. Efficacy Results in Study CS-003:

^* Based on patients (n=50) that achieved a complete response; reflects period from the time complete response was achieved.