Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Ferring Pharmaceuticals A/S, Amager Strandvej 405, 2770 Kastrup, Denmark
Pharmacotherapeutic group: Antineoplastic agents. Antineoplastic cell and gene therapy
ATC code: L01XL10
ADSTILADRIN is a non-replicating recombinant type 5 adenovirus vector-based gene therapy containing the human IFNα2b transgene. Intravesical administration of ADSTILADRIN 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.
The efficacy and safety of ADSTILADRIN was evaluated in Study CS-003 (NCT02773849), an open-label, single arm, multicentre, pivotal study in 157 patients with high-grade (HG) BCG-unresponsive NMIBC. The study included 107 patients with Carcinoma in situ (CIS) with or without concomitant HG Ta or T1 tumours (CIS ± Ta/T1), and 103 of those patients were evaluated for efficacy.
BCG-unresponsive high-risk NMIBC was defined as persistent disease following adequate BCG therapy, disease recurrence after an initial tumour-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy 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 tumour (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The study excluded patients with extra-vesical (i.e., urethra, ureter, or renal pelvis), muscle invasive (T2-T4), or metastatic urothelial carcinoma.
The primary objective was to evaluate complete response (CR) rate (as defined by negative results for cystoscopy, with TURBT/biopsies as applicable, and urine cytology). Secondary objective was to evaluate durability of CR.
Disease status was assessed every 3 months by cystoscopy, cytology and biopsies when clinically indicated. Mandatory bladder biopsies were conducted in patients remaining in response at Month 12.
Patients received ADSTILADRIN (75 mL intravesical instillation with 3 × 1011 viral particles/mL, see section 4.2) treatment every three months for 12 months in absence of HG-recurrence. All patients were offered continued ADSTILADRIN treatment in the absence of HG recurrence and followed for safety irrespective of continued treatment for up to 5 years from the first dose.
The efficacy CIS study population (n=103) characteristics were median age of 71 years (ranging from 44 to 89 years), with 76.7% of the patients being above 65 years of age. 88.3% of the patients were male and 11.7% female. Tumour pattern at study entry was CIS with T1 (4.9%), CIS with high-grade Ta (18.4%), and CIS only (76.7%). The median number of prior BCG instillations was 12 (range 8 to 18).
ADSTILADRIN met the primary endpoint of complete response at month 3 in patients with CIS ± Ta/T1.
The efficacy results are summarised in Table 2.
Table 2. Efficacy results from Study CS-003:
The European Medicines Agency has waived the obligation to submit the results of studies with ADSTILADRIN in all subsets of the paediatric population for the treatment of malignant bladder neoplasms (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
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.
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