NAV

Nadofaragene firadenovec

Identification

Summary

Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy used to treat high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS).

Brand Names
Adstiladrin
Generic Name
Nadofaragene firadenovec
DrugBank Accession Number
DB17381
Background

Nadofaragene firadenovec (nadofaragene firadenovec-vncg) is a recombinant non-replicating adenovirus serotype 5 vector containing a transgene encoding human interferon alfa-2b (IFNα2b).5 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.5,6

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.2 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.1,5 Nadofaragene firadenovec also has a manageable adverse event profile. Compared to pembrolizumab, a smaller proportion of patients experienced grade 3-4 adverse events (4% vs 12.7%).2

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Other gene therapies
Synonyms
  • Instiladrin
  • Nadofaragene firadenovec
  • Nadofaragene firadenovec-vncg
  • RAD-IFN
  • RAD-IFN-2B
  • Replication-deficient adenovirus type 5 (ad5) vector encoding the human interferon alpha 2 (ifna2, interferon alpha-2b) gene under the control of the cytomegalovirus (cmv) immediate-early enhancer/promoter
  • SCH-209702/SCH-721015
External IDs
  • RAD-IFN
  • RAD-IFN-2B
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Pharmacology

Indication

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.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofHigh risk bcg-unresponsive non-muscle invasive bladder cancer•••••••••••••••••••••••••• •• •••• ••••••• ••••••••• ••••••••••••••••
Treatment ofHigh risk bcg-unresponsive non-muscle invasive bladder cancer•••••••••••••••••••••••••• •• •••• •••• ••••••••• ••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.5

Mechanism of action

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.2,3 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.1,4,5 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.3,5

Absorption

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 12.5

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

As a gene therapy medicinal product, nadofaragene firadenovec is expected to be metabolized by nucleases throughout the body.

Route of elimination

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.5

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Toxicity information regarding nadofaragene firadenovec is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as disseminated adenovirus infection.5 Symptomatic and supportive measures are recommended. The carcinogenic, mutagenic and fertility effects of nadofaragene firadenovec have not been evaluated.5 Cynomolgus monkeys given 2.5 x 1011 or 1.25 x 1013 viral particles of nadofaragene firadenovec 90 days apart (1 x 1011 or 5x1011 viral particles/mL) experienced 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. These findings were resolved following the 57-day recovery period after the second administration. At this point, a limited number of monkeys had minimal fibrosis in the lamina propria of the bladder.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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International/Other Brands
Adstiladrin (Ferring Pharmaceuticals)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AdstiladrinSuspension300000000000 {VP}/1mLIntravesicalFerring Pharmaceuticals2023-07-01Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0OOS09O1FH
CAS number
1823059-12-6

References

General References
  1. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, Bivalacqua TJ, Montgomery JS, Lerner SP, Busby JE, Poch M, Crispen PL, Steinberg GD, Schuckman AK, Downs TM, Svatek RS, Mashni J Jr, Lane BR, Guzzo TJ, Bratslavsky G, Karsh LI, Woods ME, Brown G, Canter D, Luchey A, Lotan Y, Krupski T, Inman BA, Williams MB, Cookson MS, Keegan KA, Andriole GL Jr, Sankin AI, Boyd A, O'Donnell MA, Sawutz D, Philipson R, Coll R, Narayan VM, Treasure FP, Yla-Herttuala S, Parker NR, Dinney CPN: Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan;22(1):107-117. doi: 10.1016/S1470-2045(20)30540-4. Epub 2020 Nov 27. [Article]
  2. Kulkarni GS: Nadofaragene firadenovec: a new gold standard for BCG-unresponsive bladder cancer? Lancet Oncol. 2021 Jan;22(1):8-9. doi: 10.1016/S1470-2045(20)30586-6. Epub 2020 Nov 27. [Article]
  3. Mokkapati S, Narayan VM, Manyam GC, Lim AH, Duplisea JJ, Kokorovic A, Miest TS, Mitra AP, Plote D, Anand SS, Metcalfe MJ, Dunner K Jr, Johnson BA, Czerniak BA, Nieminen T, Heikura T, Yla-Herttuala S, Parker NR, Schluns KS, McConkey DJ, Dinney CP: Lentiviral interferon: A novel method for gene therapy in bladder cancer. Mol Ther Oncolytics. 2022 Jun 10;26:141-157. doi: 10.1016/j.omto.2022.06.005. eCollection 2022 Sep 15. [Article]
  4. Deininger S, Torzsok P, Mitterberger M, Pallauf M, Oswald D, Deininger C, Lusuardi L: From Interferon to Checkpoint Inhibition Therapy-A Systematic Review of New Immune-Modulating Agents in Bacillus Calmette-Guerin (BCG) Refractory Non-Muscle-Invasive Bladder Cancer (NMIBC). Cancers (Basel). 2022 Jan 29;14(3):694. doi: 10.3390/cancers14030694. [Article]
  5. FDA Approved Drug Products: ADSTILADRIN (nadofaragene firadenovec-vncg) suspension for intravesical use [Link]
  6. Ferring Pharmaceuticals: Ferring Receives Approval from U.S. FDA for Adstiladrin for High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer [Link]
RxNav
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Wikipedia
Nadofaragene_firadenovec

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMalignant Pleural Mesothelioma (MPM)1
3CompletedTreatmentSuperficial Bladder Cancer1
3RecruitingTreatmentBladder Cancer1
2CompletedTreatmentSuperficial Bladder Cancer1
1CompletedTreatmentBladder Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SuspensionIntravesical300000000000 {VP}/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Drug created at December 19, 2022 20:28 / Updated at December 23, 2022 00:49