Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)US: all clinical studies, including first-in-human in patients with BCG-unresponsive NMIBC, conducted in the US
Vyjuvek: what was done before first-in-human, and what came after?
beremagene geperpavec · COL7A1 (HSV-1, topical)
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Vyjuvek don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NOAEL 6.9e6 pfu (low dose) in mouse intradermal study; dose-site scabbing, inflammatory lymphocyte hyperplasia; no adverse findings per FDA (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Mouse intradermal GLP study, 5 weekly doses, with 30-day recovery
“Analysis of in vivo biodistribution after five weekly repeat ID doses of VYJUVEK in mice at 6.9 x 106 or 3.45 x 107 pfu/dose/mouse resulted in vector detection primarily at the injection site, which declined to baseline by 30 days after the last dose.”
Pivotal GLP studies
GLP BALB/c mouse studies: single IV; 5 weekly intradermal doses with 30-day recovery; single topical to wounded skin
“five repeat weekly ID administrations of VYJUVEK in BALB/c mice at 6.9 x 106 or 3.45 x 107 pfu/mouse/administration”
DART package
Species: DART
Not conducted (limited systemic biodistribution; no vector in reproductive organs after topical dosing)
“No DART studies with VYJUVEK were performed because limited systemic biodistribution of the vector was observed and no vector was detected in the reproductive organs of mice that received topical application of VYJUVEK.”
Reproductive & developmental
Not conducted (acceptable given product characteristics and safety profile)
“Animal reproductive and developmental toxicity (DART) studies were not conducted with VYJUVEK.”
PPND / ePPND: when
Not conducted: DART studies not conducted, acceptable given product characteristics and safety profile
“Animal reproductive and developmental toxicity (DART) studies were not conducted with VYJUVEK. This is acceptable based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no carcinogenic risk indicated for KB103 or wild-type HSV-1)
“No carcinogenicity/tumorigenicity studies with VYJUVEK were performed because available data for both KB103 and wild-type HSV-1 do not indicate a carcinogenic risk in humans.”
Carcinogenicity model
Not conducted; weight-of-evidence literature risk assessment instead
“No carcinogenicity studies were performed, and the applicant provided a weight of evidence risk assessment, based on a literature search up to July 2024.”
Carcinogenicity timing
Not required (no carcinogenic risk indicated by data for KB103 and wild-type HSV-1)
“No carcinogenicity/tumorigenicity studies with VYJUVEK were performed because available data for both KB103 and wild-type HSV-1 do not indicate a carcinogenic risk in humans.”
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