Vyjuvek
beremagene geperpavec
Species
Mouse
Longest study
9 wk (derived)
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (BALB/c) for GLP tox; single species
“the use of a single species (mice) for the toxicity studies is considered acceptable and in line with the”
Why that species
No justification given beyond historical use of mice; mouse skin dissimilar to human; EB mouse and human RDEB xenograft used for pharmacology
“A justification for the choice of mice is not specified, other than the suggestion that this species is historically used in toxicity studies.”
Surrogate molecule
No surrogate; clinical vector (KB103) tested in mice; human COL7 transgene
“In vivo Good Laboratory Practice (GLP) toxicology studies evaluated 1) single intravenous (IV) administration of VYJUVEK in BALB/c mice”
Species: general tox
Mouse only (BALB/c)
“Considering the nature of the product and the toxicities seen, the use of a single species (mice) for the toxicity studies is considered acceptable”
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.”
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.”
Surrogate used in
No surrogate used: clinical vector tested in BALB/c mice
“In vivo Good Laboratory Practice (GLP) toxicology studies evaluated 1) single intravenous (IV) administration of VYJUVEK in BALB/c mice”
Study lengthopen answer page →
Longest pivotal study
9 (derived from the dosing and observation schedule)
“The remaining animals were sacrificed on Day 30 or allowed to recover for an additional 30 days following completion”
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”
Route in tox
Intradermal, topical (wounded skin) and intravenous (mice)
“single topical application of VYJUVEK mixed with 3% HPMC to wounded skin of BALB/c mice at 3.48 x 107 pfu/application.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (HSV-1 does not integrate; negligible insertional mutagenesis)
“No traditional genotoxicity studies were performed.”
Carcinogenicity
Not conducted; weight-of-evidence literature risk assessment
“No carcinogenicity studies were performed, and the applicant provided a weight of evidence risk assessment”
Reproductive & developmental
Not conducted (acceptable given product characteristics and safety profile)
“Animal reproductive and developmental toxicity (DART) studies were not conducted with VYJUVEK.”
Safety pharmacology
Not conducted (locally administered, limited distribution)
“No safety pharmacology studies with KB-103 were performed.”
Genotox: Ames
Not conducted (non-integrating HSV-1 vector; low insertional mutagenesis risk)
“No genotoxicity studies with VYJUVEK were performed because HSV-1 does not integrate into or disrupt the host genome; therefore, the risk of insertional mutagenesis of KB103 is low.”
Genotox: in vitro mammalian
Not conducted (non-integrating HSV-1 vector; low insertional mutagenesis risk)
“No genotoxicity studies with VYJUVEK were performed because HSV-1 does not integrate into or disrupt the host genome; therefore, the risk of insertional mutagenesis of KB103 is low.”
Genotox: in vivo
Not conducted (non-integrating HSV-1 vector; low insertional mutagenesis risk)
“No genotoxicity studies with VYJUVEK were performed because HSV-1 does not integrate into or disrupt the host genome; therefore, the risk of insertional mutagenesis of KB103 is low.”
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.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with KB-103 were performed.”
First doseopen answer page →
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)
NOAEL / key findings
NOAEL 6.9e6 pfu (low dose) in mouse intradermal study; dose-site scabbing, inflammatory lymphocyte hyperplasia; no adverse findings per FDA
“The low dose of 6.9 x 106 pfu was considered as the NOAEL.”
Risksopen answer page →
Immune & cytokine safety
Minimal to slight lymphoid hyperplasia in spleen and lymph nodes consistent with inflammatory response to vector
“microscopic findings of minimal to slight lymphocyte follicular hyperplasia in the spleen and minimal to slight lymphocyte hyperplasia in the axillary and/or inguinal lymph nodes were consistent with an inflammatory response to KB103”
Biodistribution & persistence
Vector mainly at application/injection site, declining to baseline by 30 days after last dose; not detected in other tissues after topical dosing
“resulted in vector detection primarily at the injection site, which declined to baseline by 30 days after the last dose.”
Modality-specific risk
Replication-defective non-integrating HSV-1 vector: local inflammatory/immune reaction, limited systemic distribution; shedding assessed clinically
“No non-clinical studies investigating excretion of KB103 were conducted, and vector shedding was studied in the clinical setting.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
Anti-COL7 ADA in 72% (13/18) by week 26; 6 of 8 HSV-1 seronegative patients seroconverted
“Six of the 8 anti-HSV-1 seronegative patients seroconverted by Week 26 following treatment with VYJUVEK. For patients with available matched baseline and end-of-study serum samples, anti‑drug antibodies (ADAs) to COL7 were detected in 72% (13/18) of patients treated with VYJUVEK for up to 26 weeks.”
Label warnings
- Accidental Exposure to VYJUVEK
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
NOAEL 6.9e6 pfu (low dose) in mouse intradermal study; dose-site scabbing, inflammatory lymphocyte hyperplasia; no adverse findings per FDA
“The low dose of 6.9 x 106 pfu was considered as the NOAEL.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hypomorphic DEB mouse model and wild-type BALB/c mice: dermal transduction, COL7 expression, anchoring fibrils
“the in vivo studies in wild-type BALB/c mice and the hypomorphic DEB mouse model provided evidence that KB103 can transduce dermal cells and increase expression of COL7 protein, which is able to form anchoring fibrils.”
Why that model
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.
Reviewer's view of the efficacy data
DEB mouse study limited (non-clinical route, disease parameters not assessed) but sufficient evidence for mechanism of action
“Although the study in the hypomorphic DEB mouse model has some limitations in that the administration route differs from the clinical route and that effects on the relevant disease parameters for the proposed indication were not assessed, it does provide sufficient evidence for the underlying mechanism of action”
Flexibilityopen answer page →
Flexibility accepted
SpeciesCriticised but accepted
Toxicity tested in a single species (mouse), chosen only on historical use
Why: Nature of the product and toxicities seen; consistent with the EMA gene therapy guideline · Within the guideline · Low-risk modality
“A justification for the choice of mice is not specified, other than the suggestion that this species is historically used in toxicity studies.”
“Toxicology: Considering the nature of the product and the toxicities seen, the use of a single species (mice) for the toxicity studies is considered acceptable and in line with the “Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014)”.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Non-integrating, non-replicating vector; negligible germline transmission risk · Low-risk modality
“As the vector backbone is claimed to be non-integrating and non-replicating, it is accepted that the risk for potential germline transmission is negligible and additional DART studies are not required.”
CarcinogenicityAccepted
No carcinogenicity studies; literature weight-of-evidence risk assessment for HSV-1 instead
Why: No association between HSV-1 and cancer; EMA gene therapy guideline; low insertional mutagenesis risk · Weight of evidence · Within the guideline · Low-risk modality
“Carcinogenicity No carcinogenicity studies were performed, and the applicant provided a weight of evidence risk assessment, based on a literature search up to July 2024. This did not identify any association or risk factor identification for HSV-1 infection and cancer.”
“In-line with the CHMP’s “Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014)” the absence of standard rodent carcinogenicity studies is acceptable. The risk of insertional mutagenesis is considered low and the expressed COL7 protein is not expected to provide a proliferative advantage to cells.”
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