Zevaskyn
prademagene zamikeracel
Sources:FDA summary basis for approval ↗US prescribing information ↗FDA pharmacology/toxicology review ↗
Species
Mouse
Longest study
8 wk
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 (immunodeficient mice with implanted human keratinocyte products); no relevant large-animal species
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
Yes: representative nonclinical product (RVV-transduced human keratinocytes on human acellular dermal matrix)
“In vivo pharmacology studies were conducted with a nonclinical product representative of ZEVASKYN comprised of vector (the RVV, or vectors similar to the RVV)-transduced human keratinocytes (cells alone or cells grown into sheets) affixed to a block of human acellular dermal matrix or dermis.”
Species: general tox
Mouse only (representative product implanted into excisional wounds, 4 or 8 weeks)
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Species: DART
Not conducted (vector biodistribution confined to the implanted product)
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
Species: carcinogenicity
Not conducted (no neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
Surrogate used in
Yes: representative nonclinical product (human keratinocytes transduced with the RVV or similar vectors on human dermal matrix)
“In vivo pharmacology studies were conducted with a nonclinical product representative of ZEVASKYN comprised of vector (the RVV, or vectors similar to the RVV)-transduced human keratinocytes (cells alone or cells grown into sheets) affixed to a block of human acellular dermal matrix or dermis.”
Study lengthopen answer page →
Longest pivotal study
8 weeks
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Pivotal GLP studies
One combined toxicology/biodistribution study in mice, implantation into excisional wounds, 4- and 8-week sacrifices
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Route in tox
Implantation into excisional skin wounds (topical/cutaneous)
“Nonclinical products were then implanted into excisional wounds generated in mice.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (integration site analysis in transduced RDEB keratinocytes instead; no clonality or oncogene preference)
“Integration site analysis (ISA) was performed on RDEB keratinocytes (n=6 donors) transduced with RVV. ISA did not indicate clonality at 6-days post-keratinocyte transduction.”
Carcinogenicity
Not conducted (no neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
Instead of carcinogenicity
Integration site analysis in RVV-transduced RDEB keratinocytes (6 donors): no clonality, no preference for malignancy-associated genes
“Integration site analysis (ISA) was performed on RDEB keratinocytes (n=6 donors) transduced with RVV. ISA did not indicate clonality at 6-days post-keratinocyte transduction. There was no evidence of RVV preference to integrate near genes associated with malignancy.”
DRG histopathology
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.
Reproductive & developmental
Not conducted (vector biodistribution confined to the implanted product)
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
Safety pharmacology
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.
Genotox: Ames
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.
Genotox: in vitro mammalian
Integration site analysis in RVV-transduced RDEB keratinocytes (6 donors): no clonality, no preference near malignancy genes
“Integration site analysis (ISA) was performed on RDEB keratinocytes (n=6 donors) transduced with RVV. ISA did not indicate clonality at 6-days post-keratinocyte transduction. There was no evidence of RVV preference to integrate near genes associated with malignancy.”
Genotox: in vivo
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.
Carcinogenicity model
Not conducted (no neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
Carcinogenicity timing
Not required (not conducted given histology, low oncogenesis risk and SCC screening)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zevaskyn 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: No gross or histopathological findings in any tissue, including explanted products; no NOAEL stated (FDA summary basis for approval, p. 13)
NOAEL / key findings
No gross or histopathological findings in any tissue, including explanted products; no NOAEL stated
“There were no gross or histopathological findings in any tissue assessed, including the explanted nonclinical products.”
Risksopen answer page →
Immune & cytokine safety
Clinical only: transient anti-Col7 antibodies in 2/7 Phase 1/2a subjects; no systemic immune responses in Phase 3
“In the Phase 1/2a study, circulating anti-Col7 antibodies were detected in two out of seven subjects, which resolved without intervention by 1 year after treatment.”
Biodistribution & persistence
COL7A1 transgene DNA confined to explanted product at 4 and 8 weeks; below detection in all other tissues
“COL7A1 transgene DNA was detected in explanted nonclinical products at both sacrifice time points.”
Modality-specific risk
Retroviral insertional oncogenesis/tumorigenicity (SCC context), replication-competent retrovirus; E&L of device components
“Integration site analysis in RDEB keratinocytes transduced with LZRSE-Col7A1 showed a low level of integration distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.”
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
Circulating anti-C7 antibodies in 2 of 7 patients (resolved by 1 year); tissue-bound in 4
“Out of 7 patients, circulating anti-C7 antibodies were detected in 2 patients which resolved at 1 year follow-up. Tissue-bound anti-C7 antibodies were detected in 4 patients which resolved in 3 patients at 1 year follow-up.”
Label warnings
- Hypersensitivity Reactions
- R etroviral Vector (R VV ) -Mediated I nsertional O ncogenesis
- 3 Transmission of Infectious Agents
Hypersensitivity & infusion reactions
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 Zevaskyn 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: No gross or histopathological findings in any tissue, including explanted products; no NOAEL stated (FDA summary basis for approval, p. 13)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single implantation); mouse toxicology/biodistribution study with 4- or 8-week sacrifice
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Pivotal GLP studies
One combined toxicology/biodistribution study in mice, implantation into excisional wounds, 4- and 8-week sacrifices
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
DART package
Species: DART
Not conducted (vector biodistribution confined to the implanted product)
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
Reproductive & developmental
Not conducted (vector biodistribution confined to the implanted product)
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
PPND / ePPND: when
Not conducted: vector biodistribution confined to the implanted product
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
Carcinogenicity model
Not conducted (no neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
Carcinogenicity timing
Not required (not conducted given histology, low oncogenesis risk and SCC screening)
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
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
No gross or histopathological findings in any tissue, including explanted products; no NOAEL stated
“There were no gross or histopathological findings in any tissue assessed, including the explanted nonclinical products.”
Efficacy evidenceopen answer page →
Efficacy evidence
Representative RVV-transduced keratinocyte grafts in mouse excisional wounds: cells stayed localized, Col7 expression up to 12 months
“Nonclinical products were then implanted into excisional wounds generated in mice. RVV-transduced keratinocytes remained localized within explanted nonclinical products, and RVV-mediated expression of Col7 was detected for up to 12-months post-implantation.”
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
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.
Test articleopen answer page →
Test article vs clinical lot
Representative nonclinical product: RVV-transduced human keratinocytes (cells alone) on human acellular dermal matrix, implanted into mouse wounds
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
Vector and route
Replication-incompetent retroviral vector (LZRSE-Col7A1) in ex vivo autologous keratinocytes, applied as cell sheets
“ZEVASKYN is an autologous cell sheet-based gene therapy in which ex vivo expanded autologous keratinocytes are transduced with the LZRSE-Col7A1 RVV, a replication-incompetent retroviral vector (RVV) carrying a transgene encoding human collagen type VII alpha 1 chain (COL7A1).”
First approval
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.
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity or tumorigenicity studies; insertional oncogenesis risk deferred to a long-term postmarketing safety study
Why: No neoplastic histology, low insertional oncogenesis risk, routine SCC screening in RDEB · Weight of evidence · Other reason
“Carcinogenicity and tumorigenicity studies of ZEVASKYN were not conducted due to absence of neoplastic features on histology, low risk of insertional oncogenesis, and frequent SCC screening recommended for all subjects with RDEB.”
“The potential of insertional oncogenesis associated with ZEVASKYN’S integrating viral component will be evaluated through a safety PMR to conduct a long-term safety study in ZEVASKYN treated patients.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Vector biodistribution confined to the implanted product · Pharmacology or kinetics
“Developmental and reproductive toxicity (DART) studies of ZEVASKYN were not conducted due to the BD of RVV remaining confined to representative nonclinical products.”
OtherVerdict not stated
Toxicology and biodistribution used a representative nonclinical product (transduced cells on acellular dermal matrix) in mice for 4 or 8 weeks
“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”
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