Kresladi
marnetegragene autotemcel
Species
Mouse
Longest study
4 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only (CD18HYP/CD18KO disease models, recipient mice, NSG mice); no large-animal tox
“The applicant also used surrogate Lin- HSPCs transduced with the Chim-CD18-WPRE LV transplanted into recipient mice for their definitive in vivo toxicology and BD studies.”
Why that species
CD18-deficient mice mimic LAD-I phenotype (impaired neutrophil migration); patient CD34+ cells unavailable
“CD18HYP and CD18KO mice have deficient CD18 expression and impaired neutrophil migration and inflammatory responses similar to LAD-I patients.”
Surrogate molecule
Yes: murine Lin- HSPCs transduced with clinical vector; healthy-donor human CD34+ cells in NSG mice
“The final clinical product and source material was not used in the nonclinical studies summarized in this memo due to feasibility issues obtaining sufficient CD34+ HSCs from LAD-I patients.”
Species: general tox
Mouse only (recipient mice transplanted with transduced murine Lin- HSPCs)
“The applicant also used surrogate Lin- HSPCs transduced with the Chim-CD18-WPRE LV transplanted into recipient mice for their definitive in vivo toxicology and BD studies.”
Species: DART
Not conducted (product type; reproductive-tissue biodistribution near background)
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
Species: carcinogenicity
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Surrogate used in
Yes: CD18HYP/CD18KO mouse Lin- HSPCs transduced with the clinical vector for in vivo pharmacology
“The applicant also used surrogate Lin- HSPCs from CD18HYP and CD18KO mice transduced with the clinical vector to demonstrate donor cell engraftment and improved neutrophil extravasation to tissue-specific sites of inflammation for the in vivo pharmacology studies.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“Mice were sacrificed 1 month after Chim-CD18-WPRE LV transduced Lin- cell transplantation.”
Pivotal GLP studies
Single non-GLP 1-month IV tox/biodistribution/RCL study of transduced murine Lin- HSPCs in irradiated recipient mice (NSR-7)
“A 1-month in vivo toxicology and biodistribution (BD) study was also conducted using recipient mice for safety evaluation of Chim-CD18-WPRE LV transduced Lin- murine HSPCs.”
Route in tox
Intravenous (single administration after irradiation conditioning)
“Route of Administration IV administration”
Skipped studiesopen answer page →
Genotoxicity
Integration site analyses only (mouse and human transduced cells); no standard genotoxicity battery
“8 Analysis of Integration Profile in Mouse Transduced Cells NSR-8 9 Analysis of Integration Profile in Human Transduced Cells NSR-9”
Carcinogenicity
Not conducted (not suitable for product type); no tumorigenicity or preferential oncogene integration observed
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Reproductive & developmental
Not conducted (product type; gonadal VCN near background, low germline transmission risk)
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
Safety pharmacology
Not conducted
“Safety pharmacology studies were not conducted for this product.”
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
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 vivo
Integration site analysis in LAD-I mice and NSG mice: no evidence of genotoxicity or tumorigenicity
“Intravenous administration of KRESLADI in a mouse model of LAD-I and intravenous administration of KRESLADI manufactured from healthy donors in immunodeficient mice showed no evidence of toxicity, genotoxicity, or oncogenesis (tumorigenicity).”
Carcinogenicity model
Not conducted; no tumorigenicity in vivo and no preferential integration near proto-oncogenes on integration site analysis
“The nonclinical data provided by sponsor showed no evidence of tumorigenicity in the in vivo studies performed or preferential integration near proto-oncogenes in the integration site analysis (ISA).”
Carcinogenicity timing
Not required (not warranted given product characteristics)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“Safety pharmacology studies were not conducted for this product.”
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 Kresladi 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 adverse findings; testis degeneration and liver infiltrates attributed to irradiation/background; NOAEL not defined (FDA pharmacology/toxicology review, p. 3)
NOAEL / key findings
No adverse findings; testis degeneration and liver infiltrates attributed to irradiation/background; NOAEL not defined
“No premature mortality or unexpected deaths were observed over the course of the study period in recipient mice.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
VCN in hematopoietic organs; undetectable/low in non-hematopoietic organs and gonads; serum p24 negative (no RCL)
“Hematopoietic reconstitution was observed in the peripheral blood (PB) and BM and measurable VCN was detected in other hematopoietic organs, whereas undetectable or low VCN was observed in non-hematopoietic organs including the gonads.”
Modality-specific risk
Insertional oncogenesis/clonal dominance; polyclonal integration, no preferential integration near MECOM, LMO2, CCND2
“There were no preferred IS in/nearby genes previously associated with insertional mutagenesis in gene therapy trials such as MECOM, LMO2, and CCND2.”
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
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.
Label warnings
- Serious Infections
- Veno-Occlusive Disease
- Neutrophil Engraftment Failure
- Delayed Platelet Engraftment
- LVV-Mediated Insertional Oncogenesis
- Hypersensitivity Reactions
- Anti-retroviral Use
- Interference with Serology Testing
- Blood, organ, tissue and cell donation
InfectionsCytopeniasThrombocytopeniaSecondary malignancyHypersensitivity & 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 Kresladi 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 adverse findings; testis degeneration and liver infiltrates attributed to irradiation/background; NOAEL not defined (FDA pharmacology/toxicology review, p. 3)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; single transplant of transduced cells in a 1-month mouse toxicology/biodistribution study
“A 1-month in vivo toxicology and biodistribution (BD) study was also conducted using recipient mice for safety evaluation of Chim-CD18-WPRE LV transduced Lin- murine HSPCs.”
Pivotal GLP studies
Single non-GLP 1-month IV tox/biodistribution/RCL study of transduced murine Lin- HSPCs in irradiated recipient mice (NSR-7)
“A 1-month in vivo toxicology and biodistribution (BD) study was also conducted using recipient mice for safety evaluation of Chim-CD18-WPRE LV transduced Lin- murine HSPCs.”
DART package
Species: DART
Not conducted (product type; reproductive-tissue biodistribution near background)
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
Reproductive & developmental
Not conducted (product type; gonadal VCN near background, low germline transmission risk)
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
PPND / ePPND: when
Not conducted; not warranted given product characteristics and safety profile
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type.”
Carcinogenicity model
Not conducted; no tumorigenicity in vivo and no preferential integration near proto-oncogenes on integration site analysis
“The nonclinical data provided by sponsor showed no evidence of tumorigenicity in the in vivo studies performed or preferential integration near proto-oncogenes in the integration site analysis (ISA).”
Carcinogenicity timing
Not required (not warranted given product characteristics)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”
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 adverse findings; testis degeneration and liver infiltrates attributed to irradiation/background; NOAEL not defined
“No premature mortality or unexpected deaths were observed over the course of the study period in recipient mice.”
Efficacy evidenceopen answer page →
Efficacy evidence
CD18HYP and CD18KO LAD-I mice given vector-transduced murine Lin- cells: engraftment and enhanced neutrophil extravasation to inflamed sites
“Successful engraftment of the Chim-CD18-WPRE LV transduced Lin- cells was demonstrated in recipient CD18HYP or CD18KO mice with enhanced neutrophil extravasation to tissue-specific sites of inflammation.”
Why that model
Insufficient LAD-I patient CD34+ cells available, so surrogate murine HSPCs and healthy-donor CD34+ cells were used
“The final clinical product and source material was not used in the nonclinical studies summarized in this memo due to feasibility issues obtaining sufficient CD34+ HSCs from LAD-I patients.”
Reviewer's view of the efficacy data
FDA: no nonclinical deficiencies and no further testing requested; data support approval
“There are no nonclinical deficiencies in the pharmacology/toxicology studies. There are no requests for further nonclinical testing of KRESLADITM.”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
Clinical product not tested; surrogate murine Lin- HSPCs transduced with the clinical vector used for definitive toxicology and biodistribution
Why: Insufficient CD34+ cells obtainable from LAD-I patients
“The final clinical product and source material was not used in the nonclinical studies summarized in this memo due to feasibility issues obtaining sufficient CD34+ HSCs from LAD-I patients.”
CarcinogenicityAcceptedBeyond the letter
No traditional carcinogenicity studies; integration site analysis and in vivo observation instead
Why: Not suitable for the product type; no tumorigenicity in vivo or preferential integration near proto-oncogenes · Weight of evidence · Low-risk modality
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by sponsor showed no evidence of tumorigenicity in the in vivo studies performed or preferential integration near proto-oncogenes in the integration site analysis (ISA).”
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Product type; no concerning findings in reproductive tissues in the mouse toxicology study · Low-risk modality · Weight of evidence
“Studies were not conducted to evaluate this developmental and reproductive toxicity based on the product type and due to the lack of concerning findings in reproductive tissues in Study #7 (study report no. NSR-7).”
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with KRESLADITM. These studies are not warranted based on the drug product characteristics and safety profile.”
Safety pharmacologyVerdict not stated
No safety pharmacology studies
“Safety pharmacology studies were not conducted for this product.”
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