Tecartus
brexucabtagene autoleucel
Sources:EMA assessment report ↗FDA pharmacology/toxicology review ↗FDA summary basis for approval ↗US prescribing information ↗
Species
no relevantMouse
Longest study
30 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
No relevant species; in vitro and syngeneic mouse surrogate CAR-T only
“Since the anti-CD19 scFv utilised for KTE-X19 does only recognise human CD19, a murine surrogate model was engineered for non-clinical proof-of-concept studies in immune competent mice.”
Why that species
scFv recognizes only human CD19; no relevant animal model
“Similar as the pharmacology evaluation, also the non-clinical safety evaluation of KTE-X19 has been severely limited due to the lack of a relevant animal model.”
Surrogate molecule
Yes: anti-murine CD19 CAR (1D3 scFv) T cells in syngeneic lymphoma mice
“This surrogate model used an anti-murine CD19 CAR construct that was similar to KTE-X19 with the exception of the scFv, which has been derived from the 1D3 mAb recognizing murine CD19.”
Species: general tox
None; no GLP toxicology studies (no relevant animal model)
“Similar as the pharmacology evaluation, also the non-clinical safety evaluation of KTE-X19 has been severely limited due to the lack of a relevant animal model. Therefore, no GLP-compliant formal toxicology studies were performed.”
Species: DART
Not conducted; acceptable given product characteristics and safety profile
“No animal reproductive and developmental toxicity studies were conducted with KTE-X19, which is acceptable based on the product characteristics and safety profile.”
Species: carcinogenicity
Not conducted
“No carcinogencity/tumorigenicity studies were conducted.”
Surrogate used in
Yes: anti-murine CD19 CAR (1D3 scFv) T cells
“This surrogate model used an anti-murine CD19 CAR construct that was similar to KTE-X19 with the exception of the scFv, which has been derived from the 1D3 mAb recognizing murine CD19.”
Study lengthopen answer page →
Longest pivotal study
30 weeks
“lack of normal splenic B cells was observed 63 days, 143 days, and 209 days (the last time point examined) after anti-murine CD19 CAR T-cell infusion”
Pivotal GLP studies
None; no GLP tox. Safety assessed in surrogate syngeneic mouse pharmacology model plus vector integration site analysis
“Therefore, no GLP-compliant formal toxicology studies were performed.”
Route in tox
Intravenous (adoptive transfer in mice after 5 Gy TBI)
“Murine T cells were transduced with the anti-murine CD19 CAR construct and adoptively transferred into syngeneic mice which underwent TBI at 5 Gy for lymphodepletion”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (traditional); vector integration site analysis performed instead
“Traditional genotoxicity studies were not conducted using KTE-X19, however, given the use of a murine γ-retroviral vector to stably integrate the anti-CD19 CAR into the T cell genome, a risk associated with insertional mutagenesis exists.”
Carcinogenicity
Not conducted
“No carcinogencity/tumorigenicity studies were conducted.”
Reproductive & developmental
Not conducted (product characteristics, safety profile)
“No animal reproductive and developmental toxicity studies were conducted with KTE-X19, which is acceptable based on the product characteristics and safety profile.”
Safety pharmacology
Not conducted
“No secondary pharmacodynamics studies, safety pharmacology studies and pharmacodynamic drug interaction studies were conducted.”
Genotox: Ames
Not conducted; insertional mutagenesis risk noted from γ-retroviral vector integration
“Traditional genotoxicity studies were not conducted using KTE-X19, however, given the use of a murine γ-retroviral vector to stably integrate the anti-CD19 CAR into the T cell genome, a risk associated with insertional mutagenesis exists.”
Genotox: in vitro mammalian
Not conducted
“Traditional genotoxicity studies were not conducted using KTE-X19, however, given the use of a murine γ-retroviral vector to stably integrate the anti-CD19 CAR into the T cell genome, a risk associated with insertional mutagenesis exists.”
Genotox: in vivo
Not conducted
“Traditional genotoxicity studies were not conducted using KTE-X19, however, given the use of a murine γ-retroviral vector to stably integrate the anti-CD19 CAR into the T cell genome, a risk associated with insertional mutagenesis exists.”
Carcinogenicity model
Not conducted; acceptable based on product characteristics, safety profile and indication
“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”
Carcinogenicity timing
Not required (acceptable based on product characteristics, safety profile and indication)
“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
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 Tecartus 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 cell 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 NOAEL; surrogate mice showed prolonged B-cell aplasia (on-target/off-tumour) without overt toxicity (EMA assessment report, p. 33)
NOAEL / key findings
No NOAEL; surrogate mice showed prolonged B-cell aplasia (on-target/off-tumour) without overt toxicity
“Notably, this complete and prolonged absence of B cells was not accompanied by any evidence of overt toxicity.”
Risksopen answer page →
Immune & cytokine safety
CRS, neurotoxicity, MAS not investigated nonclinically; considered general CAR-T effects
“These toxic effects have also not been investigated in non-clinical studies which is fully acceptable considering that these effects are general effects of CAR T cells”
Biodistribution & persistence
No formal PK/biodistribution; surrogate CAR-T detected in spleen to ~1 week, not at Day 63
“Anti-murine CD19 CAR T cells were not detected in the spleens of treated mice at Day 63 after injection of CAR T cells; longer follow-up for anti-murine CD19 CAR T cells was not examined.”
Modality-specific risk
Insertional oncogenesis from gamma-retroviral vector (full-length LTRs); B-cell aplasia
“The combination of both the use of a γ-retroviral vector with full-length viral long terminal repeats (LTRs) and the high proliferative potential of the transduced T cells provides a certain risk of insertional oncogenesis”
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-FMC63 ELISA: none confirmed in MCL Study 1; two patients confirmed positive in Study 2, no effect on expansion, persistence, safety or efficacy
“No patient in Study 1 had a confirmed positive antibody result post treatment. Two patients in Study 2 had confirmed positive antibody results post treatment:”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES
- Cytokine Release Syndrome
- Neurologic Toxicities
- Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome
- Hypersensitivity Reactions
- Severe Infections
- Prolonged Cytopenias
- Hypogammaglobulinemia
- Secondary Malignancies
CytopeniasCytokine release syndromeNeurotoxicitySecondary malignancyImmune-mediated reactionsHypersensitivity & infusion reactionsInfections
US prescribing information, Boxed Warning and 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 Tecartus 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 cell 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 NOAEL; surrogate mice showed prolonged B-cell aplasia (on-target/off-tumour) without overt toxicity (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single infusion product)
“KTE-X19 is intended to be administered as a single infusion treatment therefore no repeat-dose toxicities study was conducted.”
Pivotal GLP studies
None; no GLP tox. Safety assessed in surrogate syngeneic mouse pharmacology model plus vector integration site analysis
“Therefore, no GLP-compliant formal toxicology studies were performed.”
DART package
Species: DART
Not conducted; acceptable given product characteristics and safety profile
“No animal reproductive and developmental toxicity studies were conducted with KTE-X19, which is acceptable based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted (product characteristics, safety profile)
“No animal reproductive and developmental toxicity studies were conducted with KTE-X19, which is acceptable based on the product characteristics and safety profile.”
PPND / ePPND: when
No reproductive/developmental studies; acceptable given product type, target expression and lack of a relevant animal model
“The lack of non-clinical reproductive and developmental toxicity studies is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogencity/tumorigenicity studies were conducted.”
Carcinogenicity model
Not conducted; acceptable based on product characteristics, safety profile and indication
“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”
Carcinogenicity timing
Not required (acceptable based on product characteristics, safety profile and indication)
“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”
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 NOAEL; surrogate mice showed prolonged B-cell aplasia (on-target/off-tumour) without overt toxicity
“Notably, this complete and prolonged absence of B cells was not accompanied by any evidence of overt toxicity.”
Efficacy evidenceopen answer page →
Efficacy evidence
Surrogate anti-murine CD19 CAR T cells in lymphodepleted syngeneic CD19+ B-cell lymphoma mice
“Additionally, an in vivo study conducted using an analogous murine CAR construct recognizing the murine CD19 molecule demonstrated anti-tumor activity and increased survival in a lymphodepleted syngeneic adoptive transfer mouse model of CD19+ B cell lymphoma.”
Why that model
FMC63 scFv recognises only human CD19, so a murine surrogate CAR was engineered for immunocompetent mice
“Since the anti-CD19 scFv utilised for KTE-X19 does only recognise human CD19, a murine surrogate model was engineered for non-clinical proof-of-concept studies in immune competent mice.”
Reviewer's view of the efficacy data
EMA: surrogate model acceptable with clear limitations; xenograft testing of KTE-X19 would add no significant value
“Since both models do have clear, although differing, limitations with regard to the translation of the non-clinical pharmacology data to human, additional non-clinical in vivo pharmacology data (e.g. testing of KTE-X19 in immunocompromised animals transplanted with human CD19+ tumour cells) would not add significant value to the available non-clinical and clinical pharmacology data sets.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No relevant animal model; no GLP formal toxicology studies, only safety observations in a syngeneic mouse surrogate model
Why: scFv recognises only human CD19; no relevant animal model · No relevant species
“Toxicology Similar as the pharmacology evaluation, also the non-clinical safety evaluation of KTE-X19 has been severely limited due to the lack of a relevant animal model. Therefore, no GLP-compliant formal toxicology studies were performed.”
“There were no nonclinical deficiencies identified in this submission and no outstanding requests for additional nonclinical data.”
Efficacy modelAcceptedBeyond the letter
In vivo pharmacology with surrogate anti-murine CD19 CAR T cells in syngeneic immunocompetent lymphoma mice
Why: Surrogate model overcomes xenogeneic limitations; human-cell xenograft testing would add no significant value · No relevant species · Pharmacology or kinetics
“Since both models do have clear, although differing, limitations with regard to the translation of the non-clinical pharmacology data to human, additional non-clinical in vivo pharmacology data (e.g. testing of KTE-X19 in immunocompromised animals transplanted with human CD19+ tumour cells) would not add significant value”
“in immunocompetent mice is an acceptable approach that overcomes some of the limitations of the in vivo testing of KTE-X19 in immunocompromised animals (e.g. unspecific xenogeneic immune responses of KTE-X19 in mice, lack of complex interactions of the CAR T cells with other components of the immune system).”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or tumorigenicity studies despite gamma-retroviral vector integration risk
Why: Product characteristics, safety profile and indication · Other reason
“Traditional in vitro and in vivo genotoxicity and carcinogenicity/tumorigenicity assessments of KTE-X19 were not conducted which is acceptable based on the product characteristics, safety profile and indication.”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Type of product, target antigen expression pattern and lack of a relevant animal model · No relevant species · Low-risk modality
“The lack of non-clinical reproductive and developmental toxicity studies is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
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