Kymriah
tisagenlecleucel
Sources:EMA assessment report ↗FDA pharmacology/toxicology review ↗US prescribing information ↗FDA summary basis for approval ↗
Species
no relevantMouse
Longest study
31 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; immunodeficient mouse B-ALL xenograft (non-GLP) only
“The absence of GLP compliance is acceptable since standard single or repeat-dose toxicity studies could not be performed due to lack of a relevant animal model.”
Why that species
Patient-specific human T-cell product cannot be given to immunocompetent animals
“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”
Surrogate molecule
No surrogate; human CART-19 cells (1:1 mix of LTG118/LTG119 constructs) in xenograft mice
“The exact clinical construct was used in the studies and the vectors were research grade.”
Species: general tox
Human B-ALL tumor-bearing mice only (non-GLP single IV biotoxicity/biodistribution study to Day 217); no standard repeat-dose toxicity
“An in vivo study was conducted to evaluate toxicity and BD in tumor-bearing mice receiving i.v. injection of CTL019 at 1, 5, and 20x106 cells/mouse and observed up to Day 217 post-injection (p.i.) with three terminal sacrifices.”
Species: DART
Not conducted
“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”
Species: carcinogenicity
Not conducted (no rodent carcinogenicity assessment)
“Classical genotoxicity assays and carcinogenicity assessment in rodent models were not performed for CTL019.”
Surrogate used in
No surrogate used; exact clinical CAR construct (research-grade vector) tested in mice
“The exact clinical construct was used in the studies and the vectors were research grade.”
Study lengthopen answer page →
Longest pivotal study
31 weeks
“An in vivo study was conducted to evaluate toxicity and BD in tumor-bearing mice receiving i.v. injection of CTL019 at 1, 5, and 20x106 cells/mouse and observed up to Day 217 post-injection (p.i.) with three terminal sacrifices.”
Pivotal GLP studies
No GLP tox; non-GLP biotoxicity/BD study in B-ALL tumor-bearing immunodeficient mice, single IV, to Day 217
“The nonclinical toxicology studies were not conducted in compliance with Good Laboratory Practice (GLP), because there was no independent Quality Assurance (QA) audit of integral study parts and raw data storage was not applied in compliance with GLP regulations.”
Route in tox
Intravenous
“Route of Administration Intravenous route of administration”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (classical); lentiviral integration site analysis on 14 donor products
“Genotoxicity Studies: Classical genotoxicity studies were not conducted. The provided LV integration site analysis may be relevant for evaluation of potential genotoxicity.”
Carcinogenicity
Not conducted (rodent models not appropriate for insertional mutagenesis of modified cells)
“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products.”
Instead of genotoxicity
Lentiviral insertion site analysis on CTL019 from 14 donors (2 healthy, 12 patients)
“A genomic insertion site analysis was performed on CTL019 from 14 individual donors (2 healthy donors and 12 patients representing pediatric ALL-derived and diffuse large B-cell lymphoma (DLBCL)-derived cells).”
Reproductive & developmental
Not conducted
“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”
Safety pharmacology
Not conducted
“No safety pharmacology studies have been conducted (see non-clinical discussion).”
Genotox: Ames
Not conducted (no classical genotoxicity studies)
“Genotoxicity Studies: Classical genotoxicity studies were not conducted. The provided LV integration site analysis may be relevant for evaluation of potential genotoxicity.”
Genotox: in vitro mammalian
Not conducted; lentiviral integration site analysis provided instead
“Genotoxicity Studies: Classical genotoxicity studies were not conducted. The provided LV integration site analysis may be relevant for evaluation of potential genotoxicity.”
Genotox: in vivo
Not conducted (no classical genotoxicity studies)
“Genotoxicity Studies: Classical genotoxicity studies were not conducted. The provided LV integration site analysis may be relevant for evaluation of potential genotoxicity.”
Carcinogenicity model
Not conducted; immunocompromised mice showed no abnormal growth or clonal expansion up to 7 months; integration site analysis
“In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months, which represents the longest meaningful observation period for immunocompromised mouse models.”
Carcinogenicity timing
Not required: rodent carcinogenicity studies not appropriate for genetically modified cell therapy
“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies have been conducted (see non-clinical discussion).”
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 Kymriah 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; mice up to 20x10^6 cells: no systemic toxicity or abnormal proliferation vs mock T cells; xGvHD (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
No NOAEL; mice up to 20x10^6 cells: no systemic toxicity or abnormal proliferation vs mock T cells; xGvHD
“There was no histologic evidence of systemic toxicity associated with CTL019 versus mock T cells. No abnormal cell growth was detected by clinical pathology or by PCR at any time point in any animal.”
Risksopen answer page →
Immune & cytokine safety
No cytokine/CRS studies; scFv bound only CD19 on 3550-protein array; no CD19 in human/cyno brain
“Protein array assessment for binding of murine and humanized CD19-CAR scFV to human membrane proteins showed that CD19 was identified by both biotinylated scFv fragments of human and murine, while no other human membrane protein binders were detected on the array.”
Biodistribution & persistence
Mouse: CAR-T in spleen, lung, kidney, brain, liver, heart, blood, marrow; persisted to Day 217 in mid-dose
“On day 56 post-injection, CART-19 cell signals were detected in these same tissues plus the liver, heart, blood and bone marrow in Groups 1 through 3 with more frequency in Group 1 as compared to Groups 2 and 3.”
Modality-specific risk
Insertional oncogenesis/secondary malignancy from lentiviral integration; RCL; no clonal outgrowth seen
“Insertion of lentiviral vector sequences throughout the genome has the potential to dysregulate local host cell gene expression with a theoretical risk of insertional oncogenesis resulting from disruption of normal function of genes that control cell growth and potential risk of development of secondary malignancies.”
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
Pre-dose anti-mCAR19 antibodies in 91%, 94%, 66% (Studies 1-3); treatment-induced in 9% and 33% (Studies 2, 3)
“The majority of patients, 91% in Study 1, 94% in Study 2, and 66% in Study 3, tested positive for pre-dose anti-mCAR19 antibodies prior to KYMRIAH infusion. Treatment induced anti-mCAR19 antibodies were detected in 9% and 33% of the patients in Study 2 and Study 3, respectively.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES
- Cytokine Release Syndrome
- Neurological Toxicities
- Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome
- Hypersensitivity Reactions
- Serious 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 Kymriah 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; mice up to 20x10^6 cells: no systemic toxicity or abnormal proliferation vs mock T cells; xGvHD (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single IV infusion; patient-specific product)
“The lack of repeat-dose toxicity studies is acceptable based on the fact that tisagenlecleucel will be administered as a single IV infusion, and since tisagenlecleucel is a patient specific product which is not appropriate to administer to immune competent animals.”
Pivotal GLP studies
No GLP tox; non-GLP biotoxicity/BD study in B-ALL tumor-bearing immunodeficient mice, single IV, to Day 217
“The nonclinical toxicology studies were not conducted in compliance with Good Laboratory Practice (GLP), because there was no independent Quality Assurance (QA) audit of integral study parts and raw data storage was not applied in compliance with GLP regulations.”
DART package
Species: DART
Not conducted
“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”
Reproductive & developmental
Not conducted
“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”
PPND / ePPND: when
Not conducted: no preclinical reproductive studies
“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no rodent carcinogenicity assessment)
“Classical genotoxicity assays and carcinogenicity assessment in rodent models were not performed for CTL019.”
Carcinogenicity model
Not conducted; immunocompromised mice showed no abnormal growth or clonal expansion up to 7 months; integration site analysis
“In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months, which represents the longest meaningful observation period for immunocompromised mouse models.”
Carcinogenicity timing
Not required: rodent carcinogenicity studies not appropriate for genetically modified cell therapy
“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products.”
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; mice up to 20x10^6 cells: no systemic toxicity or abnormal proliferation vs mock T cells; xGvHD
“There was no histologic evidence of systemic toxicity associated with CTL019 versus mock T cells. No abnormal cell growth was detected by clinical pathology or by PCR at any time point in any animal.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mice bearing human primary pre-B ALL xenografts: CTL019 improved survival vs mock T cells
“A series of studies in mice bearing human primary pre-B ALL conducted to evaluate anti-tumor activity of CTL019 derived from different healthy human donors showed significantly improved survival in the tumor-bearing mice receiving intravenous (i.v.) injection of CTL019 at 2x106 cells/mouse as compared to the mock T cell administered animals.”
Why that model
Patient-specific human T-cell product cannot be given to immunocompetent animals; xenograft in immunodeficient mice used
“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”
Reviewer's view of the efficacy data
Accepted; ALL-only xenograft pharmacology (no DLBCL studies) acceptable given clinical experience
“The lack of non-clinical pharmacology studies with DLBCL cells is acceptable based on the clinical experience with this indication.”
Test articleopen answer page →
Test article vs clinical lot
Pharmacology used cells transduced with UPenn/US-made research lentiviral vector; clinical studies used Oxford Biomedica vector. Bridging: No comparative in vivo studies; CHMP judged them uninformative for comparability and accepted their absence
“the pharmacology studies were conducted with cells transduced with lentiviral vector made at the University of Pennsylvania, or at a further facility in the US, whereas clinical studies were done with cells transduced with vector made by Oxford Biomedica”
Genetically modified?
Autologous CAR-T, replication-deficient lentiviral vector
“Tisagenlecleucel (KYMRIAH™, CTL019) gene transfer is accomplished via ex vivo transduction with a replication-deficient human lentiviral vector (LV) encoding the transgene.”
First approval
2017 (FDA)
“Summary Basis for Regulatory Action Date: August 30, 2017”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No single-dose or standard toxicity studies: patient-specific human cell product cannot be given to immunocompetent animals
Why: Patient-specific product not appropriate to administer to immunocompetent animals · No relevant species
“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”
GLPAcceptedBeyond the letter
Nonclinical toxicology studies not GLP-compliant (no independent QA audit, non-GLP raw data storage)
Why: Standard toxicity studies could not be performed due to lack of a relevant animal model · No relevant species
“The nonclinical toxicology studies were not conducted in compliance with Good Laboratory Practice (GLP), because there was no independent Quality Assurance (QA) audit of integral study parts and raw data storage was not applied in compliance with GLP regulations.”
“The absence of GLP compliance is acceptable since standard single or repeat-dose toxicity studies could not be performed due to lack of a relevant animal model.”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or rodent carcinogenicity studies; lentiviral integration site analysis and in vitro/in vivo outgrowth data instead
Why: Rodent assays not appropriate for insertional mutagenesis of modified cells; no adequate alternative animal models · Other reason
“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products. No alternative adequate animal models are available (SmPC, section 5.3).”
BiodistributionAccepted
Risk of inadvertent germline transmission of the CAR construct not addressed nonclinically
Why: EMA germline transmission guideline: risk for genetically modified human cells is considered low · Within the guideline · Low-risk modality
“The risk of inadvertent germline transmission of the CD19 CAR construct has not been addressed; however, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors, EMEA/273974/2005 indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered to be low”
Efficacy modelAcceptedBeyond the letter
Pharmacology studies used ALL tumour cells only; no nonclinical pharmacology with DLBCL cells
Why: Clinical experience with the DLBCL indication · Human data
“The lack of non-clinical pharmacology studies with DLBCL cells is acceptable based on the clinical experience with this indication.”
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