Carvykti
ciltacabtagene autoleucel
Species
no relevantMonkeyMouse
Longest study
14 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; NCG mouse xenografts, non-GLP NHP pilot with autologous NHP CAR-T
“Therefore, animal studies evaluating the safety profile of CARVYKTI™ were limited due to lack of a pharmacologically relevant animal species.”
Why that species
Binding domain does not bind mouse or NHP BCMA
“In vitro data indicate that does not significantly bind to recombinant mouse or NHP BCMA expressed on cells.”
Surrogate molecule
Yes: autologous cynomolgus T cells transduced with the CAR vector (non-GLP pilot)
“NHP cilta-cel was manufactured from autologous Cynomolgus monkey peripheral blood samples following a similar manufacturing method that would be used for human T cells.”
Species: general tox
Not conducted: no relevant nonclinical species; single-dose product
“No repeat dose toxicity has been performed given there is no relevant nonclinical species and that cilta-cel is administered as a single dose to patients and is anticipated to undergo expansion and persistence following administration.”
Species: DART
Not conducted: rodents and NHPs not pharmacologically relevant (no binding to mouse/NHP BCMA)
“In addition, did not bind to recombinant mouse or NHP BCMA expressed on cells (Studies #6 and #18), demonstrating that rodents and NHPs are not pharmacology relevant species for testing cilta-cel.”
Species: carcinogenicity
Not conducted: human-specific product, no cross-reactivity to mouse BCMA
“In addition, cilta-cel is a human specific CAR-T cell product and lacks cross reactivity to mouse BCMA precluding the conduct of traditional rat and mouse bioassays.”
Surrogate used in
Yes: autologous cynomolgus CAR-T cells (NHP cilta-cel) in non-GLP safety pilot
“NHP cilta-cel was manufactured from autologous Cynomolgus monkey peripheral blood samples following a similar manufacturing method that would be used for human T cells.”
Study lengthopen answer page →
Longest pivotal study
14 weeks
“Scheduled Sacrifice Time Points Day 98”
Pivotal GLP studies
No GLP tox; non-GLP cynomolgus pilot (n=2, single IV, 30 days) plus NCG mouse xenograft studies
“The applicant performed one in vivo non-GLP toxicology pilot study in Cynomolgus monkeys using autologous CAR-T cells manufactured with the second/ third generation hybrid LV developed by Legend.”
Route in tox
Intravenous infusion (after cyclophosphamide in NHP)
“The NHPs were infused with cyclophosphamide (22.3 mg/kg) on Day -3, followed by IV infusion of the CAR T cells on Day 0.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (classical); lentiviral integration site analysis instead
“No classical genotoxicity studies have been performed.”
Carcinogenicity
Not conducted (ICH S9; no mouse BCMA cross-reactivity)
“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat advanced cancer.”
Reproductive & developmental
Not conducted; binding domain not detected in human reproductive organs
“Therefore, traditional DART studies were not conducted.”
Safety pharmacology
Not conducted (targeting domain does not bind mouse BCMA)
“The absence of safety pharmacology studies is therefore, acceptable.”
Genotox: Ames
Not conducted
“Traditional genotoxicity assays and carcinogenicity assessments were not conducted.”
Genotox: in vitro mammalian
Not conducted
“Traditional genotoxicity assays and carcinogenicity assessments were not conducted.”
Genotox: in vivo
Not conducted
“Traditional genotoxicity assays and carcinogenicity assessments were not conducted.”
Carcinogenicity model
Not conducted; in vitro cytokine-independent growth and lentiviral integration-site studies showed no concern
“In vitro studies with CARVYKTI manufactured from healthy donors and patients with multiple myeloma showed no evidence of cytokine independent growth and no preferential integration near genes associated with oncogenic transformation.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat advanced cancer.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with JNJ-68284528 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 Carvykti 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; NHP 5 and 40x10^6 cells/kg: no adverse effects, transient mild blood count decreases (FDA pharmacology/toxicology review, p. 26)
NOAEL / key findings
No NOAEL; NHP 5 and 40x10^6 cells/kg: no adverse effects, transient mild blood count decreases
“There were no test article-related adverse effects on survival, clinical signs, body weights or body temperatures.”
Risksopen answer page →
Immune & cytokine safety
CRS, TLS, MAS not investigated nonclinically; off-target CLDN9 binding seen only on overexpressing cells
“These toxic effects have not been investigated in non-clinical studies which is acceptable considering that these effects are general effects of CAR T cells”
Biodistribution & persistence
No biodistribution studies; mouse CAR copies peaked ~Day 34-35, baseline by Day 48
“No biodistribution studies with JNJ-68284528 were conducted.”
Modality-specific risk
Insertional oncogenicity from lentiviral integration; off-target claudin-9 binding
“Based on this study, the risk of insertional oncogenicity is expected to be very low.”
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-CAR antibodies in 19/97 (19.6%) patients in CARTITUDE-1 and 39/186 (21%) in CARTITUDE-4; no clear impact
“In CARTITUDE-1, 19 of 97 (19.6%) patients were positive for anti-product antibodies. In CARTITUDE-4, 39 of 186 patients (21%) were positive for anti-CAR antibodies.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES
- Increased Early Mortality
- Cytokine Release Syndrome
- Neurologic Toxicities
- Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)
- Prolonged and Recurrent Cytopenias
- Infections
- Hypogammaglobulinemia
- Hypersensitivity Reactions
- Immune Effector Cell-associated Enterocolitis
- Secondary Malignancies
CytopeniasCytokine release syndromeNeurotoxicityImmune-mediated reactionsSecondary malignancyInfectionsHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first clinical trial in patients with relapsed/refractory multiple myeloma (LEGEND-2)
“In the first phase 1 single arm trial CAR T cells in patients with relapsed/refractory MM (Legend -2), ORR for the total population was 87.8%, with 64% CR and 56.8% MRD negative, VGPR was 10.8%, PR was 12.2%, CR (64%) and ORR (87.8%) in patients that had relapsed following IMiDs and PI treatment.”
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 Carvykti 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; NHP 5 and 40x10^6 cells/kg: no adverse effects, transient mild blood count decreases (FDA pharmacology/toxicology review, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no relevant species; single-dose product)
“No repeat dose toxicity has been performed given there is no relevant nonclinical species and that cilta-cel is administered as a single dose to patients and is anticipated to undergo expansion and persistence following administration.”
Pivotal GLP studies
No GLP tox; non-GLP cynomolgus pilot (n=2, single IV, 30 days) plus NCG mouse xenograft studies
“The applicant performed one in vivo non-GLP toxicology pilot study in Cynomolgus monkeys using autologous CAR-T cells manufactured with the second/ third generation hybrid LV developed by Legend.”
DART package
Species: DART
Not conducted: rodents and NHPs not pharmacologically relevant (no binding to mouse/NHP BCMA)
“In addition, did not bind to recombinant mouse or NHP BCMA expressed on cells (Studies #6 and #18), demonstrating that rodents and NHPs are not pharmacology relevant species for testing cilta-cel.”
Reproductive & developmental
Not conducted; binding domain not detected in human reproductive organs
“Therefore, traditional DART studies were not conducted.”
PPND / ePPND: when
Not conducted; acceptable given product type and BCMA expression pattern
“No non-clinical reproductive and developmental toxicity studies have been conducted, which is acceptable based on the type of product and the BCMA expression pattern.”
Carcinogenicity
Species: carcinogenicity
Not conducted: human-specific product, no cross-reactivity to mouse BCMA
“In addition, cilta-cel is a human specific CAR-T cell product and lacks cross reactivity to mouse BCMA precluding the conduct of traditional rat and mouse bioassays.”
Carcinogenicity model
Not conducted; in vitro cytokine-independent growth and lentiviral integration-site studies showed no concern
“In vitro studies with CARVYKTI manufactured from healthy donors and patients with multiple myeloma showed no evidence of cytokine independent growth and no preferential integration near genes associated with oncogenic transformation.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat advanced cancer.”
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; NHP 5 and 40x10^6 cells/kg: no adverse effects, transient mild blood count decreases
“There were no test article-related adverse effects on survival, clinical signs, body weights or body temperatures.”
Efficacy evidenceopen answer page →
Efficacy evidence
Immunodeficient (NCG) mice engrafted with human multiple myeloma cells: dose-dependent anti-tumor activity and survival
“In vivo pharmacology studies showed significant dose-dependent anti-tumor activity and increased survival following administration of LCAR-B38M CAR-T cells in immune-deficient mice engrafted with human MM cells.”
Why that model
BCMA binding domain does not bind mouse or NHP BCMA; no pharmacologically relevant species
“In vitro data indicate that does not significantly bind to recombinant mouse or NHP BCMA expressed on cells. Therefore, animal studies evaluating the safety profile of CARVYKTI™ were limited due to lack of a pharmacologically relevant animal species.”
Reviewer's view of the efficacy data
Xenograft model adequate for in vivo efficacy despite xenogenic response and lack of murine immune interactions
“Despite the known limitations of this model such as the unspecific xenogenic response of the CAR T cells or lacking interactions between the CAR T cells and the murine immune cells, the animal model is considered adequate to assess in vivo efficacy against BCMA expressing tumour cells.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No GLP-compliant formal toxicology studies and no repeat-dose study; no relevant animal species
Why: No relevant animal model; single IV infusion of a patient-specific product unsuitable for immune-competent animals · No relevant species · Within the guideline
“Similar to the pharmacokinetic evaluation, the non-clinical safety evaluation of cilta-cel was limited due to the lack of a relevant animal model. Therefore, no GLP-compliant formal toxicology studies were performed.”
“The lack of repeat-dose toxicity studies is acceptable based on the fact that cilta-cel will be administered as a single IV infusion, and since cilta-cel is a patient specific product which is not appropriate to administer to immune competent animals.”
GLPVerdict not stated
Only a non-GLP pilot in cynomolgus monkeys with autologous surrogate CAR-T cells, without control groups
“It is unclear if changes in complete blood counts were related to cyclophosphamide pretreatment or NHP cilta-cel because the study did not include cyclophosphamide only and/or vehicle control groups.”
GenotoxicityCriticised but acceptedBeyond the letter
No classical genotoxicity studies; integration site analysis on final product rather than ex vivo cells
Why: Mature T cells are highly resistant to oncogenic transformation, as documented in the literature · Low-risk modality
“Although the use of ex vivo cilta-cel would have been more suitable for the detection of dominant cell clones, the use of final product for integration analysis is considered acceptable based on the high resistance of mature T cells to oncogene transformation, which is well documented in the literature.”
BiodistributionAccepted
Inadvertent germline transmission risk not addressed by the applicant
Why: EMA guideline: germline transmission risk from genetically modified human cells is low and animal testing not recommended · Within the guideline · Low-risk modality
“The risk of inadvertent germline transmission of the cilta-cel has not been addressed by the applicant. 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 low”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Product type, target antigen expression pattern and no relevant animal model · No relevant species · Pharmacology or kinetics
“The lack of any 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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