Abecma
idecabtagene vicleucel
Sources:EMA assessment report ↗FDA pharmacology/toxicology review ↗FDA summary basis for approval ↗US prescribing information ↗
Species
no relevantMouse
Longest study
12 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
No relevant species; NSG mouse xenografts and in vitro only
“The PK and biodistribution of ide-cel were evaluated in NSG mice with and without BCMA+ xenografts.”
Why that species
Human autologous T cells do not engraft in immunocompetent animals; no representative models
“Ide-cel comprises engineered human T cells, therefore there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product.”
Surrogate molecule
No surrogate; human ide-cel tested in NSG mice with human MM xenografts
“Rapid elimination of both subcutaneous and systemic tumours and increased survival was demonstrated in NSG mice with BCMA+ xenografts after a single dose of ide-cel.”
Species: general tox
None; no repeat-dose toxicity studies (human T cells do not engraft in immunocompetent animals)
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”
Species: DART
Not conducted (product characteristics)
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
Species: carcinogenicity
Not conducted; in vitro IL-2-independent growth assay instead
“No carcinogenicity or tumorigenicity studies were conducted for bb2121. However, the applicant evaluated IL-2 independent growth in Study #10.”
Surrogate used in
No surrogate used; clinical ide-cel tested in NSG mice with BCMA+ xenografts
“Rapid elimination of both subcutaneous and systemic tumours and increased survival was demonstrated in NSG mice with BCMA+ xenografts after a single dose of ide-cel.”
Study lengthopen answer page →
Longest pivotal study
Pivotal GLP studies
None GLP; non-GLP NSG mouse PK/PD/biodistribution/general safety study (B4-15-090, single IV, 29 days)
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel”
Route in tox
Intravenous (tail vein, single dose)
“ide-cel was administered to mice as a single IV injection via tail vein with no abnormal observations recorded at the injection site.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (traditional); insertion site analysis of 20 clinical lots
“No traditional genotoxicity assays and carcinogenicity assessments were performed for bb2121.”
Carcinogenicity
Not conducted; in vitro IL-2-independent growth assay showed no transformation
“No carcinogenicity or tumorigenicity studies were conducted for bb2121. However, the applicant evaluated IL-2 independent growth in Study #10.”
Instead of genotoxicity
In vitro expansion studies (5 patient, 2 healthy donor lots) showed no transformation; insertion site analysis on products from 20 patients
“In vitro expansion studies with CAR-positive T cells (ABECMA) from five patients and two healthy donor drug product lots showed no evidence for transformation and/or immortalization of T cells. A genomic insertion site analysis of the lentiviral vector was performed on ABECMA samples from twenty (20) individual patient donors.”
Reproductive & developmental
Not conducted (product characteristics)
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
Safety pharmacology
Not conducted
“No safety pharmacology studies were conducted.”
Genotox: Ames
Not conducted (autologous human cell product)
“Ide-cel is an autologous human cellular product and therefore, standard genotoxicity studies eg, Ames assay, clastogenicity assessments were not conducted.”
Genotox: in vitro mammalian
Not conducted; vector integration site analysis of 20 clinical lots showed no preferential integration near oncogenes
“Integration site analysis was performed for 20 clinical drug product lots. The resulting data showed that the lentiviral vector does not preferentially integrate in or near genes of concern for oncogenic transformation and is consistent with other similar vectors.”
Genotox: in vivo
Not conducted (autologous human cell product)
“Ide-cel is an autologous human cellular product and therefore, standard genotoxicity studies eg, Ames assay, clastogenicity assessments were not conducted.”
Carcinogenicity model
Not conducted; in vitro IL-2-independent growth assay (5 patient, 2 healthy donors) showed no uncontrolled proliferation
“Additionally, an IL-2-independent growth assay of ABECMA® generated from five patient donors and two healthy donors showed no signs of uncontrolled cellular proliferation.”
Carcinogenicity timing
Not required; conventional animal studies not appropriate (autologous human T cells do not engraft in immunocompetent animals)
“Conventional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals and thus, in vivo nonclinical general safety, genotoxicity, carcinogenicity, developmental safety or reproductive safety studies were not conducted.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
First doseopen answer page →
First-in-human starting dose
Not explicitly stated; mouse MED 6.16x10^5 CAR+ cells corresponds to HED 2.05x10^8 CAR+ T cells (100 kg)
“expression which represents the human equivalent dose (HED) of 2.05 x 108 CAR+ T cells for a 100-kg human.”
NOAEL / key findings
No NOAEL; no bb2121-related adverse findings in mouse studies
“No bb2121-related adverse findings were reported in these studies.”
Risksopen answer page →
Immune & cytokine safety
BCMA-specific IFN-γ release in vitro; CRS not modeled; expected depletion of normal plasma cells
“It is also expected that ide-cel will deplete healthy plasma cells that express BCMA.”
Biodistribution & persistence
NSG mice: distribution to lungs, blood, bone marrow, liver, spleen; biphasic peaks Days 2/11 blood, 8/15 tissues
“A biphasic peak expansion of bb2121 cells was observed on Days 2 and 11 in the peripheral blood and Days 8 and 15 in analyzed tissues in tumor-bearing mice.”
Modality-specific risk
Insertional mutagenesis from lentiviral integration; tumorigenic transformation
“A tailored safety evaluation was conducted which focused on the investigation of the risk of insertional mutagenesis due to lentiviral integration in the genome of ide-cel CAR T cells”
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
Treatment-induced anti-CAR antibodies 53%; pre-infusion 2.6%; no clinically significant impact
“In the clinical studies, 2.6% of patients (9/349) tested positive for pre-infusion anti-CAR antibodies and treatment-induced anti-CAR antibodies were detected in 53% (186/349) of the patients.”
Label warnings
Boxed warning: Cytokine release syndrome, neurologic toxicities, hlh/mas, prolonged cytopenia, and secondary hematological malignancies
- Early Death
- Cytokine Release Syndrome (CRS)
- Neurologic Toxicities
- Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)
- Hypersensitivity Reactions
- Infections
- Prolonged Cytopenias
- Hypogammaglobulinemia
- Secondary Malignancies
CytopeniasCytokine release syndromeNeurotoxicityImmune-mediated reactionsSecondary malignancyHypersensitivity & infusion reactionsInfections
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-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
“A first-in-human, two-part, nonrandomized, open-label, multicenter, dosing finding Phase 1 study to evaluate the safety, efficacy, cellular kinetics/pharmacokinetics of a single dose of ABECMA in subjects with relapsed/refractory multiple myeloma (RRMM) (Study No. CRB-401, supportive study).”
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 explicitly stated; mouse MED 6.16x10^5 CAR+ cells corresponds to HED 2.05x10^8 CAR+ T cells (100 kg)
“expression which represents the human equivalent dose (HED) of 2.05 x 108 CAR+ T cells for a 100-kg human.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (autologous human T cells do not engraft in immunocompetent animals)
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”
Pivotal GLP studies
None GLP; non-GLP NSG mouse PK/PD/biodistribution/general safety study (B4-15-090, single IV, 29 days)
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel”
DART package
Species: DART
Not conducted (product characteristics)
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
Reproductive & developmental
Not conducted (product characteristics)
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
PPND / ePPND: when
Not conducted; DART studies not needed given product characteristics
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
Carcinogenicity
Species: carcinogenicity
Not conducted; in vitro IL-2-independent growth assay instead
“No carcinogenicity or tumorigenicity studies were conducted for bb2121. However, the applicant evaluated IL-2 independent growth in Study #10.”
Carcinogenicity model
Not conducted; in vitro IL-2-independent growth assay (5 patient, 2 healthy donors) showed no uncontrolled proliferation
“Additionally, an IL-2-independent growth assay of ABECMA® generated from five patient donors and two healthy donors showed no signs of uncontrolled cellular proliferation.”
Carcinogenicity timing
Not required; conventional animal studies not appropriate (autologous human T cells do not engraft in immunocompetent animals)
“Conventional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals and thus, in vivo nonclinical general safety, genotoxicity, carcinogenicity, developmental safety or reproductive safety studies were not conducted.”
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; no bb2121-related adverse findings in mouse studies
“No bb2121-related adverse findings were reported in these studies.”
Efficacy evidenceopen answer page →
Efficacy evidence
NSG mice bearing subcutaneous BCMA+ human MM xenografts: dose-dependent anti-tumor activity and improved survival
“In mice bearing subcutaneous BCMA+ human MM xenografts, intravenous administration of bb2121 demonstrated dose-dependent anti-tumor activity and improved survival compared to control mice.”
Why that model
Autologous human T cells do not engraft in immunocompetent animals, so immunodeficient xenograft mice were used
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”
Reviewer's view of the efficacy data
EMA: sufficient evidence of pharmacological activity and proof of concept in multiple myeloma
“Collectively, the pharmacological data provide sufficient evidence for pharmacological activity and a proof of concept for the use of ide-cel in the treatment of patients with multiple myeloma.”
Test articleopen answer page →
Test article vs clinical lot
Pharmacology used experimental CAR T batches without lot numbers; clinical drug product lots used for insertion site and growth studies. Bridging: Per certificates of testing, nonclinical experiment batches met the clinical lot release specifications
“*Lot Nos. were not assigned for CAR T cells assessed in nonclinical studies #1-8; they were manufactured under Experiment Nos.”
Genetically modified?
Autologous CD3+ CAR-T, lentiviral vector
“Idecabtagene vicleucel (ide-cel, bb2121) consists of autologous CD3+ T cells that are transduced using a lentiviral vector to express a BCMA-directed chimeric antigen receptor (CAR).”
First approval
2021 (FDA)
“Summary Basis for Regulatory Action Date: March 26, 2021”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No single or repeat-dose in vivo toxicity studies; no appropriate animal model for autologous human CAR-T cells
Why: Autologous human T cells do not graft in immunocompetent animals · No relevant species
“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or carcinogenicity studies; vector integration site analysis of clinical lots and IL-2-independent growth assay instead
Why: No preferential integration near genes of concern and no transformation observed; tumorigenic risk negligible · Weight of evidence
“No traditional genotoxicity assays and carcinogenicity assessments were performed for bb2121. The safety of bb2121 was assessed by evaluating the integration profile of the lentiviral vector.”
“No tumorigenic transformation of T cells following transduction in the ide-cel manufacturing process was observed in the IL-2 independent growth study. Moreover, there were no substantial changes in CAR T cell phenotypes or CD4:CD8 ratio, or substantial decreases in clonal diversity under any condition tested.”
DARTAcceptedBeyond the letter
No animal reproductive and developmental toxicity studies
Why: Acceptable based on the product characteristics · Low-risk modality
“No animal reproductive and developmental toxicity studies were conducted for bb2121 which is acceptable based on the product characteristics.”
BiodistributionVerdict not stated
No germline transmission studies
Why: EMA guideline: germline risk of genetically modified human cells is low; animal testing of human cells not meaningful · Within the guideline · Low-risk modality
“Further, 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 and, as animal testing of human cells may be difficult or not meaningful, non-clinical germline transmission studies of human genetically modified cells are not recommended.”
Safety pharmacologyAccepted
No dedicated safety pharmacology studies
Why: Nature of the product and in line with EMA gene therapy guideline · Within the guideline
“No dedicated Safety pharmacology and Pharmacodynamic drug interactions studies have been performed. Based on the nature of the product and in line with the Guideline on the quality, nonclinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014), this was considered acceptable.”
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