Aucatzyl
obecabtagene autoleucel
Species
no relevantMouse
Longest study
2 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; no in vivo tox. NSG xenograft (pharmacology) and human tissue cross-reactivity only
“Per the applicant, conventional nonclinical toxicology studies were not conducted because they do not yield clinically relevant information for a CAR T cell product.”
Why that species
No pharmacologically responsive species; human autologous T cells will not engraft in immunocompetent animals; immunodeficient models uninformative
“Aucatzyl, a patient-specific product, is not appropriate for administration to immunocompetent animals, as the T cells will not engraft.”
Surrogate molecule
No surrogate; nonclinical CAT19 CAR T cells from healthy-donor PBMCs with identical construct judged representative
“Despite minor differences between the nonclinical and clinical products, the constructs assessed, including the binding domain, were identical and therefore the nonclinical product is considered appropriate to assess safety and activity in the nonclinical program.”
Species: general tox
None; general toxicity studies not conducted (no pharmacologically responsive species)
“The absence of general toxicity studies is accepted, considering that there are no pharmacologically responsive animal species (as also mentioned in the scientific advice, EMA/CHMP/SAWP/586752/2019).”
Species: DART
Not conducted (ICH S9; no pharmacologically relevant species)
“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”
Species: carcinogenicity
Not conducted (ICH S9; no cross-reactivity with murine CD19)
“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (advanced cancer). In addition, there is no cross-reactivity of the CD19-CAR T cells from Aucatzyl with the murine antigen.”
Surrogate used in
No surrogate used; nonclinical CAT19 CAR T cells with identical construct judged representative
“Despite minor differences between the nonclinical and clinical products, the constructs assessed, including the binding domain, were identical and therefore the nonclinical product is considered appropriate to assess safety and activity in the nonclinical program.”
Study lengthopen answer page →
Longest pivotal study
2 weeks
“CAR T cells were present in peripheral blood as well as bone marrow two weeks post-injection.”
Pivotal GLP studies
No in vivo GLP tox; GLP human tissue cross-reactivity (42 tissues); non-GLP NALM-6 NSG xenograft, single IV dose, Day 16
“The GLP tissue cross-reactivity study was conducted to determine potential binding of 1 or 3 μg/mL CAT19 to 42 normal human tissues and blood smears.”
Route in tox
Intravenous (xenograft pharmacology study only)
“Route of Administration Intravenous (IV)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (third-generation SIN lentiviral vector, release criterion, long-term clinical monitoring for insertional mutagenesis)
“No nonclinical genotoxicity studies were conducted with obe-cel based on the genotoxic risks associated with the third-generation self-inactivating lentiviral vector used to produce obe-cel, acceptable release criterion, and inclusion of long-term clinical monitoring for insertional mutagenesis and clonality.”
Carcinogenicity
Not conducted (ICH S9; no murine CD19 cross-reactivity; murine T cells resist LV transformation)
“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (advanced cancer). In addition, there is no cross-reactivity of the CD19-CAR T cells from Aucatzyl with the murine antigen.”
Reproductive & developmental
Not conducted (ICH S9; no pharmacologically relevant species)
“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”
Safety pharmacology
Not conducted; human-specific product with immune-related risks, immunocompromised models of limited relevance
“No safety pharmacology studies with obe-cel were conducted.”
Genotox: Ames
Not conducted (standard genotoxicity not applicable to ATMPs)
“Standard in vitro and in vivo genotoxicity studies are not applicable to ATMPs.”
Genotox: in vitro mammalian
Not conducted; relies on third-generation SIN lentiviral vector, release criterion and long-term clinical monitoring for insertional mutagenesis
“No nonclinical genotoxicity studies were conducted with obe-cel based on the genotoxic risks associated with the third-generation self-inactivating lentiviral vector used to produce obe-cel, acceptable release criterion, and inclusion of long-term clinical monitoring”
Genotox: in vivo
Not conducted (standard genotoxicity not applicable to ATMPs)
“Standard in vitro and in vivo genotoxicity studies are not applicable to ATMPs.”
Carcinogenicity model
Not conducted; oncogenesis testing in mice judged difficult as murine T cells resist LV-mediated transformation
“Moreover, evaluation of oncogenesis in e.g. mice would be difficult, considering the high resistance of murine T cells against transformation by LV-related genetic insertions.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (advanced cancer).”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with obe-cel 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 Aucatzyl 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 (no tox studies); tissue cross-reactivity limited to CD19+ B cells in lymphoid tissues, no off-target binding (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
No NOAEL (no tox studies); tissue cross-reactivity limited to CD19+ B cells in lymphoid tissues, no off-target binding
“The data indicate that human tissue cross reactivity with the CAT19 CAR binding domain was consistent with the expected profile of CD19 expression on B lymphocytes.”
Risksopen answer page →
Immune & cytokine safety
No nonclinical CRS/ICANS model; CRS and neurotoxicity judged clinically manageable; CAT19 showed higher TNF-α in vitro/in vivo
“Known risks of CAR T cell therapies (e.g., CRS or neurotoxicity) can be clinically monitored and managed.”
Biodistribution & persistence
No dedicated PK/biodistribution; CAR T cells in blood and bone marrow at Day 16 in NSG mice; persistence assessed clinically
“Traditional non-clinical pharmacokinetic studies (absorption, distribution, metabolism, excretion and in vitro drug-drug interaction) have not been conducted because obe-cel is an autologous gene therapy product and there is no pharmacologically relevant species.”
Modality-specific risk
LV insertional mutagenesis/secondary malignancy (literature-based assessment), bystander transduction, follicular DC on-target off-tumor depletion
“However, it is also explained that the risk of transformation and oncogenesis with the current third generation SIN LVs and moderately active non-viral promoters is low (but not zero), especially in terminally differentiated cell types such as 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-CD19 CAR antibodies 1.6%; pre-infusion positive 8.7%
“In the FELIX study, 8.7% (11/127) of patients tested positive for anti-CD19 CAR antibodies pre-infusion. Treatment induced anti-CD19 CAR antibodies were detected in 1.6% (2/127) of patients.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES
- Cytokine Release Syndrome
- Neurologic Toxicities
- Prolonged Cytopenias
- Infections
- Hypogammaglobulinemia
- Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome
- Hypersensitivity Reactions
- Secondary Malignancies
CytopeniasCytokine release syndromeNeurotoxicitySecondary malignancyInfectionsImmune-mediated reactionsHypersensitivity & infusion reactions
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 Aucatzyl 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 (no tox studies); tissue cross-reactivity limited to CD19+ B cells in lymphoid tissues, no off-target binding (FDA pharmacology/toxicology review, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no general toxicity studies performed)
“The applicant has not performed general toxicity studies with their product.”
Pivotal GLP studies
No in vivo GLP tox; GLP human tissue cross-reactivity (42 tissues); non-GLP NALM-6 NSG xenograft, single IV dose, Day 16
“The GLP tissue cross-reactivity study was conducted to determine potential binding of 1 or 3 μg/mL CAT19 to 42 normal human tissues and blood smears.”
DART package
Species: DART
Not conducted (ICH S9; no pharmacologically relevant species)
“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”
Reproductive & developmental
Not conducted (ICH S9; no pharmacologically relevant species)
“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”
PPND / ePPND: when
Not conducted; not needed under ICH S9 (advanced cancer) and no pharmacologically relevant species
“DART studies are not needed for indications falling under ICH S9 scope (advanced cancer) and no pharmacologically relevant animal species is available.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9; no cross-reactivity with murine CD19)
“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (advanced cancer). In addition, there is no cross-reactivity of the CD19-CAR T cells from Aucatzyl with the murine antigen.”
Carcinogenicity model
Not conducted; oncogenesis testing in mice judged difficult as murine T cells resist LV-mediated transformation
“Moreover, evaluation of oncogenesis in e.g. mice would be difficult, considering the high resistance of murine T cells against transformation by LV-related genetic insertions.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“Carcinogenicity studies are not needed for indications falling under ICH S9 scope (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 (no tox studies); tissue cross-reactivity limited to CD19+ B cells in lymphoid tissues, no off-target binding
“The data indicate that human tissue cross reactivity with the CAT19 CAR binding domain was consistent with the expected profile of CD19 expression on B lymphocytes.”
Efficacy evidenceopen answer page →
Efficacy evidence
Systemic human tumor xenograft mouse model: single IV dose of obe-cel significantly reduced tumor burden by Day 12
“In vivo pharmacology studies demonstrated that a single intravenous administration of obe-cel at a dose level of 2.5 × 106 CAT19 CAR T cells/animal in a systemic human tumor xenograft mouse model resulted in significant reduction in tumor burden on Day 12 post administration.”
Why that model
Patient-specific human T cells do not engraft in immunocompetent animals, so immunodeficient xenograft models used
“Aucatzyl, a patient-specific product, is not appropriate for administration to immunocompetent animals, as the T cells will not engraft.”
Reviewer's view of the efficacy data
EMA: lower-affinity CAT CAR T cells showed enhanced anti-tumour responses vs FMC63 under stress conditions; clinical translation unknown
“Together, all these non-clinical results indicate that, under conditions designed to give CAR T cells a numeric disadvantage relative to the number of tumour cells, lower affinity CD19 CAT CAR T cells mediate enhanced anti-tumour responses and expansion as compared to higher affinity CD19 (FMC63) CAR T cells. Whether this translates into a clinical effect is not known.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No general toxicity studies; no pharmacologically relevant species for human CAR T cells
Why: No pharmacologically relevant species in which T cells engraft and reliable on- and off-target toxicity data can be obtained · No relevant species · Within the guideline
“Per the applicant, conventional nonclinical toxicology studies were not conducted because they do not yield clinically relevant information for a CAR T cell product.”
“Considering the type of product and the absence of pharmacologically relevant animal species in which T cells can engraft and reliable on- and off-target toxicity data can be obtained, the lack of general toxicity studies can be endorsed.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies conducted
Why: Safety risks are immune related, so studies in immunocompromised animals are of limited relevance · No relevant species
“Given the fact that safety aspects with this type of therapy are immune related, a toxicity study in immune compromised animal is of limited relevance. Lack of safety pharmacology testing is acceptable.”
BiodistributionAccepted
No traditional pharmacokinetic or biodistribution studies; distribution data only from xenograft pharmacology study
Why: Autologous gene therapy product with no pharmacologically relevant species · No relevant species · Within the guideline
“Traditional non-clinical pharmacokinetic studies (absorption, distribution, metabolism, excretion and in vitro drug-drug interaction) have not been conducted because obe-cel is an autologous gene therapy product and there is no pharmacologically relevant species. This is agreed.”
GenotoxicityAcceptedBeyond the letter
No genotoxicity or insertion site analysis; literature-based insertional mutagenesis risk evaluation instead
Why: Third-generation self-inactivating lentiviral vector, release criterion, long-term clinical monitoring for insertional mutagenesis · Weight of evidence · Class precedent · Human data
“No nonclinical genotoxicity studies were conducted with obe-cel based on the genotoxic risks associated with the third-generation self-inactivating lentiviral vector used to produce obe-cel, acceptable release criterion, and inclusion of long-term clinical monitoring for insertional mutagenesis and clonality.”
“The literature-based risk evaluation of insertional mutagenesis instead of actual insertion site analysis is sufficient from a non-clinical perspective.”
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