Ebvallo
tabelecleucel
Sources:EMA assessment report ↗
Species
Mouse
Longest study
20 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
SCID mice (EBV+ lymphoma xenograft, literature/PD); no tox species
“Safety pharmacology studies were not conducted due to the species-specific nature of tabelecleucel and the limited applicability of non-human toxicology models.”
Why that species
Species-specific HLA-restricted human T cell product; SCID mice permit human lymphocyte engraftment
“Because SCID mice are unable to generate functional lymphocytes, engraftment and growth of human lymphocytes and several human tumours are possible.”
Surrogate molecule
No surrogate; human tabelecleucel CTLs in immunodeficient SCID mice
“Inoculation of SCID mice with EBV+ BLCL results in development of EBV-induced immunoblastic B cell lymphomas with characteristics similar to EBV-PTLD arising in immunocompromised hosts”
Species: general tox
Not conducted (species-specific product)
“Single and repeat dose toxicity studies were not conducted as due to the species-specific nature of tabelecleucel these studies would yield no additional information to aid in the understanding of its potential toxicity in humans.”
Species: DART
Not conducted (highly species-specific pharmacology)
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
Species: carcinogenicity
Not conducted
“conventional toxicology, carcinogenicity, genotoxicity, mutagenicity and reproductive toxicology studies have not been performed with tabelecleucel.”
Surrogate used in
No surrogate used; tabelecleucel itself tested in SCID mice
“The primary goal of this study was to assess in-vivo homing and EBV specificity and efficacy of tabelecleucel in the presence or absence of IL-2.”
Study lengthopen answer page →
Longest pivotal study
20 weeks
“Two of 5 mice in each group had complete tumour regression and survived > 5 months after tabelecleucel treatment.”
Pivotal GLP studies
No GLP tox; published single-dose SCID mouse efficacy/homing studies (IP, IV 10^7 cells) and in vitro co-culture EBV transmission assay
“Studies conducted in immunodeficient animal models for EBV+ PTLD revealed no overt signs of toxicity (e.g. loss of activity or weight loss) associated with a single dose of tabelecleucel.”
Route in tox
Intraperitoneal and intravenous (mice); clinical route intravenous
“The IV inoculation of 107 EBV-specific CTL resulted in improved survival of SCID mice (n = 5)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1)); non-genetically engineered cells
“In accordance with ICH S6(R1), genotoxicity studies with tabelecleucel were not conducted.”
Carcinogenicity
Not conducted (ICH S6(R1)); in vitro EBV transmission/transformation co-culture assay done
“standard carcinogenicity bioassays are generally inappropriate for”
Reproductive & developmental
Not conducted; highly species-specific pharmacology
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
Safety pharmacology
Not conducted; species-specific product
“Safety pharmacology studies were not conducted due to the species-specific nature of tabelecleucel and the limited applicability of non-human toxicology models.”
Genotox: Ames
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1), genotoxicity studies with tabelecleucel were not conducted.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1), genotoxicity studies with tabelecleucel were not conducted.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1), genotoxicity studies with tabelecleucel were not conducted.”
Carcinogenicity model
Not conducted; in vitro co-culture study RPT-129-1002 of EBV transmission and tumorigenic effect
“The applicant conducted study RPT-129-1002 to investigate potential EBV transmission and tumorigenic effect.”
Carcinogenicity timing
Not required (ICH S6(R1): standard bioassays inappropriate)
“Tabelecleucel has not demonstrated, and is not anticipated to have, carcinogenic potential and as stated in ICH S6(R1), standard carcinogenicity bioassays are generally inappropriate for”
hERG / QT
Not conducted (species-specific product)
“Safety pharmacology studies were not conducted due to the species-specific nature of tabelecleucel and the limited applicability of non-human toxicology models.”
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 Ebvallo 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 overt toxicity (activity loss, weight loss) after single dose in immunodeficient mice (EMA assessment report, p. 31)
NOAEL / key findings
No NOAEL; no overt toxicity (activity loss, weight loss) after single dose in immunodeficient mice
“Studies conducted in immunodeficient animal models for EBV+ PTLD revealed no overt signs of toxicity (e.g. loss of activity or weight loss) associated with a single dose of tabelecleucel.”
Risksopen answer page →
Immune & cytokine safety
No cytokine or immunogenicity studies; low alloreactivity verified in release testing; CD20 not expressed (rituximab interaction unlikely)
“Ebvallo is tested for specificity of lysis of EBV+ targets, T-cell HLA restriction of specific lysis, and verification of low alloreactivity.”
Biodistribution & persistence
No PK/biodistribution studies; literature imaging in mice: infiltration of HLA-matched EBV+ tumours up to day 28, absent in mismatched
“Migration and infiltration occurred into fully HLA-matched tumours and was absent from mismatched tumours.”
Modality-specific risk
EBV transmission/transformation risk from BLCL stimulators; HLA-restricted alloreactivity
“Taken together, this data showed the lack of transmission and uncontrolled proliferation of infectious EBV to MCBC and autologous T cell depleted PBMC.”
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-HLA antibodies in 1 of 7 tested subjects; ADA conclusions not possible
“The anti-HLA antibody dataset was limited to only 7 subjects from whom only one developed a positive anti-HLA antibody result. Valid conclusions related to anti-drug antibody (ADA) induction are therefore not possible.”
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 Ebvallo 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 overt toxicity (activity loss, weight loss) after single dose in immunodeficient mice (EMA assessment report, p. 31)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (species-specific product)
“Single and repeat dose toxicity studies were not conducted as due to the species-specific nature of tabelecleucel these studies would yield no additional information to aid in the understanding of its potential toxicity in humans.”
Pivotal GLP studies
No GLP tox; published single-dose SCID mouse efficacy/homing studies (IP, IV 10^7 cells) and in vitro co-culture EBV transmission assay
“Studies conducted in immunodeficient animal models for EBV+ PTLD revealed no overt signs of toxicity (e.g. loss of activity or weight loss) associated with a single dose of tabelecleucel.”
DART package
Species: DART
Not conducted (highly species-specific pharmacology)
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
Reproductive & developmental
Not conducted; highly species-specific pharmacology
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
PPND / ePPND: when
Not conducted; highly species-specific pharmacology
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“conventional toxicology, carcinogenicity, genotoxicity, mutagenicity and reproductive toxicology studies have not been performed with tabelecleucel.”
Carcinogenicity model
Not conducted; in vitro co-culture study RPT-129-1002 of EBV transmission and tumorigenic effect
“The applicant conducted study RPT-129-1002 to investigate potential EBV transmission and tumorigenic effect.”
Carcinogenicity timing
Not required (ICH S6(R1): standard bioassays inappropriate)
“Tabelecleucel has not demonstrated, and is not anticipated to have, carcinogenic potential and as stated in ICH S6(R1), standard carcinogenicity bioassays are generally inappropriate for”
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 overt toxicity (activity loss, weight loss) after single dose in immunodeficient mice
“Studies conducted in immunodeficient animal models for EBV+ PTLD revealed no overt signs of toxicity (e.g. loss of activity or weight loss) associated with a single dose of tabelecleucel.”
Efficacy evidenceopen answer page →
Efficacy evidence
SCID mice with EBV+ BLCL-induced B cell lymphomas (IP/SC) treated with autologous tabelecleucel
“The in vivo experiments demonstrated a pronounced therapeutic effect/increased survival of SCID mice suffering from intraperitoneal EBV-induced lymphoblastic B cell lymphomas (EBV-BLCL) that were treated with autologous (with respect to EBV-BLCL) tabelecleucel.”
Why that model
SCID mice lack functional lymphocytes, allowing engraftment of human lymphocytes and human tumours
“Because SCID mice are unable to generate functional lymphocytes, engraftment and growth of human lymphocytes and several human tumours are possible.”
Reviewer's view of the efficacy data
Experiments demonstrate in vivo proof-of-principle
“Altogether, the experiments demonstrate in vivo-proof of-principle.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No single- or repeat-dose toxicity studies; no relevant animal model for an HLA-restricted human T-cell product
Why: Species-specific product; animal or in vitro models cannot accurately predict its toxicity in humans · No relevant species
“Single and repeat dose toxicity studies were not conducted as due to the species-specific nature of tabelecleucel these studies would yield no additional information to aid in the understanding of its potential toxicity in humans.”
“Due to the nature of the product, in vitro assays and studies in ex vivo models or in vivo models cannot accurately assess and predict the toxicological characteristics of this product in humans.”
DARTVerdict not stated
No reproductive or developmental toxicity studies
Why: Highly species-specific pharmacology · No relevant species
“Due to the highly species-specific nature of the pharmacology associated with tabelecleucel, nonclinical reproductive/developmental toxicity studies were not submitted with this application.”
Safety pharmacologyVerdict not stated
No safety pharmacology studies
Why: Species-specific product; limited applicability of non-human toxicology models · No relevant species
“Safety pharmacology studies were not conducted due to the species-specific nature of tabelecleucel and the limited applicability of non-human toxicology models.”
BiodistributionVerdict not stated
No conventional pharmacokinetic or biodistribution studies; persistence and homing addressed by published mouse imaging literature
Why: Not applicable to cell-based products per CHMP guideline on human cell based medicinal products · Within the guideline
“Conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable for tabelecleucel as described in the CHMP’s 2006 Guideline on human cell based medicinal products (EMEA/CHMP/410869/2006).”
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