ChondroCelect
characterised viable autologous cartilage cells
Sources:EMA assessment report ↗
Species
MouseOther
Longest study
53 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
Nude mouse (ectopic), sheep and goat (orthotopic); non-GLP combined PD/PK/tox
“Non-clinical studies were performed as combined pharmacodynamic / pharmacokinetic (distribution) / toxicological studies in the ectopic mouse (nu/nu model) and in orthotopic models in sheep and goats.”
Why that species
Orthotopic large-animal cartilage defect models; nude mice to avoid rejection of human cells
“orthotropic animal model showed that implantation of human or allogeneic chondrocytes causes an immune response to the CBMP, resulting in poor repair.”
Surrogate molecule
Yes: ChondroCelect-like autologous goat chondrocytes and human cells in nude mice
“In goats ChondroCelect-like chondrocytes showed a more stable cartilage forming potential than dedifferentiated chondrocytes.”
Species: general tox
No repeat-dose studies; single-dose studies in nude mice (12 wk), sheep (14 wk), goats (53 wk) deemed sufficient
“the observation period of the single dose studies described above were up to 12 weeks in mice, 14 weeks in sheep and 53 weeks in goats”
Species: DART
Not conducted (negligible risk given nature and intended use)
“Taking into account the nature of the product and its intended clinical use the risk for reproductive and developmental toxicity is considered to be negligible.”
Species: carcinogenicity
Not conducted (in vitro senescence study instead)
“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
Surrogate used in
Yes: ChondroCelect-like autologous goat chondrocytes in goat models
“In goats ChondroCelect-like chondrocytes showed a more stable cartilage forming potential than dedifferentiated chondrocytes.”
Study lengthopen answer page →
Longest pivotal study
53 weeks
“the observation period of the single dose studies described above were up to 12 weeks in mice, 14 weeks in sheep and 53 weeks in goats”
Pivotal GLP studies
Non-GLP single-dose studies: mouse (12 wk), sheep (14 wk), goat (53 wk), local implantation
“These studies were non-GLP which is not in conformity with the pharmaceutical standards.”
Route in tox
Intramuscular/subcutaneous (mice); ACI implantation into cartilage defect (sheep, goats)
“Female NMRI nu/nu mice received intramuscular or subcutaneous injections of human articular chondrocytes”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (per cell-based product guideline)
“The omission of genotoxicity studies in the development program for ChondroCelect is in line with EMEA/CHMP/410869/2006.”
Carcinogenicity
Not conducted; in vitro serial passaging senescence study instead
“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
Reproductive & developmental
Not conducted; risk considered negligible
“the omission of reproductive and developmental toxicity studies in the development program for ChondroCelect is acceptable”
Safety pharmacology
Not conducted; locally administered cells
“the omission of safety pharmacological studies is in line with the guideline on human cell based medicinal products (EMEA/CHMP/410869/2006).”
Genotox: Ames
Not conducted (EMEA/CHMP/410869/2006)
“The omission of genotoxicity studies in the development program for ChondroCelect is in line with EMEA/CHMP/410869/2006.”
Genotox: in vitro mammalian
Not conducted (EMEA/CHMP/410869/2006)
“The omission of genotoxicity studies in the development program for ChondroCelect is in line with EMEA/CHMP/410869/2006.”
Genotox: in vivo
Not conducted (EMEA/CHMP/410869/2006)
“The omission of genotoxicity studies in the development program for ChondroCelect is in line with EMEA/CHMP/410869/2006.”
Carcinogenicity model
Not conducted; in vitro senescence study of serially passaged human chondrocytes
“In order to address the carcinogenic potential of ChondroCelect, the Applicant performed an in vitro study to evaluate senescence of human articular chondrocytes after serial passaging, using ChondroCelect culture conditions.”
Carcinogenicity timing
Not required (absence of standard studies accepted)
“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
hERG / QT
Not conducted (locally administered cells; per EMEA/CHMP/410869/2006)
“the omission of safety pharmacological studies is in line with the guideline on human cell based medicinal products (EMEA/CHMP/410869/2006).”
First doseopen answer page →
First-in-human starting dose
Clinical dose 0.8-1 x10^6 cells/cm2 based on animal studies, literature and ACI experience (not a formal FIH calculation)
“The dose selection was based on a combination of animal studies conducted by TiGenix, published literature and experience in humans with ACI.”
NOAEL / key findings
No NOAEL; no systemic toxicity; synovitis (~70% at 10 wk) and cell penetration into subchondral bone
“No effects on body systems or systemic toxicity was seen in the mice, sheep or goats”
Risksopen answer page →
Immune & cytokine safety
Human/allogeneic chondrocytes caused immune response and poor repair in orthotopic model
“implantation of human or allogeneic chondrocytes causes an immune response to the CBMP, resulting in poor repair.”
Biodistribution & persistence
Two goat studies with fluorescently tagged cells: cells persist as part of new cartilage; migration assessed
“implanted cells become a structural part of newly formed cartilage.”
Modality-specific risk
Subchondral bone penetration, synovitis, tumorigenic growth (negligible in vitro)
“The observed synovitis and the reported penetration of the transplanted cells in the subchondral bone have been identified in the RMP as potential safety concerns”
Anti-drug antibodies: animals
Human or allogeneic chondrocytes caused an immune response and poor repair in orthotopic model
“orthotropic animal model showed that implantation of human or allogeneic chondrocytes causes an immune response to the CBMP, resulting in poor repair.”
Anti-drug antibodies: patients
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.
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
Clinical dose 0.8-1 x10^6 cells/cm2 based on animal studies, literature and ACI experience (not a formal FIH calculation)
“The dose selection was based on a combination of animal studies conducted by TiGenix, published literature and experience in humans with ACI.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; long single-dose observation (up to 53 weeks in goats) judged sufficient
“As the observation period of the single dose studies described above were up to 12 weeks in mice, 14 weeks in sheep and 53 weeks in goats, these studies are considered to be sufficient to assess the long-term effects of ChondroCelect.”
Pivotal GLP studies
Non-GLP single-dose studies: mouse (12 wk), sheep (14 wk), goat (53 wk), local implantation
“These studies were non-GLP which is not in conformity with the pharmaceutical standards.”
DART package
Species: DART
Not conducted (negligible risk given nature and intended use)
“Taking into account the nature of the product and its intended clinical use the risk for reproductive and developmental toxicity is considered to be negligible.”
Reproductive & developmental
Not conducted; risk considered negligible
“the omission of reproductive and developmental toxicity studies in the development program for ChondroCelect is acceptable”
PPND / ePPND: when
Not conducted; negligible risk given nature of product and intended use
“Taking into account the nature of the product and its intended clinical use the risk for reproductive and developmental toxicity is considered to be negligible.”
Carcinogenicity
Species: carcinogenicity
Not conducted (in vitro senescence study instead)
“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
Carcinogenicity model
Not conducted; in vitro senescence study of serially passaged human chondrocytes
“In order to address the carcinogenic potential of ChondroCelect, the Applicant performed an in vitro study to evaluate senescence of human articular chondrocytes after serial passaging, using ChondroCelect culture conditions.”
Carcinogenicity timing
Not required (absence of standard studies accepted)
“In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
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 systemic toxicity; synovitis (~70% at 10 wk) and cell penetration into subchondral bone
“No effects on body systems or systemic toxicity was seen in the mice, sheep or goats”
Efficacy evidenceopen answer page →
Efficacy evidence
Ectopic nu/nu mouse model and orthotopic goat cartilage-defect model (ChondroCelect-like goat cells)
“Primary pharmacodynamic studies were performed in two animal models, an ectopic model in nu/nu mice and an orthotopic model in goats.”
Why that model
Human chondrocytes in goats gave poor repair, possibly due to immune reaction to human cells
“In another study in goats comparing passage 1 versus passage 5 expanded human articular chondrocytes according to ChondroCelect culture process all animals showed poor repair, possibly due to an immunological reaction to the human cells.”
Reviewer's view of the efficacy data
Goat studies adequate as proof of principle but data very limited; no valid correlation of ECFA score with repair
“The studies in goats are adequate to demonstrate proof of principle in a clinically relevant setting. However, the set of data is very limited and the Applicant did not demonstrate a valid correlation between the ECFA histology score and cartilage repair in the orthotopic goat model.”
Flexibilityopen answer page →
Flexibility accepted
GLPCriticised but acceptedBeyond the letter
All nonclinical studies non-GLP, run as combined pharmacodynamic/distribution/toxicity studies in nude mice, sheep and goats
Why: Specificity of the development programme for this product · Other reason
“These studies were non-GLP which is not in conformity with the pharmaceutical standards. However, these deficiencies were considered by CHMP to be tolerable in view of the specificity of the development programme for this particular product.”
“The implications of this deficiency to the validity and significance of the safety data collected in the pivotal goat study are considered tolerable.”
Study lengthAccepted
No repeat-dose toxicity study; single-dose implantation studies with observation up to 12 weeks (mice), 14 weeks (sheep), 53 weeks (goats)
Why: Long single-dose observation periods; omission in line with cell-based product guideline EMEA/CHMP/410869/2006 · Within the guideline · Weight of evidence
“As the observation period of the single dose studies described above were up to 12 weeks in mice, 14 weeks in sheep and 53 weeks in goats, these studies are considered to be sufficient to assess the long-term effects of ChondroCelect.”
“Therefore the omission of repeat-dose toxicity studies is in line with the EMEA guideline EMEA/CHMP/410869/2006.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity study in vivo; in vitro senescence study of serially passaged human chondrocytes instead
Why: No immortalisation during limited in vitro culture; tumorigenic risk negligible · Weight of evidence
“In order to address the carcinogenic potential of ChondroCelect, the Applicant performed an in vitro study to evaluate senescence of human articular chondrocytes after serial passaging, using ChondroCelect culture conditions.”
“The results provide sufficient evidence that immortalisation of human chondrocytes during limited time in in vitro culture conditions would not occur, and that the risk of tumorigenic growth is negligible. In view of these results, the absence of standard carcinogenicity studies was considered to be acceptable.”
DARTAccepted
No reproductive or developmental toxicity studies
Why: Nature of the product and its intended clinical use make the risk negligible · Low-risk modality · Within the guideline
“Taking into account the nature of the product and its intended clinical use the risk for reproductive and developmental toxicity is considered to be negligible.”
“Therefore, the omission of reproductive and developmental toxicity studies in the development program for ChondroCelect is acceptable and in line with the EMEA guideline EMEA/CHMP/410869/2006.”
Similar precedents
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