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.”
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).”
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”
Similar precedents
MACIautologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesOther species · 53 wkSpheroxspheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsOther species · 39 wkHoloclarautologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem cellsNo relevant species · none