Alofisel
darvadstrocel
Sources:EMA assessment report ↗
Species
RatMouse
Longest study
26 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
Immunocompromised athymic nude rats (GLP); nude mice for tumourigenicity
“The applicant has chosen immunocompromised athymic rats to perform the biodistribution, toxicology and tumourigenicity studies.”
Why that species
Athymic rats minimise rejection of human cells and extend persistence; immunocompetent rats rejected the cells
“in order to minimize the immune recognition and potential rejection of human eASC in the experimental animal models and to extend Cx601 persistence”
Surrogate molecule
No surrogate; human eASC tested in immunodeficient rats and mice (xenogeneic)
“Human eASC preparations from six donors (3 men and 3 women) were expanded to population doubling levels equal to levels of product for clinical use.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Animals were euthanised at 2 or 26 weeks after the final infusion.”
Pivotal GLP studies
GLP athymic rat: 2 doses 2 weeks apart, perianal (up to 12/24 wk post-dose) and IV (26 wk); 26-wk biodistribution
“Two repeat-dose toxicity studies were conducted with human eASC in male and female athymic nude rats (Crl:NIH-Foxn1rnu) via the perianal route”
Route in tox
Perianal + intrarectal (clinical), intravenous (systemic), intravaginal (supportive)
“Several routes of administration were investigated: a combination of perianal + intrarectal administration reflecting the intended clinical route, the intravenous route exemplifying a systemic administration”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; cell-based product does not interact with DNA
“Genotoxicity studies are not applicable for the product, considering the cell-based nature of the product, which precludes interaction directly with DNA or other chromosomal material.”
Carcinogenicity
Not conducted (conventional); in vitro senescence/karyotype/soft agar and mouse tumourigenicity, no tumours
“In in vivo tumourigenicity tests, nude mice administered a subcutaneous injection of eASC at various population doubling levels, equal to levels of product for clinical use, all survived to scheduled sacrifice and no tumour-formation was observed.”
Reproductive & developmental
Not conducted; no migration into reproductive organs in biodistribution
“Reproductive and developmental toxicity studies have not been performed for Alofisel because preclinical biodistribution studies indicated no migration and integration of eASC into reproductive organs”
Safety pharmacology
CNS: functional observational battery in rats showed no effect; CV/respiratory not performed
“eASC treatment did not affect any of the neurological parameters evaluated in the Functional Observational Battery Test”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Perianal doses up to 2.5x10^6 cells/rat well tolerated; IV 10x10^6 cells caused fatal pulmonary embolism
“Taken together, two administrations of eASC two weeks apart at doses up to 2.5 x 106 cells were well tolerated in athymic nude rats when administered via the perianal route.”
Risksopen answer page →
Immune & cytokine safety
Low T-cell recognition and delayed NK elimination in vitro; immunocompetent rats showed rejection-type inflammation
“Data generated in other toxicity studies show low potential for T-cell mediated eASC recognition, in vitro and delayed NK cell mediated elimination.”
Biodistribution & persistence
Rats: eASC persisted short term (day 14), restricted to rectum/jejunum locally; lungs after IV
“In conclusion, when administered locally human eASC is only persistent for a short period of time in rats.”
Modality-specific risk
Ectopic tissue formation and tumourigenicity (RMP potential risk); pulmonary embolism if systemic
“Ectopic tissue formation and tumourigenicity has therefore been included in the RMP as important potential risk and will be followed up with the agreed post-authorisation safety study (PASS).”
Similar precedents
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