Zemcelpro
dorocubicel
Sources:EMA assessment report ↗
Species
MonkeyRatMouse
Longest study
28 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Female sub-lethally irradiated NSG mice (human cells); UM171 compound PK/tox in NSG mouse, rat, cynomolgus monkey
“All in vivo studies have been conducted with female NSG mice.”
Why that species
UM171 has no activity on mouse HSCs; human cells in immunocompromised NSG mice needed (homologous murine product not possible)
“because the applicant explained that UM171 had no activity on mouse HSCs (i.e. homologous murine product not possible).”
Surrogate molecule
No surrogate; human product tested in NSG mice
“The human cell product has been used in these immunocompromised animals”
Study lengthopen answer page →
Longest pivotal study
28 weeks
“were not associated with any adverse histopathological changes to 28 weeks after administration of the cells.”
Pivotal GLP studies
No GLP product tox; non-GLP NSG mouse transplant studies (up to 28 wk) and non-GLP single-dose UM171 rat and cynomolgus studies
“Three male cynomolgus monkey were dosed with three consecutive IV doses (1 week apart) of 2.3, 23 and 230 µg/kg.”
Route in tox
Intravenous (cells in NSG mice; UM171 in rat/monkey)
“subsequently transplanted IV at three different doses into sub-lethally irradiated mice”
Skipped studiesopen answer page →
Genotoxicity
Done for residual UM171 only (Ames, CHO micronucleus negative) plus cytogenetics of treated cells; none for cells
“An AMES and a micronucleus test were conducted to assess the genetic safety of UM171”
Carcinogenicity
Not conducted
“Carcinogenicity studies were not submitted, which can be agreed.”
Reproductive & developmental
Not conducted
“No reproductive and developmental toxicity studies were presented.”
Safety pharmacology
In vitro hERG assay with residual UM171 (non-GLP), no relevant block
“UM171 appeared not to have a relevant blocking effect on the channel activity.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No toxicity from UM171 at HED 8,000-20,000x human exposure (8 ng/kg); no treatment-related histopathology in NSG mice
“Intravenous administration at doses 8,000-20,000 times higher than the estimated human exposure to UM171 demonstrated no toxicity in rats (single-dose study) or cynomolgus monkeys”
Risksopen answer page →
Immune & cytokine safety
No immunogenicity/cytokine studies; DP2 not tested in vivo as GvHD expected in NSG mice from mature immune cells
“in vivo transplantation cannot be performed with DP2 due to an expected GvHD reaction in the NSG mice caused by mature immune cells in this fraction.”
Biodistribution & persistence
Not studied; cell distribution not evaluated, assumed like normal allogeneic stem cell transplant
“The distribution of the UM171-treated cells is not evaluated.”
Modality-specific risk
Unintended epigenetic changes from UM171 expansion; long-term engraftment/stemness; no long-term clinical safety data
“whether there are unintended epigenetic changes is not addressed.”