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”
Species: general tox
UM171 only: rat (single dose) and cynomolgus monkey (3 doses, 7-day washout)
“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 (administrated 3 times with a 7-day washout period before testing the next dose).”
Species: DART
Not conducted (not for use in pregnancy; minimal residual UM171)
“No reproductive and developmental toxicity studies on either UM171 or dorocubicel were conducted by the applicant. The applicant contended that such studies are unnecessary as ECT-001-CB is not recommended for use in pregnant women, and only minimal residual amounts of UM 171 were detected in dorocubicel.”
Species: carcinogenicity
Not conducted (ICH S9; advanced cancer population)
“The applicant did not perform any carcinogenicity studies, which is in line with ICH S9 since the product is to be used in patients with advanced cancer.”
Surrogate used in
No surrogate; UM171 inactive on mouse HSCs, so human cells used in immunocompromised mice
“The human cell product has been used in these immunocompromised animals, because the applicant explained that UM171 had no activity on mouse HSCs (i.e. homologous murine product not possible).”
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.”
Genotox: Ames
Negative (UM171; non-GLP and GLP Ames)
“Genotoxicity of UM171 was evaluated in a non-GLP AMES test at first with no mutagenic response observed. After receiving scientific advice from EMA the applicant conducted an additional GLP compliant AMES test in accordance with ICH S2 and OECD guidance with no mutagenic response observed.”
Genotox: in vitro mammalian
In vitro micronucleus in CHO cells (UM171): negative
“UM171 was considered to be negative, i.e. the test item did not induce chromosome breaks and/or loss in cultured CHO cells.”
Genotox: in vivo
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.
Carcinogenicity model
Not conducted; no neoplasia seen in NSG mouse studies of UM171-expanded cells
“There was also no indication of neoplasia in the in vivo toxicological studies of UM171 expanded cells in NSG mice.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“The applicant did not perform any carcinogenicity studies, which is in line with ICH S9 since the product is to be used in patients with advanced cancer.”
hERG / QT
UM171 (0.1-10 µM): non-significant current decrease; no relevant hERG block (non-GLP)
“UM171 (0.1 to 10 µM) did decrease the current through the channel, but this was not statistically significant compared to baseline. Taken together, 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
Why it's blank
The public FDA and EMA reviews of Zemcelpro 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 toxicity from UM171 at HED 8,000-20,000x human exposure (8 ng/kg); no treatment-related histopathology in NSG mice (EMA assessment report, p. 45)
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.”
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
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
Canada: dose de-escalation study (Study 001) at 2 sites in patients needing allogeneic stem cell transplant
“Study-001 is a prospective, single-arm, multicentre, open-label phase I-II dose de-escalation study of ECT-001-CB in patients who need an allogeneic hematopoietic stem cell transplant but lack a suitable donor. The study was conducted at 2 study sites in Canada and is completed.”
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 Zemcelpro 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 toxicity from UM171 at HED 8,000-20,000x human exposure (8 ng/kg); no treatment-related histopathology in NSG mice (EMA assessment report, p. 45)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (product given once)
“Repeat dose studies were not conducted and are not relevant for the product as it is applied only once.”
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.”
DART package
Species: DART
Not conducted (not for use in pregnancy; minimal residual UM171)
“No reproductive and developmental toxicity studies on either UM171 or dorocubicel were conducted by the applicant. The applicant contended that such studies are unnecessary as ECT-001-CB is not recommended for use in pregnant women, and only minimal residual amounts of UM 171 were detected in dorocubicel.”
Reproductive & developmental
Not conducted
“No reproductive and developmental toxicity studies were presented.”
PPND / ePPND: when
No reproductive/developmental studies; acceptable as not for use in pregnancy and minimal residual UM171
“The applicant contended that such studies are unnecessary as ECT-001-CB is not recommended for use in pregnant women, and only minimal residual amounts of UM 171 were detected in dorocubicel. The absence of such studies is considered acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9; advanced cancer population)
“The applicant did not perform any carcinogenicity studies, which is in line with ICH S9 since the product is to be used in patients with advanced cancer.”
Carcinogenicity model
Not conducted; no neoplasia seen in NSG mouse studies of UM171-expanded cells
“There was also no indication of neoplasia in the in vivo toxicological studies of UM171 expanded cells in NSG mice.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“The applicant did not perform any carcinogenicity studies, which is in line with ICH S9 since the product is to be used in patients with advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
UM171: no toxicity in rat/monkey at doses 8,000-20,000x estimated human exposure
“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”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo primary and secondary engraftment of UM171-cultured human cord blood CD34+ cells; in vitro expansion studies
“In vivo engraftment studies were conducted to show primary and secondary engraftment of UM171-cultured human CD34+ cord blood cells, thereby also evaluating the impact of changes in culture conditions.”
Why that model
UM171 has no activity on mouse HSCs, so a homologous murine product was not possible
“The human cell product has been used in these immunocompromised animals, because the applicant explained that UM171 had no activity on mouse HSCs (i.e. homologous murine product not possible).”
Reviewer's view of the efficacy data
No firm conclusions from nonclinical PD; efficacy must come from clinical studies
“Taken together, no firm conclusions can be drawn from the non-clinical primary PD data and therefore information on the efficacy of Zemcelpro should come from clinical studies.”
Flexibilityopen answer page →
Flexibility accepted
GLPAcceptedBeyond the letter
UM171 toxicity studies in rats (single dose) and monkeys (three doses) not GLP-compliant
Why: Weight-of-evidence approach; no further questions raised · Weight of evidence
“The single dose toxicity study in rats and the “repeat dose toxicity study” (3x administration with a 7- day washout period) in non-human primates were not in accordance with GLP.”
“Based on a 'weight of evidence approach,' it is therefore not deemed relevant to raise questions about this and the submitted discussion is considered sufficient.”
GLPAcceptedBeyond the letter
hERG assay with residual UM171 not GLP-compliant
Why: Anticipated residual UM171 level in the product (8 ng/kg) is negligible · Pharmacology or kinetics
“According to ICH S7A and B, safety PD studies such as the hERG assay should be performed in compliance with GLP. However, the study was not GLP compliant.”
“However, since the anticipated residual UM171 level in dorocubicel (8 ng/kg for a 70 kg adult) is negligible, the lack of GLP compliance is considered acceptable.”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies with UM171 or the cell product
Why: Not recommended in pregnancy; only minimal residual UM171 in the product · Pharmacology or kinetics
“The applicant contended that such studies are unnecessary as ECT-001-CB is not recommended for use in pregnant women, and only minimal residual amounts of UM 171 were detected in dorocubicel. The absence of such studies is considered acceptable.”
Efficacy modelCriticised but acceptedBeyond the letter
Manufacturing culture conditions with UM171 not fully substantiated with nonclinical data
Why: No concerns based on submitted clinical data; long-term safety and efficacy followed post-marketing · Human data
“Moreover, adaptations in the production process related to culture of the cells with UM171 have not been fully substantiated with thorough non-clinical data. Based on the submitted clinical data, there are no concerns.”
“However, long term safety and efficacy will be followed up in the post-marketing studies.”
Similar precedents
OmisirgeCell therapy · omidubicel · Expanded cord blood HPCRodent only · 12 wkTregziCell therapy · allogeneic Treg immunotherapy with HSPC and T cells (Orca-T) · Allogeneic Treg + HSPC + TconNo relevant species · n/aZalmoxisCell therapy · allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsRodent only · 3 wkBeqvezGene therapy · fidanacogene elaparvovec · Factor IXMonkey + rodent · 104 wkGrafapexSmall molecules · treosulfan · DNA alkylationMonkey + rodent · 4 wkHemgenixGene therapy · etranacogene dezaparvovec · Factor IXMonkey + rodent · 26 wk