Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Zemcelpro: what was done before first-in-human, and what came after?
dorocubicel · UM171-expanded cord blood CD34+
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.”
Same question, other cell therapies
Carvykti
ciltacabtagene autoleucel · BCMA CAR-TCountry not stated; first clinical trial in patients with relapsed/refractory multiple myeloma (LEGEND-2)
MACI
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesOutside the United States: all clinical studies ex-US (countries not named)
Tecelra
afamitresgene autoleucel · MAGE-A4 TCR-TCountry not stated; first-in-human dose-escalation and expansion study in HLA-A*02 patients with MAGE-A4-positive advanced tumors
Yescarta
axicabtagene ciloleucel · CD19 CAR-TCountry not stated; initial dose-finding study NCI 09-C-0082 in patients with advanced B-cell malignancies
Alofisel
darvadstrocel · Allogeneic adipose MSCNot stated in public reviews
Amtagvi
lifileucel · TIL therapyNot stated in public reviews
Aucatzyl
obecabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Breyanzi
lisocabtagene maraleucel · CD19 CAR-TNot stated in public reviews
ChondroCelect
characterised viable autologous cartilage cells · Autologous chondrocytesNot stated in public reviews
Ebvallo
tabelecleucel · EBV-specific allogeneic T cellsNot stated in public reviews
Encelto
revakinagene taroretcel · CNTF (encapsulated RPE cell implant)Not stated in public reviews
Gintuit
allogeneic cultured keratinocytes and fibroblasts in bovine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Holoclar
autologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem cellsNot stated in public reviews
Kymriah
tisagenlecleucel · CD19 CAR-TNot stated in public reviews
Lantidra
donislecel · Allogeneic pancreatic isletsNot stated in public reviews
Laviv
azficel-T · Autologous fibroblastsNot stated in public reviews
Omisirge
omidubicel · Expanded cord blood HPCNot stated in public reviews
Provenge
sipuleucel-T · PAP-GM-CSF (autologous APC)Not stated in public reviews
Rethymic
allogeneic processed thymus tissue · Allogeneic thymus tissueNot stated in public reviews
Ryoncil
remestemcel-L · Allogeneic BM-MSCNot stated in public reviews
Spherox
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsNot stated in public reviews
StrataGraft
allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Tecartus
brexucabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T) · Allogeneic Treg + HSPC + TconNot stated in public reviews
Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsNot stated in public reviews