Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Zalmoxis: what was done before first-in-human, and what came after?
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cells
Before first-in-human
First-in-human: where
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.
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 Zalmoxis 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 NOAEL; GvHD occurred in mice but with lower incidence/severity than unmanipulated PBL; limited safety assessment (EMA assessment report, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; single-dose toxicity assessed within immunodeficient-mouse GvHD pharmacodynamic studies
“Single dose toxicity has been assessed in the immunodeficient animal models in the pharmacodynamic studies. Repeat dose toxicity Repeat-dose toxicity studies were not submitted (See discussion on non-clinical aspects).”
Pivotal GLP studies
No GLP tox; two integrated PD/PK/tox NOD/SCID GvHD mouse studies (20x10^6 cells/mouse), up to ~3 weeks
“Single dose toxicity has been assessed in the immunodeficient animal models in the pharmacodynamic studies.”
DART package
Species: DART
Not conducted; absence considered justified
“The lack of studies on reproductive and development toxicity is justified.”
Reproductive & developmental
Not conducted; justified
“The lack of studies on reproductive and development toxicity is justified.”
PPND / ePPND: when
No reproductive toxicology studies; omission considered acceptable
“Conventional toxicology, carcinogenicity, mutagenicity and reproductive toxicology studies have not been performed, which is considered acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted (species-specific product; rodent/NHP carcinogenicity studies not appropriate)
“The MM-TK DP is a species specific product and therefore standard carcinogenicity studies using rodents or non-human primates as described in the ICH guidelines are not appropriate.”
Carcinogenicity model
No in vivo study; in vitro clonality, insertion-site profile, growth-factor-independent growth and RCR assessments
“The in vitro studies pertain 1) evaluation of clonality of the transduced cell population, 2) characterisation of the insertional pattern, 3) evaluation of growth-factor independent growth, and 4) assessment of break out of replication competent retroviruses (RCR).”
Carcinogenicity timing
Not required: species-specific product, standard rodent/NHP carcinogenicity studies not appropriate; in vitro oncogenic-risk studies instead
“The MM-TK DP is a species specific product and therefore standard carcinogenicity studies using rodents or non-human primates as described in the ICH guidelines are not appropriate.”
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
Zemcelpro
dorocubicel · UM171-expanded cord blood CD34+Canada: dose de-escalation study (Study 001) at 2 sites in patients needing allogeneic stem cell transplant
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