Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
MACI: what was done before first-in-human, and what came after?
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytes
Before first-in-human
First-in-human: where
Outside the United States: all clinical studies ex-US (countries not named)
“Note: No IND(s) is associated with this file. All clinical studies were conducted outside of the United States (OUS).”
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 MACI 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; no significant safety signals; mild transient inflammation, mild early lameness in horses recovered by 53 weeks (FDA pharmacology/toxicology review, p. 3)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single implantation); longest study 53-week horse implant study
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”
Pivotal GLP studies
Combined GLP-type pharm/tox 53-week equine study (27 horses, stifle trochlear defect implant); 12- and 24-week rabbit studies
“A definitive 53-week study was conducted in 27 horses (Study # GENZ-09-4417) to evaluate the safety and the activity of MACI”
DART package
Species: DART
Not conducted; local knee administration with minimal systemic entry
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
Reproductive & developmental
Not conducted (local administration, minimal systemic entry, mature autologous cells)
“Per the applicant, studies were not conducted to evaluate this safety endpoint because the product is administered locally in the knee with minimal to no product entry systemically.”
PPND / ePPND: when
Not conducted: local knee implantation, no systemic distribution
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies.”
Carcinogenicity model
Not conducted; no tumors in the one-year horse study
“No tumors were detected in the one-year animal study, thus indicating that tumor formation is unlikely.”
Carcinogenicity timing
Not required: local implantation site, no systemic distribution, membrane not genotoxic
“The applicant did not conduct carcinogenicity or developmental and reproductive toxicity studies. This is acceptable considering the local anatomic site of MACI implantation, the absence of systemic MACI distribution following administration”
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)
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
Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsNot stated in public reviews