Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Spherox: what was done before first-in-human, and what came after?
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroids
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 Spherox 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 treatment-related adverse effects or signs of general/local toxicity in any study (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration of spheroids in all in vivo studies)
“In the in vivo studies, a single dose of spheroids was either injected or implanted into a knee joint or administered subcutaneously in the back of the animal.”
Pivotal GLP studies
GLP Merino sheep 6/9-month implantation (failed, implant lost); GLP NSG mouse 6-month biodistribution/tumourigenicity; minipig 2-month
“study Merino sheep was designed to evaluate local and systemic toxicity during 6 months of implantation of autologous spheroids in a femoral condyle defect.”
DART package
Species: DART
Not conducted; autologous cells with local mechanism of action and limited biodistribution
“Reproductive and developmental toxicity studies were not conducted. In line with guidelines on cell-based medicinal products (EMEA/CHMP/410869/2006), the applicant has provided an acceptable justification for omitting these studies: Spherox contains autologous cells with a local mechanism of action, and the risk for biodistribution of cells is limited.”
Reproductive & developmental
Not conducted; autologous cells with local action and limited biodistribution
“Reproductive and developmental toxicity studies were not conducted.”
PPND / ePPND: when
Not conducted: autologous cells with local action and limited biodistribution
“Reproductive and developmental toxicity studies were not conducted. In line with guidelines on cell-based medicinal products (EMEA/CHMP/410869/2006), the applicant has provided an acceptable justification for omitting these studies”
Carcinogenicity
Species: carcinogenicity
No conventional carcinogenicity; 6-month GLP tumourigenicity study in immunodeficient mice
“including the 6 months GLP study in immunodeficient mice which support the absence of the tumourigenic potential.”
Carcinogenicity model
GLP NSG mouse study, human spheroids implanted subcutaneously: no tumour or ectopic tissue formation after 6 months
“In a GLP compliant study using immunodeficient NSG mice, biodistribution of cells out from human Spheroxs implanted subcutaneously into the back was investigated after 4 weeks. There were no indications of significant systemic distribution of the cells, or were there any indications of tumour or ectopic tissue formation after 6 months in the tumourigenicity part of this study.”
Carcinogenicity timing
Not required: conventional carcinogenicity omitted per cell-based product guideline
“No genotoxicity, conventional carcinogenicity and reproductive- and developmental toxicity studies were performed which is in line with the guideline on cell-based medicinal products (EMEA/CHMP/410869/2006).”
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
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