Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Holoclar: what was done before first-in-human, and what came after?
autologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem 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 Holoclar 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 animal tox. In vitro: no chromosomal aberrations, soft agar negative (EMA assessment report, p. 18)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; animal toxicity studies omitted (no suitable animal model)
“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”
Pivotal GLP studies
No in vivo tox; in vitro karyotype, growth factor dependence and soft agar assays
“in order to investigate the proliferative capacity of the 3T3-J2 feeder cells, the applicant performed in vitro karyotype analysis and soft agar assays.”
DART package
Species: DART
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Reproductive & developmental
Not conducted; no systemic exposure and autologous product
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible”
PPND / ePPND: when
Not conducted: reproductive toxicity testing omitted (autologous, no systemic exposure)
“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
Carcinogenicity model
Not conducted; three in vitro tumorigenicity assays (karyotype, growth factor dependence, soft agar) indicated low risk
“tumourigenicity of Holoclar drug substance and product was investigated in three different in vitro approaches, all of which pointed towards a low risk of tumour formation.”
Carcinogenicity timing
Not required: conventional carcinogenicity not performed; in vitro tumorigenicity assays instead
“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”
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
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Tecelra
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Aucatzyl
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Breyanzi
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ChondroCelect
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Ebvallo
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Encelto
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Gintuit
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Kymriah
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Lantidra
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Laviv
azficel-T · Autologous fibroblastsNot stated in public reviews
Omisirge
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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
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Spherox
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsNot stated in public reviews
StrataGraft
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Tecartus
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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