Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Encelto: what was done before first-in-human, and what came after?
revakinagene taroretcel · CNTF (encapsulated RPE cell implant)
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 Encelto 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 set for device; minimal lens, vitreous and ocular inflammation; no systemic findings. rhCNTF DART NOAELs used for margins of exposure (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; long-term intravitreal implantation toxicity study in minipigs and pigs
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study in 4–8-month-old minipigs, 4–10-year-old pigs, and catastrophic device failure of NT-501 was evaluated by ITV injection of unencapsulated NTC-201-6A cells into 8-9 month old minipigs.”
Pivotal GLP studies
Non-GLP 12-week rabbit ocular tox/PK; 3-part minipig/pig long-term ITV implant study to 6 months; unencapsulated-cell device failure study in minipigs
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study”
DART package
Species: DART
Rat and rabbit (4 DART studies of SC rhCNTF: fertility and teratogenicity)
“Four Developmental and Reproductive Toxicity (DART) studies were conducted in rats and rabbits to establish the risks to fertility and teratogenicity associated with the subcutaneous (SC) administration of high doses of rhCNTF.”
Reproductive & developmental
Four DART studies of SC rhCNTF in rats and rabbits; no teratogenicity; exemption for device via margin of exposure
“There were no rhCNTF-related teratologic changes reported in the fetuses.”
PPND / ePPND: when
Rat SC rhCNTF study from pre-mating to postpartum Day 21 with pup postnatal development, completed before the marketing application
“In female rats administered rhCNTF at dose levels of 0, 10, 100, or 300 μg/kg/day SC for 2 weeks prior to mating to postpartum Day 21, mating performance, fertility and gestational parameters were normal. No adverse effects on fetuses or pup postnatal development were reported.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted per toxicological risk assessments)
“Studies to evaluate the carcinogenicity/tumorigenicity of ENCELTO were not conducted. These studies are not warranted based on the safety profile described in the provided toxicological risk assessments (TRAs).”
Carcinogenicity model
Not conducted; waived via toxicological risk assessments for rhCNTF and ENDO medium
“The applicant provided TRAs conducted by to support waivers for carcinogenicity/tumorigenicity studies for rhCNTF and the medium used within the device, human Endothelial-SFM medium (ENDO medium).”
Carcinogenicity timing
Not required (waiver rationale accepted by reviewer)
“This reviewer agrees with the rationale provided in the TRAs for not conducting carcinogenicity/tumorigenicity studies.”
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
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