Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Carvykti: what was done before first-in-human, and what came after?
ciltacabtagene autoleucel · BCMA CAR-T
Before first-in-human
First-in-human: where
Country not stated; first clinical trial in patients with relapsed/refractory multiple myeloma (LEGEND-2)
“In the first phase 1 single arm trial CAR T cells in patients with relapsed/refractory MM (Legend -2), ORR for the total population was 87.8%, with 64% CR and 56.8% MRD negative, VGPR was 10.8%, PR was 12.2%, CR (64%) and ORR (87.8%) in patients that had relapsed following IMiDs and PI treatment.”
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 Carvykti 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; NHP 5 and 40x10^6 cells/kg: no adverse effects, transient mild blood count decreases (FDA pharmacology/toxicology review, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no relevant species; single-dose product)
“No repeat dose toxicity has been performed given there is no relevant nonclinical species and that cilta-cel is administered as a single dose to patients and is anticipated to undergo expansion and persistence following administration.”
Pivotal GLP studies
No GLP tox; non-GLP cynomolgus pilot (n=2, single IV, 30 days) plus NCG mouse xenograft studies
“The applicant performed one in vivo non-GLP toxicology pilot study in Cynomolgus monkeys using autologous CAR-T cells manufactured with the second/ third generation hybrid LV developed by Legend.”
DART package
Species: DART
Not conducted: rodents and NHPs not pharmacologically relevant (no binding to mouse/NHP BCMA)
“In addition, did not bind to recombinant mouse or NHP BCMA expressed on cells (Studies #6 and #18), demonstrating that rodents and NHPs are not pharmacology relevant species for testing cilta-cel.”
Reproductive & developmental
Not conducted; binding domain not detected in human reproductive organs
“Therefore, traditional DART studies were not conducted.”
PPND / ePPND: when
Not conducted; acceptable given product type and BCMA expression pattern
“No non-clinical reproductive and developmental toxicity studies have been conducted, which is acceptable based on the type of product and the BCMA expression pattern.”
Carcinogenicity
Species: carcinogenicity
Not conducted: human-specific product, no cross-reactivity to mouse BCMA
“In addition, cilta-cel is a human specific CAR-T cell product and lacks cross reactivity to mouse BCMA precluding the conduct of traditional rat and mouse bioassays.”
Carcinogenicity model
Not conducted; in vitro cytokine-independent growth and lentiviral integration-site studies showed no concern
“In vitro studies with CARVYKTI manufactured from healthy donors and patients with multiple myeloma showed no evidence of cytokine independent growth and no preferential integration near genes associated with oncogenic transformation.”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat advanced cancer.”
Same question, other cell therapies
MACI
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Gintuit
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Holoclar
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Kymriah
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Lantidra
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Laviv
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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