Skysona
elivaldogene autotemcel
Species
Mouse
Longest study
13 wk (derived)
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse only: myeloablated immunodeficient NSG/NSGS mice given human CD34+ HSCs
“pivotal combined in vivo pharmacology, single-dose toxicity, genotoxicity and biodistribution studies in immunodeficient (NSG and NSGS) mice”
Why that species
Human cells rejected by immunocompetent animals, so immune-incompetent mice used; species barrier limits translatability
“they will be rejected. Therefore immune”
Surrogate molecule
No surrogate vector; clinical Lenti-D vector in human healthy-donor CD34+ HSCs (not patient cells) xenografted into mice
“Lenti-D donors lentiviral vector transduced human CD34+ HSCs from healthy”
Study lengthopen answer page →
Longest pivotal study
13 (derived from the dosing and observation schedule)
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
Pivotal GLP studies
Single 92-day GLP IV toxicity/biodistribution study (NC-12-007) in myeloablated NSG mice, 1x10^6 cells/mouse; no repeat-dose studies
“A 92-day GLP toxicology study in myeloablated mice evaluated a single administration of 1x106 Lenti-D transduced healthy human CD34+ HSCs/mouse.”
Route in tox
Intravenous
“Route of Administration Intravenous”
Skipped studiesopen answer page →
Genotoxicity
Standard genotox not relevant; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”
Carcinogenicity
Not conducted (traditional studies unsuitable for product); ISA on engrafted marrow instead
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Reproductive & developmental
Not conducted; no findings in reproductive tissues in mouse GLP study
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
Safety pharmacology
Not conducted; no overt CNS, CV or respiratory toxicity in two animal studies
“No dedicated safety pharmacology studies have been carried out.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
True NOAEL not determined; ~5x10^7 CD34+ cells/kg (max feasible, 10x minimum clinical dose); early deaths in both test and control groups
“Although a true no observed adverse effect level (NOAEL) could not be determined, the dose level administered in this study, approximately 5x107 CD34+ cells/kg, represents the maximum feasible dose”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Biodistribution & persistence
Human and vector sequences in all tissues tested through 3 months; highest in bone marrow, then lung, liver, spleen; lowest in brain, intestine, muscle
“the highest concentration (copies/µg) was observed in bone-marrow were signals above the upper LoQ were observed.”
Modality-specific risk
Insertional mutagenesis/oncogenesis from lentiviral integration; clinical hematologic malignancy concern; IVIM and ISA used
“There was a reduced potential for immortalization induced by insertional mutagenesis of the clinical vector, Lenti-D, compared to positive control vectors.”