Lenmeldy
atidarsagene autotemcel
Species
Mouse
Longest study
52 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (As2-/- MLD model, murine ARSA-LV HSPCs) for pivotal GLP; immunodeficient mice for human-cell biodistribution
“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”
Why that species
As2-/- mouse used as MLD disease model; recapitulates some pathology but milder phenotype than patients
“The applicant has used the As2-/- mouse as a disease model for MLD in children.”
Surrogate molecule
Yes: murine Lin- HSPCs from As2-/- mice transduced with ARSA LVV (plus healthy human HSPCs) used instead of patient cells
“Therefore, lineage negative (Lin-) mHSPCs (derived from the BM of As2-/- mice) and healthy hHSPCs (derived from umbilical cord blood or BM) transduced with ARSA LVV were used for the majority of the nonclinical studies.”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“Scheduled Sacrifice Time Points 52 weeks post-dose”
Pivotal GLP studies
GLP toxicology/tumorigenicity study, As2-/- mice, single IV ARSA-LV or mock HSPCs, 52 weeks post-dose
“Toxicology and tumorigenicity study in ARSA KO mice treated with ARSA-/- HSPCs transduced with ARSA.LV Vector”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Conducted: integration site analysis, in vitro immortalization assay, tumor-prone Cdkn2a-/- mouse; no insertional transformation
“Genotoxicity risk was assessed in vitro using hHSPCs derived from healthy donors and MLD patients and showed no effects of LVV transduction or ARSA overexpression on the proliferation or differentiation of hHSPCs.”
Carcinogenicity
Not conducted (not warranted); tumorigenicity assessed within GLP mouse study
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200.”
Reproductive & developmental
Not conducted (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
Safety pharmacology
Not conducted; no CNS, cardiovascular or respiratory toxicity seen in animal studies
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No formal NOAEL; no test-article toxicity or malignancy at 1x10^6 cells/mouse (40-50x10^6 cells/kg); findings from As2-/- phenotype and irradiation
“No test article-related mortality, toxicity or hematologic malignancy was observed, with study findings primarily attributed to the As2-/- phenotype, irradiation, and incidental age-related findings.”
Risksopen answer page →
Immune & cytokine safety
No anti-ARSA antibodies or adverse neurobehavioral effects in mice; anti-ARSA antibodies in 15% of patients clinically
“No development of anti-ARSA antibodies or adverse neurobehavioral effects were observed in As2-/- mice transplanted with ARSA LVV-transduced mHSPCs.”
Biodistribution & persistence
Engrafts BM, spleen, thymus, liver; lower levels in brain; integrated LVV persists stably; shedding risk low
“In addition to the bone marrow, spleen, thymus, and liver, transduced human cells were also detected at lower levels in the mouse brain, demonstrating migration of the transduced cells into target organs.”
Modality-specific risk
Insertional mutagenesis/oncogenesis of LVV; none seen in tumor-prone mouse (SIN vector); conditioning-related toxicity
“Libmeldy-related LV showed no considerable insertional transformation potential in the tumour-prone mice, which is most likely due to the absence of active LTRs (i.e. LV is self-inactivating).”