Genglycos
pariglasgene brecaparvovec
Species
MonkeyMouse
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (adult and juvenile C57BL/6N) and juvenile cynomolgus monkey; GLP single-dose studies
“Three separate 92-day, single-dose toxicology studies were conducted in healthy adult and juvenile mice.”
Why that species
Not stated in public reviews
Surrogate molecule
No surrogate; clinical vector DTX401 tested in mouse and NHP
“Test Article DTX401 (lot # D401-500P-W22-02)”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“To evaluate potential toxicity of IV DTX401 administration in NHPs with a 6-month recovery period.”
Pivotal GLP studies
Three 92-day single-dose IV studies in adult/juvenile mice; one 6-month single-dose IV GLP study in juvenile cynomolgus monkeys
“One 6-month, single-dose toxicology study was conducted in healthy juvenile non-human primates (NHPs)”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted (low AAV integration risk); vector integration assessed in germline transmission study
“studies were not conducted to evaluate genotoxicity as they expect that the risk of DTX401 insertion is low.”
Carcinogenicity
Not conducted (AAV8 predominantly episomal; no link between AAV integration and hepatic tumors)
“studies were not conducted to evaluate carcinogenicity/tumorigenicity”
Reproductive & developmental
Embryo-fetal development and germline transmission studies in mice; NOAEL 7.0x10^13 gc/kg; no germline integration
“IV administration of DTX401 at 7 × 1013 gc/kg to pregnant dams at presumed gestational day (GD) 6 resulted in DTX401 DNA detection in placenta but not offspring livers”
Safety pharmacology
Incorporated into 6-month monkey study (respiratory, cardiovascular, neurological); no in vitro studies
“Relevant safety pharmacology endpoints (respiratory, cardiological, and neurological endpoints) were evaluated in Study #11”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 1.0x10^13 gc/kg adult mouse (hepatic necrosis, Kupffer cell changes above); 7.0x10^13 juvenile mouse; ~1.3x10^14 gc/kg NHP
“identified a NOAEL equivalent to 1.3 × 1014 gc/kg of GENGLYCOS”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV8 nAbs in all dosed mice and NHPs; AAV8 T-cell responses in mice; sporadic cytokine elevations; juvenile immune stimulation
“T-cell responses to the AAV8 peptide pool were observed in 2/10 mice on Day 29 and in 6/10 mice on Day 92.”
Biodistribution & persistence
Highest in liver; vector DNA in all tissues incl. gonads (DNA and RNA); clearance from blood ~24 weeks in patients
“DTX401 biodistribution (BD) was highest in the liver and vector DNA was detected in all evaluated tissues, including the ovaries and testes”
Modality-specific risk
AAV8 hepatotoxicity (ALT elevations, hepatic necrosis), immune responses, and theoretical integration/tumorigenicity
“In adult mice, the no observed adverse effect level (NOAEL) for IV administration of DTX401 was 1.0 × 1013 gc/kg, based on findings of single-cell hepatic necrosis”