Hemgenix
etranacogene dezaparvovec
Species
MonkeyMouse
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Mouse and cynomolgus monkey
“The toxicology data package of etranacogene dezaparvovec and AMT-060 included single IV dose toxicity studies up to duration of 6 months with 6 months observation period in C57Bl/6 mice and cynomolgus macaques, and a reproduction and developmental toxicity study in mice.”
Why that species
NHP most relevant as natural AAV host; mouse and monkey hepatocytes transduced and express hFIX
“From the pharmacokinetic point of view, non-human primates were the most relevant species”
Surrogate molecule
Yes: predecessor vector AMT-060 (wild-type hFIX, differs by 2 nucleotides) used in several studies; AMT-061 also tested
“AMT-060 instead of etranacogene dezaparvovec was used in several toxicological studies provided.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“At 26 weeks following IV administration of 5x1012 to 9x1013 gc/kg HEMGENIX in NHPs, high levels of vector DNA were detected in a dose-dependent manner in the liver.”
Pivotal GLP studies
GLP single-dose IV studies in C57Bl/6 mice and cynomolgus monkeys (13-26 weeks observation); mouse paternal germline transmission study
“The single IV dose toxicology studies and the analysis of the safety parameters were performed under GLP compliance.”
Route in tox
Intravenous (single dose), mimicking clinical route
“IV-route of administration, the clinical route, is used in all toxicological studies.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted as standard battery; integration site analysis (LAM-PCR) in mouse and NHP liver showed low random integration
“For both species, the majority of the identified vector DNA sequences represented episomal forms that were not integrated into the host DNA.”
Carcinogenicity
Not conducted (not warranted based on nonclinical safety profile)
“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”
Reproductive & developmental
Paternal germline transmission/fertility study in male mice only; no transmission, no fertility effects; EFD/PPND not required
“However, there were no adverse effects on mating rates or fertility indices.”
Safety pharmacology
Incorporated into NHP toxicity studies (ECG); no test article effects
“With regard to ECG readings no effects related to the test article were observed with AMT-060.”
First doseopen answer page →
First-in-human starting dose
Not stated for FIH; later clinical dosing informed by predecessor AMT-060 clinical data
“The supporting clinical data from the predecessor product that used a similar vector (AAV5) as HEMGENIX was used to inform dosing for later clinical studies, and assessments of vector viral kinetics.”
NOAEL / key findings
NOAEL 9x10^13 gc/kg NHP (4.5x clinical), 5x10^13 mice; transient ALT/AST rise, clotting changes, mouse pulmonary thrombi
“The identified no-observed-adverse-effect-level was 9x1013 gc/kg.”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV5 capsid IgG persisting 6 months; anti-hFIX antibodies in 5/12 NHPs reducing FIX levels
“Antigenicity endpoints were included in single dose toxicity studies, capsid antigens generally caused high titres of anti AAV5 antibodies. In addition, anti-human FIX antibodies were observed inconsistently in NHP.”
Biodistribution & persistence
Liver highest, then adrenal, spinal cord; vector in testis/epididymis/semen at 26 wks; saliva/urine clear by ~week 8-12
“Vector DNA was also identified in the adrenal glands and spinal cord, followed by limited vector presence in various tissue types.”
Modality-specific risk
AAV integration/insertional oncogenesis (dose-dependent), germline transmission, thrombosis from high FIX activity, DRG toxicity
“Dose is considered a pivotal factor with regards to the frequency of integration and with that a main contributor to the risk of insertional oncogenesis.”