Beqvez
fidanacogene elaparvovec
Species
MonkeyMouseDogRabbit
Longest study
104 wk
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
Cynomolgus monkey and mouse (tox); hemophilia B dog and mouse (pharmacology); rabbit (shedding)
“A toxicology study was also conducted evaluating IV administration of AAVRh74var Padua in nonhuman primates (NHP) at dose levels ranging from 1 x 1012 vg/kg to 5 x 1012 vg/kg.”
Why that species
Not stated in public reviews
Surrogate molecule
Yes: canine FIX surrogate vector for dog pharmacology; tox used closely related predecessor vector
“In vivo pharmacology was evaluated using a surrogate BEQVEZ product, AAVRh74var-cFIX-R338L, which expresses a transgene encoding canine factor IX, in a juvenile hemophilia B dog model.”
Study lengthopen answer page →
Longest pivotal study
104 weeks
“Single-Dose Intravenous Study of PF 06838435 in Monkeys with a 13- or 104-Week Observation Phase”
Pivotal GLP studies
GLP single IV NHP study (30/90-day recovery, to day 542); 12-month mouse study; GLP 2-year NHP integration study
“A GLP Toxicity Study of -hFIX-Padua by Intravenous Infusion in Monkeys with a 30- or 90- day Recovery Period”
Route in tox
Single intravenous infusion / slow bolus
“Route of Administration IV infusion (30 minute) via saphenous vein”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (classical); vector integration site analysis in dog and NHP liver instead
“Based on the IS profile, genotoxicity from vector integration appears to be a low risk.”
Carcinogenicity
Not conducted (not warranted given product characteristics, BD/tox data, population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted.”
Reproductive & developmental
Not conducted (male-only population); rabbit semen shedding/germline study only
“This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
Safety pharmacology
Not conducted
“No safety pharmacology studies with BEQVEZ were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings
“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology.”
Risksopen answer page →
Immune & cytokine safety
Anti-hFIX and anti-capsid antibodies in most NHPs, rising over time, correlated with declining hFIX
“The levels of both anti-hFIX and anti-AAV antibodies increased with time, which correlated with a decline in plasma hFIX protein levels.”
Biodistribution & persistence
Vector in all NHP tissues incl. brain/testes; highest liver, spleen, lymph nodes; liver to day 542; rabbit semen to 4 months
“The highest vector DNA concentrations were detected in the liver, spleen, and inguinal lymph nodes.”
Modality-specific risk
AAV vector integration/hepatic oncogenicity; <0.1% integrated, no clonal expansion; thrombosis; germline transmission
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”