Kebilidi
eladocagene exuparvovec
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Rat (pivotal GLP); cynomolgus monkey for biodistribution/excipient studies
“The nonclinical safety program conducted to characterize the toxicity and biodistribution of eladocagene exuparvovec comprised of two studies, a 30-day study, and a 6 month study, both in rats.”
Why that species
Not stated in public reviews
Surrogate molecule
No surrogate; clinical vector in rat; NHP used rAAV2-hAADC and rAAV2-eGFP reporter vector
“The recombinant adeno-associated virus, serotype 2 (rAAV2) vector was identical to that used for eladocagene exuparvovec and this study also evaluated limited toxicological parameters.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“There were no significant adverse findings noted in a 6-month toxicology study in rats administered dose levels ranging from 7.5x108 – 7.5x109 vg/animal.”
Pivotal GLP studies
Rat single-dose intraputaminal 30-day and 6-month GLP tox/BD; NHP 30-day poloxamer study; NHP 4-week route BD study
“Two single-dose studies were conducted to assess toxicity at 30-days and 6 months.”
Route in tox
Bilateral intraputaminal infusion (also substantia nigra in rat; ICV/IT in NHP BD study)
“In the 6-month study a single eladocagene exuparvovec administration via bilateral IPI at doses up to 7.5×109 vg was generally well tolerated with no obvious signs of toxicity.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
Carcinogenicity
Not conducted (product characteristics and patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”
Reproductive & developmental
Not conducted (local brain delivery, no systemic exposure or gonadal distribution)
“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
Safety pharmacology
CNS (FOB) endpoints incorporated into 6-month GLP rat tox study; no stand-alone studies
“Stand-alone safety pharmacology studies were not conducted with eladocagene exuparvovec. An evaluation of CNS effects was included in the 6-month GLP toxicology study.”
First doseopen answer page →
First-in-human starting dose
Prior adult PD rAAV2-hAADC clinical doses (up to 3x10^11 vg) scaled by brain mass; 1.8x10^11 vg (~60%)
“The applicant justified this dose on the basis that clinical studies in adult PD using rAAV2-hAADC reported that doses up to 3x 1011 vg of rAAV2-hAADC in a volume of 4×50 μl were well tolerated following bilateral, intraputaminal infusions during a single operative session.”
NOAEL / key findings
Rat NOAEL 7.5x10^9 vg (highest dose; ~21x margin by brain weight); no significant adverse findings
“Since there were no toxicologically significant findings at the high dose, the no observed adverse effect level (NOAEL) was set at the high dose (7.5x109 vg).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent anti-AAV2 capsid ADA in rats; no effect on biodistribution or expression; anti-AADC not assessed
“The formation of anti-drug antibodies against the AAV2 vector capsid was dose dependent with the highest incidence observed in Group 4 high-dose animals at Days 30 and 180.”
Biodistribution & persistence
Mostly CNS, highest in putamen; vector persists to D180 with decline; no blood/CSF shedding in rat
“Persistence of vector DNA was most notable in the putamen, cerebrum, cerebellum, and spinal cord at all time points, with the highest levels in the putamen.”
Modality-specific risk
Off-target spread/ectopic dopamine-serotonin expression, poloxamer 188 brain safety, insertional mutagenesis
“That being said, one cannot dismiss the possibility that the transgene will spread to adjacent brain regions (e.g. globus pallidus, caudate, amygdala) at least in some individuals.”