Kebilidi: what was done before first-in-human, and what came after?

“rAAV2-hAADC was subsequently tested in the first-in-human clinical trials of patients with Parkinson’s disease at dose levels of 9×1010 and 3×1011 vg via bilateral intra-putaminal dosing (Christine 2009, Muramatsu 2010).”

“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.”

“Eladocagene exuparvovec is a single dose gene therapy with persistent gene expression through 6 months in rodents (Leidos 8366537, AADC-003) which provides chronic exposure and, therefore, no repeat-dose studies were conducted.”

“Two single-dose studies were conducted to assess toxicity at 30-days and 6 months.”

“No specific developmental and reproductive toxicology studies were conducted by the applicant with eladocagene exuparvovec, in agreement with CHMP.”

“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.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”

“No nonclinical studies were conducted to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of eladocagene exuparvovec-tneq as such studies were not warranted based on the product characteristics and target patient population.”

“The applicant has provided a discussion on the risk of insertional mutagenesis and carcinogenic potential. Based on the weight of evidence discussed there appears to be a low risk for genomic integration or tumorigenicity in post­mitotic neuronal cells.”

“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”