Kymriah

“The absence of GLP compliance is acceptable since standard single or repeat-dose toxicity studies could not be performed due to lack of a relevant animal model.”

“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”

“The exact clinical construct was used in the studies and the vectors were research grade.”

“An in vivo study was conducted to evaluate toxicity and BD in tumor-bearing mice receiving i.v. injection of CTL019 at 1, 5, and 20x106 cells/mouse and observed up to Day 217 post-injection (p.i.) with three terminal sacrifices.”

“The nonclinical toxicology studies were not conducted in compliance with Good Laboratory Practice (GLP), because there was no independent Quality Assurance (QA) audit of integral study parts and raw data storage was not applied in compliance with GLP regulations.”

“Route of Administration Intravenous route of administration”

“Genotoxicity Studies: Classical genotoxicity studies were not conducted. The provided LV integration site analysis may be relevant for evaluation of potential genotoxicity.”

“Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically modified cell therapy products.”

“No preclinical reproductive studies were conducted with CTL019 to assess whether it can cause fetal harm when administered to a pregnant woman.”

“No safety pharmacology studies have been conducted (see non-clinical discussion).”

“There was no histologic evidence of systemic toxicity associated with CTL019 versus mock T cells. No abnormal cell growth was detected by clinical pathology or by PCR at any time point in any animal.”

“Protein array assessment for binding of murine and humanized CD19-CAR scFV to human membrane proteins showed that CD19 was identified by both biotinylated scFv fragments of human and murine, while no other human membrane protein binders were detected on the array.”

“On day 56 post-injection, CART-19 cell signals were detected in these same tissues plus the liver, heart, blood and bone marrow in Groups 1 through 3 with more frequency in Group 1 as compared to Groups 2 and 3.”

“Insertion of lentiviral vector sequences throughout the genome has the potential to dysregulate local host cell gene expression with a theoretical risk of insertional oncogenesis resulting from disruption of normal function of genes that control cell growth and potential risk of development of secondary malignancies.”