Strimvelis: which tox species, and why?

“The use of NSG mouse strain (deficient in mature T/B/NK cells) for the non-clinical biodistribution/single-dose toxicology study after engraftment of CD34+ cells derived from healthy human UCB, transduced with GSK3336223 vector, was endorsed by the CAT/CHMP prior to MAA submission.”

“Subsequently, the results of two bio-distribution studies were submitted using the NSG mouse based on the reports presented that indicate this is a valid model for immunodeficient mice, which can be used as recipient of HSPC transplantation, with longer survival rates and reduced frequency of spontaneous tumours as compared to ADA-/- mice.”

“The test item used in the biodistribution studies (referred to as GSK3235757A) comprised of CD34+ cells derived from healthy human UCB transduced with GSK3336223 vector and is accepted as representative of Strimvelis.”

“Toxicology was evaluated in a single dose (IV) mouse (NSG) biodistribution/toxicology studies.”

“No reproductive or developmental toxicity studies were conducted with GSK2696273.”

“Accordingly, the SmPC states that carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.”

“GSK3235757A stands for Healthy human UCB transduced with GSK3336223 vector; GSK2959346 stands for Murine lin- BM cells transduced with GSK3336223 vector.”