Strimvelis

“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.”

“The observation time to determine survival, engraftment and clinical signs in this combined biodistribution/toxicology study was 16 weeks.”

“In this study, NSG mice (n=10/sex/group) were pre-conditioned with busulfan [40 mg/kg total dose over 2 days; intraperitoneal (IP)] prior to dosing transduced cells”

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

“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”

“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.”

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

“As per the applicant’s statement, no safety pharmacology studies were considered feasible in animals or relevant to the administration of GSK2696273 to humans.”

“The first ADA/SCID clinical protocol for Study Number AD1117054 was based on the optimised transduction conditions from the nonclinical studies described above.”

“In this study, mice were administered 10 x106 CD34+ cells/kg (approximately the midpoint of the dose range to be infused in human subjects) without test-item-related adverse effects.”

“Biodistribution analysis did not show any evidence of transduction of non-target cells: vector DNA was only detected in the presence of donor cells.”

“From a non-clinical perspective, the carcinogenic potential due to insertional mutagenesis and the potential for subsequent clonal expansion cannot be determined at the time of assessment.”