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

“GSK2696273 was first administered to humans in 2000 in a pilot clinical study with one subject with confirmed ADA-SCID who had no HLA-identical sibling or prior ERT therapy received treatment and follow-up at Hadassah University (Jerusalem, Israel), with the cooperation of HSRTIGET.”

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

“Due to the nature of Strimvelis, repeat dose toxicity studies were not conducted since GSK2696273 consists of patient-derived cells that are intended to consist of the ADA gene, to allow for expression of the related ubiquitous protein at or below physiological levels.”

“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”

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

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

“No reproductive or developmental toxicity studies were conducted with GSK2696273. Patients will receive a low dose of busulfan as pre-conditioning treatment.”

“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.”

“Conducted pilot studies indicate that a tumourgenicity study is not feasible since it was not possible to demonstrate long-term engraftment of transduced cells in mice.”

“In summary, in previous scientific advice, it was agreed that the tumourgenicity risk assessment for GSK2696273 could be based on clinical data and literature on similar vectors if tumourgenicity/general toxicity studies were unsuccessful in allowing for the determination of optimal conditions for a full tumourgenicity study.”