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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“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.”

“No immunogenicity testing has been conducted. The applicant stated that GSK2696273 is comprised predominately of autologous-derived cells with intracellular ADA, in which an immunogenic response of any sort would be unlikely.”

“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.”

“The doses administered provide only safety margin of approximately half the highest dose administered in humans (20 x106 CD34+ cells/kg).”

“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.”

“In vivo: Immunodeficient mice were implanted with human hematolymphoid tissues (SCID-hu mice), irradiated and transplanted with a single dose of cultured/transduced CD34+ cells. The transduced CD34+ cells engrafted in mice, produced vector-marked and transgene expressing T and B cells and maintained in vivo lymphoid reconstitution capacity.”

“Because ethical restrictions of harvesting of human bone marrow for experimental purposes limit in vivo studies of the human hematolymphoid system, substitute human to small animal xenotransplantation models has been employed.”

“Pharmacology studies indicated that the gene is expressed at the relevant site(s) at an appropriate level and that functional activity is realised.”

“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.”

“GSK2696273 consists of an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase complementary DNA sequence. It is intended to be administered on a single occasion since after infusion CD34+ cells migrate to the bone marrow where they engraft”