Skysona: what flexibility did regulators accept, and why?

“The safety data from immune-deficient mice are considered less relevant in predicting the human situation. When it comes to cell therapies, it is well established that animal models are poor predictors of safety in humans.”

“Although the value of using immune-incompetent mice to predict safety issues for a human cell therapy is questionable, the strains have been used as a model for HSC engraftment and their use can from that point be justified.”

“Traditional carcinogenicity studies were not conducted for eli-cel. However, integration site analysis (ISA) was performed on Lenti-D transduced pre-transplant human CD34+ HSCs and post-transplant engrafted bone marrow cells (BMCs) from animals in the GLP toxicology study harvested at 29 and 92 days.”

“However, these shortcomings are not considered enough for demanding additional analysis and could be considered covered by the clinical monitoring, were subjects in the clinical studies are monitored by ISA every 6 months up to 5 years after treatment and patients are to be monitored annually for leukemia/lymphoma for 15 years post treatment.”

“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”

“Reproductive and developmental toxicity studies were not performed for eli-cel which is acceptable based on the product characteristics and safety profile.”

“Given that the cells are transduced ex vivo with a replication-incompetent vector and no residual free viral particles are present in the Lenti-D Drug Product, the risk for germ line transmission is considered regarded very limited and rather theoretical.”

“Also, patients will be preconditioned with the reprotoxic busulfan, often resulting in infertility. The omission of specific germ line transmission studies is therefore acceptable.”