Module 9 2024

03/09/2024

Kymriah: Non-clinical Summary

• Lack of non-clinical pharmacology studies was considered acceptable due to the clinical experience with the indication • As the product is patient specific it was deemed inappropriate to administer to immune competent animals

• No adequate animal models to assess the risk of genotoxicity

• In vitro expansion studies with CAR positive T cells from healthy volunteers and patients showed no evidence for transformation and/or immortalisation of T cells • In vivo studies in immunocompromised mice did not show signs of abnormal cell growth of signs of clonal cell expansion for up to 7 months

• Overall non-clinical package deemed adequate

The Organisation for Professionals in Regulatory Affairs

Kymriah European Assessment Report 28 th June 2018

25

Kymriah: Clinical Results

• Four Phase 2, open-label studies investigating the safety and efficacy were conducted • Dose was determined based upon dose-response relationship: • Previous clinical experience: • Efficacy endpoints: response at 3 months, duration of response, time to response, progression free survival, event free survival • Previous safety concerns: • Occurrence of cytokine release syndrome (CRS); any grade and grade 3/4 • Neurological events • Time to resolution of hematopoietic cytopenia

• Starting dose determined as 0.6 to 6.0 x 10 8 CAR-positive viable T cells

• Final dose in SmPC: 1.2 x 10 6 to 6 x 10 8 cells

The Organisation for Professionals in Regulatory Affairs

Kymriah European Assessment Report 28 th June 2018

26

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