Module 9 2024

03/09/2024

Addressing the Risks and a Holistic Approach

Activated CD4+ T cells associated with higher grade (grade 3/4) CRS

Build the most robust data collection platform possible

Bachanova et al., 2019. Blood (2019) 134 (Supplement_1): 242

Collect all the manufacturing and analytical data

Collect all preclinical data

Rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS

Collect patient-related data

Assess whether the analytical methods are good/specific/accurate/robust enough Have retrospective looks at the entirety of the data across functions at regular intervals

Den Q et al. Nature Med (2020) 26:1878

The Organisation for Professionals in Regulatory Affairs Holistic data quality and patient data integration to generate knowledge

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RBA and Benefit / Risk Assessment Integrating γ -retroviral vector may cause leukomogenesis via insertional mutagenesis

● X-SCID GT treated babies developed leukemia in early 2000

● A more recent case of leukemia observed in ADA patient treated with Strimvelis

● Better understand of vector biology, improved vector design and integration mapping

● New tools for site specific recombination and genome editing

5 deaths occurred in the Juno Rocket trial of cerebral edema in 2016 (last reported Nov. ASH meeting) did not stop CAR-T development

Long term severe adverse event might be expected with stem gene therapy

A new paradigm is emerging: the hazard is part of the MoA and of the potential benefit

The Organisation for Professionals in Regulatory Affairs

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