Quantitative Systems Pharmacology Model of Sickle Cell Disease and Response to Gene Editing Therapy to Support Clinical Development of SAR445136 (BIVV003)

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene that produces abnormal hemoglobin (HbS), leading to clinical manifestations such as painful vaso-occlusive crises, anemia, and shortened lifespan due to organ damage. SAR445136 (BIVV003) is a zinc finger nuclease ex vivo gene editing therapy in Ph1/2 clinical development for treatment of SCD (PRECIZN-1; NCT03653247). SAR445136 targets the erythroid specific enhancer (ESE) region of the transcription factor BCL11A, which controls the switch from fetal hemoglobin (HbF) to adult forms (HbA in healthy subjects and HbS in SCD subjects). By expressing increased levels of HbF, SAR445136-edited cell progeny exhibit reduced HbS polymerization which is expected to ameliorate RBC sickling and the SCD phenotype.