The Benefits Trial of PB-04 to Evaluate Safety, PK, and Preliminary Efficacy in Inducing Fetal Globin Expression in Beta Thalassemia Intermedia and Sickle Cell Disease

Increased expression of fetal globin (HBG) has been shown to reduce clinical severity of beta-globin disorders and increase survival in sickle cell disease (SCD), through improved globin chain balance in beta thalassemia and reduced HbS polymerization. Pharmacologic approaches are considered most feasible for a majority of patients. Both proportions of F-cells and quantity of hemoglobin F (HbF)/cell are important for therapeutic effects. PB-04 was identified in a high-throughput screen of US and EU-approved drugs to activate HBG gene transcription, without cytotoxicity, to induce fetal globin expression (gamma globin mRNA, F-cells, HbF/cell, HbF), and to suppress or displace 4 repressors of the fetal globin gene promoter (BCL11A, LSD-1, KLF-1, and HDAC-3) in hemoglobinopathy patients' erythroid progenitors. PB-04 enhanced HbF in progenitors from hydroxyurea (HU)-treated patients with sickle cell disease. In in vivo studies, PB-04 induced fetal globin expression >20-fold with oral dosing in anemic baboons, and by 3.5-fold in mice transgenic for 2 copies of the human β-globin gene locus. This agent has been approved and in broad use for Parkinson's Disease treatment for 5 decades in Europe and Canada, to enhance the PK of an active Parkinson's agent, solely in a combination formulation. Because of its safety with chronic dosing up to 1300 mg/day, PB-04 is therefore of interest for repurposing in the treatment of thalassemia and SCD.