Session: 113. Hemoglobinopathies, Excluding Thalassemia—Basic and Translational Science: Poster III
Hematology Disease Topics & Pathways:
sickle cell disease, Diseases, Non-Biological, Therapies, Hemoglobinopathies, pharmacology
Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to approximately 30% HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF.
Preclinical studies using a variety of in vitro assays have demonstrated the potential of FTX-6058 as a clinical development candidate for potential treatment of hemoglobinopathies, such as SCD and ꞵ-thalassemia, via upregulation of HbF. IND enabling studies for FTX-6058 have been completed.
Keywords: hemoglobin, fetal hemoglobin, HbF, HBG1/2, sickle cell disease, gene regulation
Disclosures: Stuart: Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah: Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Efremov: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Thompson: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham: Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company.