Session: 802. Chemical Biology and Experimental Therapeutics: Poster I
Hematology Disease Topics & Pathways:
sickle cell disease, Diseases, Non-Biological, thalassemia, Therapies, Hemoglobinopathies, Clinically relevant, 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 with desirable DMPK properties suitable for clinical testing. 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 30% absolute 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. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model.
Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed.
Disclosures: Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart: Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie: Fulcrum Therapeutics: Current Employment. Roth: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes: 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. Peters: Fulcrum Therapeutics: Current Employment. Li: Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski: Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno: Fulcrum Therapeutics: Current Employment. Stickland: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid: Fulcrum Therapeutics: 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 Therepeutics: Current Employment, Current equity holder in publicly-traded company.
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