Session: 113. Hemoglobinopathies, Excluding Thalassemia—New Genetic Approaches to Sickle Cell Disease: Poster I
Hematology Disease Topics & Pathways:
Anemias, sickle cell disease, HSCs, Diseases, sickle cell trait, Non-Biological, Animal models, thalassemia, Therapies, red blood cells, Hemoglobinopathies, Biological Processes, Technology and Procedures, Cell Lineage, Study Population, pharmacology, flow cytometry, mass cytometry
The in vivo target engagement (TE) and pharmacologic effects of FTX-6058 were characterized in wild-type CD-1 mice and humanized Townes SCD mice, with TE also confirmed in non-human primates. In CD-1 mice, once-daily (QD) FTX-6058 oral administration induced TE in a time- and dose-dependent manner and most markedly in erythroid lineage (Ter119+) cells derived from bone marrow, the putative therapeutic compartment, and increased transcript levels of Hbb-bh1, a murine embryonic hemoglobin surrogate for human HBG gene. Steady state TE in circulating monocytes, following repeated QD FTX-6058 administration, correlated well with that in bone marrow-derived erythroid cells, suggesting peripheral monocytes as a suitable surrogate for assessing erythroid TE activity in Fulcrum’s Phase 1 study. In non-human primate cynomolgus monkeys, QD oral dosing of FTX-6058 as early as for 7 days induced robust and comparable TE in bone marrow derived CD34+ erythroid progenitors and circulating monocytes, further supporting the use of monocytes to assess TE in bone marrow. Mouse data also provided evidence of the reversibility of TE effects once dosing is stopped.
In repeat-dose studies in the humanized Townes SCD mouse model, FTX-6058 was superior to standard of care hydroxyurea as measured by human HBG1 transgene induction and increased %F-cells and HBG1 protein levels. Furthermore, the induction of %F cells was sustainable for several days after dosing cessation.
These in vivo studies have demonstrated that FTX-6058 engages its novel biological target in multiple preclinical models and induces HbF expression at plasma concentrations likely to b e readily achievable in clinic, and peripheral monocytes is a suitable surrogate for assessing TE in bone marrow erythroid cells, which could be beneficial to patients with SCD.
Disclosures: Xie: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Roth: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Efremov: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Silver: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Thompson: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stickland: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.