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Article Abstract
This report details the discovery path of GBT021601 (osivelotor) (), a novel, small molecule, sickle hemoglobin (HbS) polymerization inhibitor. Following a streamlined testing funnel with cassette dosing in rat pharmacokinetic (PK) studies, we identified this next-generation HbS polymerization inhibitor, which had improved PK properties compared with the first-in-class drug, voxelotor (). GBT021601 has ∼4.8-fold greater exposure and a ∼3.5-fold longer half-life in rats compared with voxelotor. In a murine model of sickle cell disease (SCD), GBT021601 treatment resulted in an increase in hemoglobin oxygen affinity, a reduction in sickling of red blood cells (RBCs), and an increase in both RBC half-life and hemoglobin levels not seen with voxelotor preclinically. The improved half-life and exposure appear to translate to similar levels of HbS occupancy at lower doses than voxelotor, thus reducing treatment burden. GBT021601 is being investigated in a phase 2/3 clinical trial for the treatment of patients with SCD (NCT05431088).
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358975 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5c00076 | DOI Listing |
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