Voxelotor (GBT440, GTx011) is a novel small moleculehemoglobin modifierwhich increases hemoglobin oxygen affinity.
In vitro
GBT440 is a new potent allosteric effector of sickle cell hemoglobin that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. GBT440 inhibits these isozymes(CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4) with IC50 ranging from 7.9 to 148 μM. It is not a substrate for either P-gp or BCRP transporters It binds to the N-terminal a chain of Hb
In vivo
GBT440 has favorable oral bioavailability of 60, 37, and 36% in rats, dogs, and monkeys, respectively, with similar blood and plasma half-lives of approximately 20 h each. T1/2 value of GBT440 in all animal species is significantly shorter than the T1/2 of red blood cells (∼20 days), which supports that binding of GBT440 to hemoglobin is a reversible process. GBT440 is currently in Phase 3 clinical trials (NCT03036813) in SCD patients GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. In a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. GBT440 shows dose proportional PK, a terminal half-life of 1.5-3 d.
1.Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC et al.. (2019) A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.. N Engl J Med, 381 (6):(509-519). [PMID:31199090]
2.Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y et al.. (2017) Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.. ACS Med Chem Lett, 8 (3):(321-326). [PMID:28337324]
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