Abstract:
2,2-dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S-β0 thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg-kg (n = 15), 40 mg-kg (n = 18) and 50 mg-kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg-kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg-kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48percent) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg-kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80percent), and 12 (23percent) had increases ≥4percent. The mean increase in Hb F was 2percent [95percent confidence interval (CI), 0.8-3.2percent] in 21 subjects receiving HQK-1001 alone and 2.7percent (95percent CI, 1.7-3.8percent) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g-dL (95percent CI, 0.5-1.0 g-dL), and 13 subjects (25percent) had increases ≥1 g-dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. Am. J. Heamtol. 88:E255-E260, 2013. © 2013 Wiley Periodicals, Inc.