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Publication Type
Journal Article
Author, Analytic
Kutlar, A.; Reid, M.; Inati, A.; Taher, A.; Abboud, M. R.; El-Beshlawy, A.; Buchanan, G. R.; Smith, H.; Ataga, K.; Perrine, S.; Ghalie, R.
Author Affiliation, Ana.
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Article Title
A dose escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease
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Connective Phrase
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Journal Title
American Journal of Hematology
Translated Title
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Reprint Status
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Date of Publication
2013
Volume ID
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Issue ID
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Page(s)
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Language
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Location/URL
http:; onlinelibrary.wiley.com/doi/10.1002/ajh.23533/full
ISSN
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Notes
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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/?(0) 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 (48%) 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 (80%), and 12 (23%) had increases ?4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases ?1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease.....
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