A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

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/β(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.

• Authors: Abdullah Kutlar, Marvin E Reid, Adlette Inati, Ali T Taher, Miguel R Abboud, Amal El-Beshlawy, George R Buchanan, Hedy Smith, Kenneth I Ataga, Susan P Perrine, Richard G Ghalie
• Journal: American journal of hematology (Am J Hematol) Vol. 88 Issue 11 Pg. E255-60 (Nov 2013) ISSN: 1096-8652 [Electronic] United States
• PMID: 23828223 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Antisickling Agents
• Butyrates
• Hematinics
• Fetal Hemoglobin
• 2,2-dimethylbutyric acid
• Hydroxyurea

Topics

• Administration, Oral
• Adolescent
• Adult
• Anemia, Sickle Cell (blood, drug therapy, metabolism)
• Antisickling Agents (therapeutic use)
• Butyrates (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Child
• Cohort Studies
• Dose-Response Relationship, Drug
• Female
• Fetal Hemoglobin (analysis, biosynthesis, genetics)
• Gastritis (chemically induced, epidemiology)
• Hematinics (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Heterozygote
• Humans
• Hydroxyurea (therapeutic use)
• Incidence
• Male
• Middle Aged
• Patient Dropouts
• Promoter Regions, Genetic (drug effects)
• Sickle Cell Trait (blood, complications, drug therapy, metabolism)
• Up-Regulation (drug effects)
• Young Adult
• beta-Thalassemia (complications)