A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

Abstract

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β(0) thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: -0.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation.

• Authors: Marvin E Reid, Amal El Beshlawy, Adlette Inati, Abdullah Kutlar, Miguel R Abboud, Johnson Haynes Jr, Richard Ward, Bruce Sharon, Ali T Taher, Wally Smith, Deepa Manwani, Richard G Ghalie
• Journal: American journal of hematology (Am J Hematol) Vol. 89 Issue 7 Pg. 709-13 (Jul 2014) ISSN: 1096-8652 [Electronic] United States
• PMID: 24677033 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antisickling Agents
• Butyrates
• Placebos
• Fetal Hemoglobin
• 2,2-dimethylbutyric acid

Topics

• Administration, Oral
• Adolescent
• Adult
• Anemia, Sickle Cell (blood, drug therapy)
• Antisickling Agents (therapeutic use)
• Butyrates (adverse effects, therapeutic use)
• Child
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Fetal Hemoglobin (biosynthesis)
• Humans
• Male
• Middle Aged
• Placebos
• Young Adult