title: 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.affiliation: Sickle Cell Unit, University of West Indies, Mona, Jamaica.
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Reid
authors.forename: Amal
authors.initials: A
authors.lastname: El Beshlawy
authors.forename: Adlette
authors.initials: A
authors.lastname: Inati
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Abboud
authors.forename: Johnson
authors.initials: J
authors.lastname: Haynes
authors.forename: Richard
authors.initials: R
authors.lastname: Ward
authors.forename: Bruce
authors.initials: B
authors.lastname: Sharon
authors.forename: Ali T
authors.initials: AT
authors.lastname: Taher
authors.forename: Wally
authors.initials: W
authors.lastname: Smith
authors.forename: Deepa
authors.initials: D
authors.lastname: Manwani
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ghalie
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy*; D000986:Antisickling Agents / Q000627:therapeutic use*; D002087:Butyrates / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D055815:Young Adult
chemical_list: D000986:Antisickling Agents; D002087:Butyrates; D010919:Placebos; D005319:Fetal Hemoglobin; C074677:2,2-dimethylbutyric acid