title: 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.affiliation: Adult Sickle Cell Center, Georgia Regents University Medical Center, Augusta, GA, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Reid
authors.forename: Adlette
authors.initials: A
authors.lastname: Inati
authors.forename: Ali T
authors.initials: AT
authors.lastname: Taher
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Abboud
authors.forename: Amal
authors.initials: A
authors.lastname: El-Beshlawy
authors.forename: George R
authors.initials: GR
authors.lastname: Buchanan
authors.forename: Hedy
authors.initials: H
authors.lastname: Smith
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Ataga
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
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* / Q000378:metabolism; D000986:Antisickling Agents / Q000627:therapeutic use; D002087:Butyrates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D005756:Gastritis / Q000139:chemically induced / Q000453:epidemiology; D006397:Hematinics / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010352:Patient Dropouts; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012805:Sickle Cell Trait / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D055815:Young Adult; D017086:beta-Thalassemia / Q000150:complications
chemical_list: D000986:Antisickling Agents; D002087:Butyrates; D006397:Hematinics; D005319:Fetal Hemoglobin; C074677:2,2-dimethylbutyric acid; D006918:Hydroxyurea