title: A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease.
abstract: Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α(2) γ(2) ) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.
authors.affiliation: Department of Medicine, Sickle Cell Center, Medical College of Georgia, Augusta, GA, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ataga
authors.forename: Marvin
authors.initials: M
authors.lastname: Reid
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Vichinsky
authors.forename: Lynne
authors.initials: L
authors.lastname: Neumayr
authors.forename: Loray
authors.initials: L
authors.lastname: Blair-Britt
authors.forename: Richard
authors.initials: R
authors.lastname: Labotka
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Keefer
authors.forename: William A
authors.initials: WA
authors.lastname: Wargin
authors.forename: Ronald
authors.initials: R
authors.lastname: Berenson
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy*; D001682:Biological Availability; D002087:Butyrates / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis / Q000096:biosynthesis*; D006397:Hematinics / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D002087:Butyrates; D006397:Hematinics; D005319:Fetal Hemoglobin; C074677:2,2-dimethylbutyric acid