title: A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in β-thalassaemia intermedia and HbE/β-thalassaemia.
abstract: β-thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK-1001), an orally bioavailable short-chain fatty acid derivative, induces γ-globin expression experimentally and is well-tolerated in normal subjects. Accordingly, a randomized, blinded, placebo-controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β(0) thalassaemia and seven with β(+)/β(0) thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK-1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t(1/2) of 10-12 h. Adverse events with HQK-1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK-1001 with longer dosing to definitively evaluate its haematological potential appears warranted.
authors.affiliation: Thalassemia Research Centre, Mahidol University, Nakhonpathon, Thailand.
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Adlette
authors.initials: A
authors.lastname: Inati
authors.forename: Noppadol
authors.initials: N
authors.lastname: Siritanaratku
authors.forename: Swee L
authors.initials: SL
authors.lastname: Thein
authors.forename: William C
authors.initials: WC
authors.lastname: Wargin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Koussa
authors.forename: Ali
authors.initials: A
authors.lastname: Taher
authors.forename: Nattawara
authors.initials: N
authors.lastname: Chaneim
authors.forename: Michael
authors.initials: M
authors.lastname: Boosalis
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; D002087:Butyrates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013156:Splenectomy; D016896:Treatment Outcome; D055815:Young Adult; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery
chemical_list: D002087:Butyrates; D005319:Fetal Hemoglobin; C074677:2,2-dimethylbutyric acid