A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in beta-thalassaemia intermedia and HbE/beta-thalassaemia

作者：Fucharoen Suthat; Inati Adlette; Siritanaratku Noppadol; Thein Swee L; Wargin William C; Koussa Suzanne; Taher Ali; Chaneim Nattawara; Boosalis Michael; Berenson Ronald; Perrine Susan P^*

来源：British Journal of Haematology, 2013, 161(4): 587-593.

DOI：10.1111/bjh.12304

• beta thalassaemia intermedia
• fetal haemoglobin
• clinical trial
• pharmacokinetics

-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 -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/0 thalassaemia and seven with +/0 thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK-1001 or placebo were administered once daily for 8weeks at four dose levels (10, 20, 30, or 40mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t1/2 of 1012h. Adverse events with HQK-1001 treatment were not significantly different from placebo treatment. The 20mg/kg treatment doses increased median HbF above baseline levels by 6 center dot 6% and 4 center dot 4g/l (P%26lt;0 center dot 01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11g/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.

• 出版日期2013-5