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

• Published in: British journal of haematology Vol. 161; no. 4; pp. 587 - 593
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.05.2013
• Subjects: Administration, Oral; Adolescent; Adult; Anemias. Hemoglobinopathies; beta thalassaemia intermedia; beta-Thalassemia - drug therapy; beta-Thalassemia - genetics; beta-Thalassemia - surgery; Biological and medical sciences; Butyrates - administration & dosage; Butyrates - adverse effects; Butyrates - pharmacology; Butyrates - therapeutic use; clinical trial; Diseases of red blood cells; Female; fetal haemoglobin; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Male; Medical sciences; Middle Aged; pharmacokinetics; Splenectomy; Treatment Outcome; Tumors; Young Adult; Hemoglobinopathy; Hematology; Hemopathy; fetal haemoglobin; Genetic disease; β-Thalassemia intermedia; Globin; Randomization; Hemolytic anemia; Cancerology; Gene; beta thalassaemia intermedia; Phase II trial; Phase I trial; Hemoglobin; Clinical trial; Fetus; Genetics; Pharmacokinetics
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.12304

Summary 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/β0 thalassaemia and seven with β+/β0 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 t1/2 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.