Treatment of β-thalassemia is still largely dependent on supportive care, including blood transfusions and iron chelation. No oral drugs have been shown to consistently improve the severe anemia in thalassemia. Hematopoietic stem cell transplantation is potentially curative, but only a fraction of patients are eligible. Reactivation of fetal globin gene expression and increased γ-globin chain production is an attractive therapeutic approach, because it can compensate for defective β-globin chain production and the consequent α/β-chain imbalance that is a hallmark of β-thalassaemia.

HQK-1001 (2,2-dimethylbutyrate, sodium salt), a new butyrate derivative with moderate potency but greater bioavailability, no cytotoxicity, and no HDAC-inhibitory activity compared to earlier butyrates, was shown to stimulate γ-globin production and erythropoiesis in animal models and in vitro. HQK-1001 reactivates γ-globin gene expression by inducing targeted dissociation of the inhibitory complex HDAC3 and its adaptor protein NCoR from the γ-globin gene promoter. HQK-1001 also enhances erythropoiesis by prolonging phosphorylation and activation of STAT-5, and enhancing Bcl-xL expression. In a multicenter dose-escalation study, HQK-1001 administered orally at 10, 20, 30 and 40 mg/kg once daily for 8 weeks in 21 subjects with non-transfusion-dependent β-thalassemia (NTDT) was well-tolerated and increased fetal hemoglobin (Hb F) in most subjects, with best results observed at 20 mg/kg. This single-center study (NCT01642758) evaluated HQK-1001 administered at 20 mg/kg/day for a longer duration than previously studied.

Patients 18-50 years old with NTDT of Mediterranean phenotypes were eligible if their hemoglobin (Hb) was between 6.0 and 9.0 g/dL within the prior 30 days and had no transfusions within the prior 3 months. HQK-1001 was administered at 20 mg/kg once daily for 24 weeks. Folic acid was administered daily and oral iron supplementation was prescribed if serum ferritin was <700 ng/mL and stopped if ferritin exceeded 1000 ng/mL. Clinical and laboratory assessments were performed every 4 weeks. Ten subjects were enrolled, 7 male and 3 female, with a mean age of 29.4 years (range: 18-52 years). Eight subjects were splenectomized and 2 had palpable splenomegaly. Mean laboratory values at baseline were Hb F = 26.6% (range: 7.9-73.8%), Hb = 7.7 g/dL (range: 6.2-9.6 g/L) and reticulocytes = 10.9% (range: 7.1-15.7%). β-thalassemia mutations included homozygous IVS I-6 (C-T) in 7 of 10 subjects; and single subjects with homozygous cd29, homozygous IVS I-110 (G-A), and heterozygous IVSI-110 (G-A) / IVS II-I (G-A). One subject discontinued participation at Week 16 because of worsening anemia requiring a transfusion. Hb F increased in all subjects (range: 2.3-9.8%), with a mean increase of 4.8% (p < 0.0001). Total Hb increased in 7 subjects, with a mean increase of 0.6 g/dL (range: 0.1-1.5 g/dL) in those with increased Hb F. Adverse events were mild or moderate and reversible; fatigue, in 3 subjects, was the most common, followed by nausea, epigastric pain, dyspepsia, and fever, reported in 2 subjects each. There were mild and reversible increases in AST in 5 subjects and ALT in 4. Analyses of 3 major genetic modifier loci influencing baseline HbF levels identified favorable SNPs in the HMIP locus in 4 subjects, in BCL-11A in 3 subjects, and Xmn-I in one. No association was identified between specific modifiers and pharmacodynamic responses in this small group.

In conclusion, HQK-1001 was well-tolerated and resulted in increased Hb F in all subjects and a modest increase in total Hb in 70% of subjects. The findings suggest that further HQK-1001 studies enrolling larger numbers of genetically characterized patients for longer periods appear warranted.

Funding for this study was provided by a research grant from HemaQuest Pharmaceuticals and by the Georges N. Khoriaty Foundation.


Inati:HemaQuest Pharmaceuticals: Research Funding. Perrine:Phoenicia BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; HemaQuest Pharmaceuticals: Equity Ownership. Ghalie:HemaQuest Pharmaceuticals: Employment.

Author notes


Asterisk with author names denotes non-ASH members.