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• W2094869620 abstract "The β-thalassaemia syndromes represent a World Health Organization-designated global health burden (Weatherall, 2010). Reactivation of fetal globin (HbF) expression is a rational therapeutic approach in inherited β-globin disorders, because the fetal HBG (γ-globin genes) are universally present and appropriately contextually integrated in the HBB (β-globin gene) locus in haematopoietic stem cells (Bauer et al, 2012). The defective production of β-globin chains in β-thalassaemia can be compensated for by an increase in γ-globin chains, which pair with α-globin chains to form HbF, thereby decreasing the α/non α-globin imbalance, the hallmark of β-thalassaemia. Several classes of HbF inducers have been investigated in β-thalassaemia, including cytotoxic agents, DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors including short chain fatty acids, thalidomide derivative, and erythropoietin, but no consistently effective agents have been identified (Musallam et al, 2013). The short chain fatty acids arginine butyrate, sodium phenylbutyrate, and isobutyramide were shown to increase HbF in β-thalassaemia and sickle cell disease, but had to be administered intravenously or by large oral daily doses, which is not practical for widespread long-term use (Perrine et al, 1993; Collins et al, 1995; Capellini et al, 2000). The orally bioavailable butyrate derivative 2,2-dimethylbutyrate sodium salt (HQK-1001) does not exhibit HDAC2 inhibitory activity and stimulates HBG expression and erythropoiesis in animal models and in vitro at concentrations readily achievable in humans(Pace et al, 2002; Mankindy et al, 2006). In a proof-of-concept study, HQK-1001 at 10, 20, 30, and 40 mg/kg administered daily for 8 weeks in 21 subjects with non-transfusion dependent β-thalassaemia was well-tolerated (Fuchareon et al, 2013). HQK-1001 at 20 mg/kg, which provided the best results, increased HbF in eight of nine subjects with a median increase of 6·6% and 4·4 g/l, and increased total haemoglobin in four of nine subjects by a mean of 11 g/l. Here, a single-centre study was conducted to evaluate HQK-1001 at 20 mg/kg per day administered for a longer period (NCT 01642758). Adult patients with β-thalassaemia intermedia characterized by two β-globin mutations were eligible if their haemoglobin was between 60 and 90 g/l on two occasions during the 30-d screening period. Patients were excluded if they were transfused within the previous 3 months, received iron chelation agents within the previous 7 d, another investigational agent within the previous 30 d, erythropoietic agents within the previous 90 d, or hydroxycarbamide within the previous 6 months, or had pulmonary hypertension requiring oxygen therapy, alanine aminotransferase (ALT) > four times the upper limit of normal, or serum creatinine >135 μmol/l. HQK-1001 capsules (HemaQuest Pharmaceuticals, San Diego, CA, USA) was administered at 20 mg/kg once daily for 24 weeks. Folic acid was given daily, and to prevent iron-deficient inefficient erythropoiesis, oral iron was given if serum ferritin was <1500 pmol/l, but stopped if ferritin levels were >2250 pmol/l. After signing an Ethics Committee approved informed consent form, subjects were assessed clinically and underwent laboratory tests twice during a 30-d screening period, every 4 weeks while receiving HQK-1001, and then 4 weeks after the end of dosing. Ten subjects were enrolled, seven male and three female, with a mean age of 29·4 years (range 18–52 years). Eight subjects were splenectomized; two had palpable splenomegaly at 4 and 7 cm below the left costal margin. The mean (range) baseline values were: HbF 26·6% (7·9–73·8%), absolute HbF 20·1 g/l (5·5–53·9 g/l), total haemoglobin 77·4 g/l (61·5–96·0 g/l), platelet count 782 × 109/l (486–1039 × 109/l), reticulocytes 10·9% (7·1–15·7%), and serum ferritin 3188 pmol/l (375–9772 pmol/l). Nine subjects completed the study and one subject was discontinued at Week 16 because of worsening anaemia requiring a transfusion. Mean compliance with HQK-1001, calculated as the ratio of the number of HQK-1001 capsules taken divided by the number of capsules prescribed, was 92·5%; two subjects had compliance <90%. Treatment was generally well-tolerated. All adverse events, except one case of vertigo, were graded as mild or moderate, and were reversible. Fatigue was the most common adverse event, reported in three subjects. In contrast, five subjects reported increased activity and improved mood. Two subjects each reported nausea, epigastric pain, dyspepsia or fever. The most common laboratory abnormalities were mild and reversible increases in aspartate aminotransferase (AST) in five subjects and in ALT in four. Fetal globin increased in all subjects, with peak increase occurring after a mean of 14 weeks of therapy; the mean (range) increase from baseline was 4·8% (2·3–9·8%) for HbF% (P = 0·0006) and 3·19 g/l (0·5–6·6 g/l) for absolute HbF (P = 0·001). Total haemoglobin increased in seven subjects, with a mean increase of 4·7 g/l (range 1·0–10·0 g/l). Figure 1 shows the baseline and peak value by subject for HbF and total haemoglobin. Table 1 presents each subject's thalassaemia mutations and polymorphisms for three quantitative trait loci (QTL) that were shown to strongly influence baseline HbF levels (Thein et al, 2009). Seven subjects were homozygous for the IVS I-6 (C-T) β + thalassemia mutation and only three were heterozygous for a favourable genetic modifier. This study demonstrates that HQK-1001 at 20 mg/kg per day for 24 weeks was well tolerated, significantly increased HbF, and modestly increased total haemoglobin. An interim analysis of a recently completed study of HQK-1001 at 20 mg/kg per day for 26 weeks in 10 patients with Hb E-β-thalassaemia showed higher mean increase in HbF of 10% (range 4·3–20·9%), with an increase in total haemoglobin >5 g/l in three subjects (Fuchareon et al, 2012). These patients all had a β0–thalassaemia mutation, and nine had at least one favourable allele for the Xmn-I QTL, which is linked to the HBB:c.79G>A (βE globin) gene in that population. Three trials have now demonstrated that HQK-1001 increases HbF in β-thalassaemia. It remains to be determined whether the magnitude of increase in HbF is sufficient to reduce long-term complications of chronic haemolysis, ineffective erythropoiesis, anaemia, and transfusion requirements. Further studies 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. SP and DC were supported by NIH grant R01-DK-52962. ClinServ International monitored the study. AGCT Inc. performed the analysis of the Xmn-I polymorphism. Cloret Carl assisted in the manuscript preparation. AI, SP, and RG designed the research; AI, MK, AT, SK and TA performed research; DC and HA performed genetic studies; RG and SP analysed the data and wrote the manuscript; AI and SP revised the manuscript. SP is founder and equity owner and RG is an employee of HemaQuest Pharmaceuticals. The other authors declare no competing financial interests." @default.
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• W2094869620 date "2013-11-13" @default.
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• W2094869620 title "A phase 2 study of HQK-1001, an oral fetal haemoglobin inducer, in β-thalassaemia intermedia" @default.
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• W2094869620 doi "https://doi.org/10.1111/bjh.12635" @default.
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