A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

Abstract

-dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/b 0 thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n 5 15), 40 mg/kg (n 5 18) and 50 mg/kg (n 5 19), either alone (n 5 21) or with hydroxyurea (n 5 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases 4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases 1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. Am. J. Hematol. 88:E255-E260, 2013.

Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells

“…Also, the capability of SCFAs to induce ␥ globin gene expression and F-reticulocytes has been evaluated in transgenic mice and baboons (48)(49)(50). Among them, 2,2-dimethylbutyrate (HQK-1001) has been found to be the most potent oral ␥ globin gene inducer and is now being tested for use in SCD, ␤-thalassemia intermedia, and HbE/␤-thalassemia in phase II clinical trials (15,(51)(52)(53)(54). However, the therapeutic effects of HQK-1001 in patients who are irresponsive to HU treatment are presently unknown.…”

Erythroid differentiation ability of butyric acid analogues: Identification of basal chemical structures of new inducers of foetal haemoglobin

“…A key example is the recently developed sodium 2,2 dimethylbutyrate (HQK-1001), object of patenting (US8618068) and ongoing phase II clinical trials on patients affected by sickle cell disease (Kutlar et al, 2013;Reid et al, 2014) and different types of β-thalassaemia (Patthamalai et al, 2014;Inati et al, 2014). As far as clinical trials, several examples are present in the literature including those based on sodium butyrate and sodium phenylbutyrate (Dover et al, 1994, Collins et al, 1995, Sher et al, 1995, arginine butyrate (McMahon et al, 2010) and isobutyramide (Domenica Cappellini et al, 2000).…”

“…Several studies report in vivo experiments using both mouse (Pace et al, 1996, Partington et al, 1984and Perrine et al, 1988, both primates and humans (Constantoulakis et al, 1989a, Lavelle et al, 1993, Constantoulakis et al, 1988, Fucharoen et al, 2013aand Kutlar et al, 2013) models demonstrating the expected clinical effects of this class of foetal haemoglobin inducers. The activity of sodium butyrate and sodium phenylbutyrate and analogues exhibiting similar mechanism of action have been evaluated in clinical trials (Dover et al, 1994, Sher et al, 1995, Collins et al, 1995, Perrine et al, 2011and Patthamalai et al, 2014 demonstrating induction of foetal haemoglobin in some patients with thalassaemia.…”

2015 Clinical trials update in sickle cell anemia

“…MTD, safety, and effect on HbF induction are being determined for Pomalidomide, a derivative of thalidomide that also inhibits angiogenesis, in SCD patients greater than 18 years of age and who are also hydroxyurea refractory or intolerant (Table I). A phase 2 clinical trial for 2,2-dimethylbutyrate’s (HQK-1001), an oral HbF inducer, was recently terminated early for lack of effects [15,44]. Inhibition of histone deacetylase (HDAC) is being investigated as a mechanism to increase HbF; Vorinostat’s phase 2 clinical trial was recently closed due to the lack of measurable effects, while panobinostat (LBH589) is still in phase 1.…”