Development of non-cytotoxic, orally-active therapeutics, which induce fetal globin production, would be beneficial for treatment of beta-thalassemias and hemoglobinopathies. The short-chain fatty acids (SCFA) butyrate and phenylbutyrate are active fetal globin inducers, but their clinical application has been limited by inhibition of erythropoiesis and unfavorable PK profiles. HQK-1001 is a SCFA which stimulates fetal globin gene expression in reporter gene assays, erythroid progenitors, transgenic mice, and anemic baboons. HQK-1001 also stimulates human erythroid progenitor (BFU-E) proliferation by a mean of 30% above controls, and increased red blood cell counts in phlebotomized baboons. HQK-1001 has demonstrated a wide safety margin in pre-clinical toxicology testing, with no significant adverse effects in sub-chronic (6-month) studies and negative mutagenicity testing. Based on these pre-clinical data, a placebo-controlled, randomized, blinded, single-dose escalating Phase 1 trial was conducted to evaluate HQK-1001 at 4 dose levels ranging from 2 to 20 mg/kg in 32 normal volunteers. The drug was welltolerated, with no significant adverse events. Pharmacokinetic analyses showed low intersubject variability, a linear increase in Cmax and AUC with increasing dose, and T½ of 11 hours, indicating suitability for once-daily dosing. Administration under fed conditions demonstrated equivalent AUC to fasting conditions. In a subsequent 14-day Phase 1 dosing study in 41 normal subjects, the drug was also well-tolerated, with no significant adverse effects at the studied dose levels (5, 10 and 15 mg/kg). F-reticulocytes increased in subjects treated with 5 to 10 mg/kg doses. Absolute reticulocytes increased significantly above baseline (p <0.02 – 0.002) following 14-day dosing at all dose levels, while no significant change occurred in placebo controls. These first-in-human clinical studies demonstrating safety of HQK-1001 in 73 normal volunteer subjects and an improved pharmacologic profile over prior SCFAs indicate that HQK-1001 merits further clinical investigation in anemic patients with beta-globin gene disorders.

Disclosures: Perrine:HemaQuest Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Welch:HemaQuest Pharmaceuticals: Employment, Equity Ownership. Keefer:Hemaquest Pharmaceuticals: Research Funding. Boosalis:Hemaquest Pharmaceuticals: stock options. Case:HemaQuest Pharmaceuticals: Employment. Faller:Hemaquest Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties. Berenson:Hemaquest Pharmaceuticals: Employment, Equity Ownership.

Author notes

Corresponding author