A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer,in sickle cell disease |
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| Authors: | Abdullah Kutlar Marvin E Reid Adlette Inati Ali T Taher Miguel R Abboud Amal El‐Beshlawy George R Buchanan Hedy Smith Kenneth I Ataga Susan P Perrine Richard G Ghalie |
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| Institution: | 1. Adult Sickle Cell Center, Georgia Regents University Medical Center, , Augusta, GA, USA;2. Sickle Cell Unit, University of West Indies Medical Center at Mona, , Mona, Kingston, Jamaica;3. Department of Pediatrics, Rafik Hariri University Hospital, , Bir Hassan, Beirut, Lebanon;4. Department of Internal Medicine, American University of Beirut Medical Center, , Riad El Solh, Beirut, Lebanon;5. Department of Pediatrics, American University of Beirut Medical Center, Hamra, Beirut, , Lebanon;6. Department of Pediatrics, Cairo University Pediatric Hospital, , Cairo, Egypt;7. Department of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, , Dallas,TX, USA;8. Department of Hematology, Tufts University Medical Center, , Boston, MA, USA;9. Comprehensive Sickle Cell Program, University of North Carolina, , Chapel Hill, NC, USA;10. Hemoglobinopathy Thalassemia Research Unit, Boston University Cancer Center, , Boston, MA, USA;11. HemaQuest Pharmaceuticals, 11995 El Camino Real, , San Diego, CA, USA. |
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| Abstract: | 2,2‐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/β0 thalassemia. HQK‐1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 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. Heamtol. 88:E255–E260, 2013. © 2013 Wiley Periodicals, Inc. |
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