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

Abdullah Kutlar, Marvin E. Reid, Adlette Inati, Ali T. Taher, Miguel R. Abboud, Amal El-Beshlawy, George R. Buchanan, Hedy Smith, Kenneth Ataga, Susan P. Perrine, Richard G. Ghalie

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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/β 0 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.

Original languageEnglish (US)
JournalAmerican Journal of Hematology
Volume88
Issue number11
DOIs
StatePublished - Nov 1 2013

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2,2-dimethylbutyric acid
Globins
Sickle Cell Anemia
Sickle Hemoglobin
Fetal Hemoglobin
Hydroxyurea
Confidence Intervals
Thalassemia
Maximum Tolerated Dose
Gastritis
Drug-Related Side Effects and Adverse Reactions
Blood Transfusion
Hemoglobins

All Science Journal Classification (ASJC) codes

  • Hematology

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A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. / Kutlar, Abdullah; Reid, Marvin E.; Inati, Adlette; Taher, Ali T.; Abboud, Miguel R.; El-Beshlawy, Amal; Buchanan, George R.; Smith, Hedy; Ataga, Kenneth; Perrine, Susan P.; Ghalie, Richard G.

In: American Journal of Hematology, Vol. 88, No. 11, 01.11.2013.

Research output: Contribution to journalArticle

Kutlar, A, Reid, ME, Inati, A, Taher, AT, Abboud, MR, El-Beshlawy, A, Buchanan, GR, Smith, H, Ataga, K, Perrine, SP & Ghalie, RG 2013, 'A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease', American Journal of Hematology, vol. 88, no. 11. https://doi.org/10.1002/ajh.23533
Kutlar, Abdullah ; Reid, Marvin E. ; Inati, Adlette ; Taher, Ali T. ; Abboud, Miguel R. ; El-Beshlawy, Amal ; Buchanan, George R. ; Smith, Hedy ; Ataga, Kenneth ; Perrine, Susan P. ; Ghalie, Richard G. / A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. In: American Journal of Hematology. 2013 ; Vol. 88, No. 11.
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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/β 0 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.",
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AU - Inati, Adlette

AU - Taher, Ali T.

AU - Abboud, Miguel R.

AU - El-Beshlawy, Amal

AU - Buchanan, George R.

AU - Smith, Hedy

AU - Ataga, Kenneth

AU - Perrine, Susan P.

AU - Ghalie, Richard G.

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AB - 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/β 0 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.

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