A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease

Abdullah Kutlar, Kenneth Ataga, Marvin Reid, Elliott P. Vichinsky, Lynne Neumayr, Loray Blair-Britt, Richard Labotka, Jonathan Glass, Jeffrey R. Keefer, William A. Wargin, Ronald Berenson, Susan P. Perrine

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.

Original languageEnglish (US)
Pages (from-to)1017-1021
Number of pages5
JournalAmerican Journal of Hematology
Volume87
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

2,2-dimethylbutyric acid
Globins
Sickle Cell Anemia
Hemoglobins
Placebos
Pharmaceutical Preparations
Fetal Hemoglobin
Holidays
Thalassemia
Therapeutics
Drug-Related Side Effects and Adverse Reactions
Sodium

ASJC Scopus subject areas

  • Hematology

Cite this

Kutlar, A., Ataga, K., Reid, M., Vichinsky, E. P., Neumayr, L., Blair-Britt, L., ... Perrine, S. P. (2012). A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. American Journal of Hematology, 87(11), 1017-1021. https://doi.org/10.1002/ajh.23306

A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. / Kutlar, Abdullah; Ataga, Kenneth; Reid, Marvin; Vichinsky, Elliott P.; Neumayr, Lynne; Blair-Britt, Loray; Labotka, Richard; Glass, Jonathan; Keefer, Jeffrey R.; Wargin, William A.; Berenson, Ronald; Perrine, Susan P.

In: American Journal of Hematology, Vol. 87, No. 11, 01.11.2012, p. 1017-1021.

Research output: Contribution to journalArticle

Kutlar, A, Ataga, K, Reid, M, Vichinsky, EP, Neumayr, L, Blair-Britt, L, Labotka, R, Glass, J, Keefer, JR, Wargin, WA, Berenson, R & Perrine, SP 2012, 'A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease', American Journal of Hematology, vol. 87, no. 11, pp. 1017-1021. https://doi.org/10.1002/ajh.23306
Kutlar, Abdullah ; Ataga, Kenneth ; Reid, Marvin ; Vichinsky, Elliott P. ; Neumayr, Lynne ; Blair-Britt, Loray ; Labotka, Richard ; Glass, Jonathan ; Keefer, Jeffrey R. ; Wargin, William A. ; Berenson, Ronald ; Perrine, Susan P. / A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. In: American Journal of Hematology. 2012 ; Vol. 87, No. 11. pp. 1017-1021.
@article{3049714da150496cb90b3723344a9f01,
title = "A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease",
abstract = "Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.",
author = "Abdullah Kutlar and Kenneth Ataga and Marvin Reid and Vichinsky, {Elliott P.} and Lynne Neumayr and Loray Blair-Britt and Richard Labotka and Jonathan Glass and Keefer, {Jeffrey R.} and Wargin, {William A.} and Ronald Berenson and Perrine, {Susan P.}",
year = "2012",
month = "11",
day = "1",
doi = "10.1002/ajh.23306",
language = "English (US)",
volume = "87",
pages = "1017--1021",
journal = "American Journal of Hematology",
issn = "0361-8609",
publisher = "Wiley-Liss Inc.",
number = "11",

}

TY - JOUR

T1 - A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease

AU - Kutlar, Abdullah

AU - Ataga, Kenneth

AU - Reid, Marvin

AU - Vichinsky, Elliott P.

AU - Neumayr, Lynne

AU - Blair-Britt, Loray

AU - Labotka, Richard

AU - Glass, Jonathan

AU - Keefer, Jeffrey R.

AU - Wargin, William A.

AU - Berenson, Ronald

AU - Perrine, Susan P.

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.

AB - Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK-1001), an orally-bioavailable, promoter-targeted fetal globin gene-inducing agent, was evaluated in a randomized, blinded, dose-ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6-week cycles, with a two-week interim dose holiday. Twenty-one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK-1001 was well-tolerated with no unexpected drug-related adverse events; a dose-limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo-treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK-1001 in sickle cell disease.

UR - http://www.scopus.com/inward/record.url?scp=84867904678&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867904678&partnerID=8YFLogxK

U2 - 10.1002/ajh.23306

DO - 10.1002/ajh.23306

M3 - Article

C2 - 22887019

AN - SCOPUS:84867904678

VL - 87

SP - 1017

EP - 1021

JO - American Journal of Hematology

JF - American Journal of Hematology

SN - 0361-8609

IS - 11

ER -