Beta thalassemia intermedia syndromes are genetic anemias caused by mutations which reduce production of beta globin, a major component of adult hemoglobin A, the protein which delivers oxygen throughout the body. Patients suffer from poor growth, fatigue, heart failure, endocrine deficiencies, and eventually, many require chronic blood transfusions. There is no approved therapeutic for the deficiency of beta globin chains in beta thalassemia.
This trial will study an oral therapeutic which stimulates production of fetal globin, an alternate type which is produced by all humans, but is normally switched off in infancy. This type of globin can compensate for the missing protein in beta thalassemia.

Start Date01 May 2012

Sponsor / Collaborator

Boston University

[+1]

NCT01322269 / CompletedPhase 2

A Randomized, Open-Label, Multi-Dose Study of HQK-1001 in Subjects With Sickle Cell Disease

The purpose of this study is to evaluate the safety and tolerability of three dose levels of HQK-1001 administered once daily for 26 weeks in subjects with sickle cell disease.

Start Date01 Apr 2011

Sponsor / Collaborator

HemaQuest Pharmaceuticals, Inc.

100 Clinical Results associated with HemaQuest Pharmaceuticals, Inc.

0 Patents (Medical) associated with HemaQuest Pharmaceuticals, Inc.

Literatures (Medical) associated with HemaQuest Pharmaceuticals, Inc.

06 Dec 2014·Blood

Intra-Patient Variability in Fetal Hemoglobin Measurements over Time in Sickle Cell Disease Patients Not on Fetal Hemoglobin Inducing Agents

Author: Manwani, Deepa ; Ghalie, Richard G. ; Knapp, Esther E ; Kutlar, Abdullah ; Cohen, Hillel W

AbstractIntroduction:We previously reported results of the placebo-controlled phase II study of the short-chain fatty acid derivative 2,2-dimethylbutyrate in inducing fetal hemoglobin (Hb F) in 76 patients with sickle cell disease (SCD). The primary endpoint was a comparison of Hb F levels in the treatment versus the placebo arms. Week 24 interim analyses revealed no statistically significant difference in change in Hb F levels between the 2 groups. We examined the placebo arm in order to assess untreated, intra-patient variability of Hb F%.Methods:Only Hb F values performed by HPLC at the central reference laboratory (Georgia Health Science University) were included. Any Hb F values determined within a 3 month period after a blood transfusion were excluded. Baseline and at least one subsequent Hb F levels were available in 37 of the 38 patients randomized to the placebo arm, which were included in the analysis. Serial determinations were performed at 4 week intervals, resulting in a total of 348 determinations and a median of 9 values per patient (range 2 - 15). Mean and standard deviation of repeat measures of Hb F% in each individual patient were calculated. A mean ± SD of the individual coefficients of variation (SD/mean of repeat measures for each individual) was calculated. Peak-to-trough (maximum - minimum) ranges of repeated measures were also calculated per individual and quartiles for the group determined. To assess the potential for regression to the mean from baseline, we calculated the median peak-to-trough within quartiles of baseline Hb F. We assessed the difference between maximum and minimum values as a percentage of the maximum or percentage deviation from personal best Hb F%, and finally we examined the association of baseline Hb F, age, gender and race with the degree of variability.Results:Patient median (range) age was 25.9 years (12 – 46), 24 (63%) were female, the genotype was Hb SS in 30 patients (79%) and Hb S/β0 thalassemia in 8 (21%), and no patient was treated with hydroxycarbamide at enrollment. Median (range) values of Hb F percentage at baseline were 7.5% (0.5 – 23.4). The mean coefficient of variation of all Hb F values was 13%, with a peak to trough median (range) of 1.8 (0.1 - 9.8). The mean percentage Hb F % variability over time was 31.8% (S.D +/- 18) and median (range) value of 26.1 (7.2-80) with quartiles depicted in Table 1. Baseline Hb F% negatively correlated with the percentage variability and this association was highly statistically significant (Spearman rho –0.34, p = 0.04).Table I: Intra-patient variability in successive Hb F% levels expressed as a percentage deviation from peak values Quartiles Range of Values (% difference between maximum and minimum HbF) n < 25th 7.2-20.6 9 25-49 20.7-26.1 10 50-74 26.2- 39.2 9 75-100 39.3-80 9Discussion:There is substantial Hb F variability among patients not on any Hb F inducer. This variability has not been previously reported and influences both the standard deviation and standard error, and would likely lower the statistical power of any comparative analysis in a clinical trial. Thus, sample sizes should be larger to be able to detect a sizeable difference between experimental and control groups.Variability among treated patients is harder to assess because it is difficult to separate out intrinsic variability from treatment effects and medication adherence. We have not attempted to assess the intra-patient variability in Hb F among patients given study drug in this study. However, it seems reasonable to assume that the variability seen in untreated patients would also be seen, to some degree, within treated patients. Thus, using Hb F percentage alone as a measure of medication compliance (with a Hb F inducing agent) may not be reliable.Possible explanations for this variability over time include artifacts of laboratory technique, increased hemolysis with increased erythropoietic drive, worsening renal function (and subsequent decrease in erythropoietin production), and bone marrow infarction, leading to disrupted hematopoiesis.DisclosuresKutlar: NIH/NIMHD: Research Funding. Ghalie:HemaQuest Pharmaceuticals, Inc.: Employment.

20 Mar 2014·BloodQ1 · MEDICINE

A phase 2 trial of HQK-1001 in HbE-β thalassemia demonstrates HbF induction and reduced anemia

Q1 · MEDICINE

Letter

Author: Fuchareon, Suthat ; Chui, David H. K. ; Perrine, Susan P. ; Chaneiam, Nattawara ; Ghalie, Richard G. ; Patthamalai, Poramin ; Boosalis, Michael S.

This article describes the phase 2 trial of HQK-1001 in Hb E-β thalassemia demonstrates HbF induction and reduced anemia.

15 Nov 2013·Blood

A Phase 2 Trial Of The Fetal Hemoglobin Inducer HQK-1001 (2,2-dimethylbutyrate, Sodium Salt) In Non-Transfusion-Dependent β-Thalassemia

Author: Koussa, Suzanne ; Inati, Adlette ; Nasr, Therese Abi ; Kahale, Mario ; Abbas, Hussein A ; Taher, Ali T ; Ghalie, Richard G. ; Perrine, Susan P

AbstractTreatment of β-thalassemia is still largely dependent on supportive care, including blood transfusions and iron chelation. No oral drugs have been shown to consistently improve the severe anemia in thalassemia. Hematopoietic stem cell transplantation is potentially curative, but only a fraction of patients are eligible. Reactivation of fetal globin gene expression and increased γ-globin chain production is an attractive therapeutic approach, because it can compensate for defective β-globin chain production and the consequent α/β-chain imbalance that is a hallmark of β-thalassaemia.HQK-1001 (2,2-dimethylbutyrate, sodium salt), a new butyrate derivative with moderate potency but greater bioavailability, no cytotoxicity, and no HDAC-inhibitory activity compared to earlier butyrates, was shown to stimulate γ-globin production and erythropoiesis in animal models and in vitro. HQK-1001 reactivates γ-globin gene expression by inducing targeted dissociation of the inhibitory complex HDAC3 and its adaptor protein NCoR from the γ-globin gene promoter. HQK-1001 also enhances erythropoiesis by prolonging phosphorylation and activation of STAT-5, and enhancing Bcl-xL expression. In a multicenter dose-escalation study, HQK-1001 administered orally at 10, 20, 30 and 40 mg/kg once daily for 8 weeks in 21 subjects with non-transfusion-dependent β-thalassemia (NTDT) was well-tolerated and increased fetal hemoglobin (Hb F) in most subjects, with best results observed at 20 mg/kg. This single-center study (NCT01642758) evaluated HQK-1001 administered at 20 mg/kg/day for a longer duration than previously studied.Patients 18-50 years old with NTDT of Mediterranean phenotypes were eligible if their hemoglobin (Hb) was between 6.0 and 9.0 g/dL within the prior 30 days and had no transfusions within the prior 3 months. HQK-1001 was administered at 20 mg/kg once daily for 24 weeks. Folic acid was administered daily and oral iron supplementation was prescribed if serum ferritin was <700 ng/mL and stopped if ferritin exceeded 1000 ng/mL. Clinical and laboratory assessments were performed every 4 weeks. Ten subjects were enrolled, 7 male and 3 female, with a mean age of 29.4 years (range: 18-52 years). Eight subjects were splenectomized and 2 had palpable splenomegaly. Mean laboratory values at baseline were Hb F = 26.6% (range: 7.9-73.8%), Hb = 7.7 g/dL (range: 6.2-9.6 g/L) and reticulocytes = 10.9% (range: 7.1-15.7%). β-thalassemia mutations included homozygous IVS I-6 (C-T) in 7 of 10 subjects; and single subjects with homozygous cd29, homozygous IVS I-110 (G-A), and heterozygous IVSI-110 (G-A) / IVS II-I (G-A). One subject discontinued participation at Week 16 because of worsening anemia requiring a transfusion. Hb F increased in all subjects (range: 2.3-9.8%), with a mean increase of 4.8% (p < 0.0001). Total Hb increased in 7 subjects, with a mean increase of 0.6 g/dL (range: 0.1-1.5 g/dL) in those with increased Hb F. Adverse events were mild or moderate and reversible; fatigue, in 3 subjects, was the most common, followed by nausea, epigastric pain, dyspepsia, and fever, reported in 2 subjects each. There were mild and reversible increases in AST in 5 subjects and ALT in 4. Analyses of 3 major genetic modifier loci influencing baseline HbF levels identified favorable SNPs in the HMIP locus in 4 subjects, in BCL-11A in 3 subjects, and Xmn-I in one. No association was identified between specific modifiers and pharmacodynamic responses in this small group.In conclusion, HQK-1001 was well-tolerated and resulted in increased Hb F in all subjects and a modest increase in total Hb in 70% of subjects. The findings suggest that further HQK-1001 studies enrolling larger numbers of genetically characterized patients for longer periods appear warranted.Funding for this study was provided by a research grant from HemaQuest Pharmaceuticals and by the Georges N. Khoriaty Foundation.Disclosures:Inati: HemaQuest Pharmaceuticals: Research Funding. Perrine:Phoenicia BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; HemaQuest Pharmaceuticals: Equity Ownership. Ghalie:HemaQuest Pharmaceuticals: Employment.

News (Medical) associated with HemaQuest Pharmaceuticals, Inc.

09 Dec 2008

·www.biospace.com

HemaQuest Announces Clinical Progress on New Sickle Cell Anemia Drug

SAN FRANCISCO, CA--(Marketwire - December 09, 2008) - HemaQuest Pharmaceuticals announced today the successful completion of Phase 1 clinical trials of HQK-1001, an orally-administered therapeutic which the company is developing to treat hemoglobin disorders, including sickle cell anemia and beta thalassemia. The company presented the results at the annual meeting of the American Society of Hematology in San Francisco.

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Dimebutic acid ( β-globin )	Anemia, Sickle Cell More	Discontinued
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