Trial of HQK-1001 in Beta Thalassemia Intermedia in Lebanon (LB-04-THAL)

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.

This is a trial of an experimental oral medicine which stimulates production of fetal hemoglobin, an innate type of hemoglobin which is normally made but is suppressed in infancy. Fetal globin (HbF) can perform the function of the missing beta globin and reduce anemia in beta thalassemia, when it is produced in higher amounts than normal. In this trial, 10 patients with beta thalassemia intermedia in Lebanon will all receive the study drug for 6 months at a dose which has been previously shown to be safe in normal volunteers and in beta thalassemia and sickle cell patients and to stimulate fetal globin production in many, when given for brief periods. The purpose of this trial is the following: To determine if total hemoglobin levels increase above baseline in some subjects when the study drug is taken for 26 weeks. To determine if fetal globin is increased above baseline levels in a proportion of subjects when the study drug is taken for 26 weeks. To determine the number of adverse events which occur with 26 weeks of administration of the study drug in beta thalassemia intermedia subjects. After a screening period, the subjects will take the study drug at home once a day. They will be seen once every 4 weeks for examinations and laboratory tests during the dosing period and for 4 weeks afterwards. This trial will provide an important step in evaluating a potential treatment for patients with beta thalassemia intermedia, that can be used around the world, if it is effective and safe.

To measure changes from baseline in total hemoglobin when HQK-1001 is administered orally for 26 weeks in subjects with beta thalassemia intermedia.

Baseline hemoglobin levels will be determined in each subject and averaged from levels obtained on a screening visit and on day one of the study, before any drug is taken. Hemoglobin levels will then be analyzed every 4 weeks during 26 weeks of taking the study drug and for 4 weeks after the dosing is completed. Changes from baseline will be determined.

To measure the number of adverse events which occur with HQK-1001 treatment when given over 26 weeks in beta thalassemia intermedia.

Adverse events which occur during HQK-1001 administration for 26 weeks will be recorded every 4 weeks.

To measure changes from baseline in HbF during treatment with HQK-1001 for 26 weeks in beta thalassemia intermedia.

Levels of HbF will be averaged from a screening visit and day 1 of the study, prior to any drug treatment. HbF levels will then be measured every 4 weeks during treatment and for 4 weeks after the treatment, and compared to each subject's baseline value. The number of subjects in which an increase in HbF develops above individuals' average baseline value will be obtained.

Inclusion Criteria: Diagnosis of beta thalassemia intermedia Ages 16-50 years Average total Hgb levels between 6.0 and 9.0 gm/dl within 30 days of initial dose of study drug Able to comply with all study procedures If female and of childbearing potential, must have a documented negative pregnancy test prior to entry and every 4 weeks Exclusion Criteria: Red blood cell transfusions within 3 months prior to administration of study drug QT Segment corrected (QTc)> 450 msec Use of Erythropoiesis Stimulating Agents(ESAs)within 9 days of first dose Hydroxyurea treatment within 6 months of first study drug History of significant arrythmias, syncope, or resuscitation Alanine Transaminase (ALT)> 4x upper limit of normal Serum creatinine > 1.5 mg/dl Sse of iron chelating agents within 7 days of first dose Pulmonary hypertension requiring oxygen therapy

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