Oral Therapeutic for Beta-Thalassemia

DESCRIPTION (provided by applicant): The beta thalassemia syndromes are prevalent genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin and cause early mortality from complications of blood transfusions. These conditions can be ameliorated by reactivating production of fetal hemoglobin (Hb F) in the patients' blood. Pharmacologic re-induction of HbF has been achieved in two-thirds of patients with these diseases in clinical trials, using first generation short-chain fatty acid (SCFA) therapeutics. Some of the treated patients experienced both biochemical and clinical / hematologic improvement, and became independent of blood transfusions for several years. The first SCFA therapies, butyrate and phenylbutyrate, required IV infusions or large amounts of drug (20-30 grams/day) which are difficult for long-term use. Combined therapy with rhu- EPO to stimulate erythropoiesis and with Butyrate to induce fetal globin expression produced additive effects, suggesting that both actions are necessary for an optimal definitive treatment for beta thalassemia. During the Phase I STTR, the applicant organization developed a new SCFA (sodium ST-7) which has substantial advantages over the first generation agents, in inducing Hb F and also stimulating erythroid cell proliferation, with oral-bioavailability, and with pharmacokinetics demonstrating feasibility for once/day oral administration at tolerable doses (0.5-1 gram for an adult). The agent has proven effective and safe in a primate model for Hb F induction and in mice transgenic for the human globin genes. In this Phase II STTR application, we propose to conduct the additional preclinical development studies required by the FDA to obtain Investigational New Drug status for Phase I clinical trials of this lead erythropoietic HbF-inducer (sodium ST-7). The goals of this proposal are: 1) To conduct the preclinical toxicology studies required for an IND for sodium ST-7 to stimulate HbF and erythropoiesis; 2) To prepare an IND application for phase I clinical trials of the erythropoietic Hb F-inducing agent; 3) To evaluate four other novel Hb F-inducing compounds for pharmacokinetics and pharmacodynamics in baboons, as potential back-up therapeutics.