SBIR-STTR Award

The beta thalassemias are genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin and are among the most common genetic diseases worldwide, although they comprise an orphan condition in the U.S. The beta thalassemia syndromes are characterized by excess alpha globin chains, which are toxic to the developing red blood cell and cause rapid apoptosis, resulting in severe anemia and early mortality from complications of blood transfusions, including infections and iron overload. Pharmacologic reactivation of the genes for fetal globin can compensate for the deficient beta globin chains, and this approach has been successfully demonstrated with a short chain fatty acid, arginine butyrate, given intravenously, and a derivative, sodium phenylbutyrate, which requires large drug quantities that are difficult for patient to tolerate. A more tolerable oral therapeutic which both stimulate fetal globin and erythropoiesis is needed for long-term therapy of most patients. The investigators have developed a new-generation short chain fatty acid derivative (ST7), which stimulates both fetal globin gene expression and erythropoiesis in anemic and non-anemic animal models, and enhances proliferation and survival of erythroid cells, including cultured thalassemic erythroid progenitor cells. This lead candidate is orally-bioavailable with PK profiles at low oral doses which are superior to previous short chain fatty acid therapies. The investigators propose in this application: 1) to perform the medicinal formulation required for a new IND; and 2) to refine low-dose regimens for subsequent clinical trials in humans. These are tasks required for development of ST7 as a new oral therapeutic for treatment of patients with beta thalassemia

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.

Thesaurus Terms:
blood disorder chemotherapy, drug screening /evaluation, erythropoiesis, fatty acid analog, gene expression, hemoglobin F, nonhuman therapy evaluation, oral administration, thalassemia pharmacokinetics baboon, dog, juvenile animal, laboratory rat