SBIR-STTR Award

The beta-hemoglobinopathies (sickle cell disease and beta-thalassemia) are the most common genetic diseases in the world. The symptoms of these diseases can be ameliorated or eliminated by pharmacological induction of fetal hemoglobin (Hb F) expression. Butyrate induces high levels of Hb F in many patients, but must be given only at intermittent intervals (pulsed) because it inhibits erythroid cell growth. This antiproliferative activity limits its potential use in inducing gamma-globin, because drug administration must be limited to intermittent use. The short half-life of the drug and the need for IV administration further limits its general utility. The applicant's goal is to develop an Hb F-inducing compound which does not inhibit cell growth, has a long half-life, and is active when administered orally, as a more effective therapeutic. A plan is described for preclinical investigation of new compounds which provide potential advantages over existing Hb F stimulants. Lead compounds from three chemical classes have been shown to: 1) induce Hb F in vitro to a similar level as does butyrate; 2) stimulate F-reticulocytes in vivo in baboons; and 3) be metabolically stable and reach adequately high and sustained plasma levels after oral administration. Furthermore, three new lead compounds and chemical classes avoid the adverse properties of butyrate itself in that they do not inhibit erythroid progenitor cell growth. The chemical classes of these three compounds can serve as backbone structures for additional modification to theoretically further enhance potential therapeutic properties, if necessary. The sequential studies as detailed in this proposal will determine if these three lead compounds may themselves be optimal for development, or whether any of the other derivatives they have synthesized have an even more attractive profile for clinical development. PROPOSED COMMERCIAL APPLICATION: An oral therapeutic which will ameliorate the clinical symptoms of sickle cell anemia and the anemia of beta thalassemia

Sickle cell disease (SCD) and beta-thalassemia are genetic disorders caused by molecular mutations affecting the genes for adult hemoglobin. With a world-wide birth prevalence of 2/1,000, hemoglobin disorders are the most common genetic diseases in the world (360,000 patients/year - 250,000 with sickling disorders and 110,000 with thalassemias. These conditions can be ameliorated by reactivating production of fetal hemoglobin (Hb F) in the patient?s blood. Pharmacologic re-induction of fetal hemoglobin has been achieved in these diseases using a first generation intravenous therapeutic, a short-chain fatty acid (SCFA) salt, and these treated patients experienced both biochemical and clinical improvement in their diseases, with excellent safety profiles. During the Phase I STTR, the applicant organization developed third-generation SCFAs with substantial advantages over the first generation agent, including enhanced Hb F-and cellular growth stimulatory activity, oral-bioavailability, and prolonged biological half-lives. These agents have proven effective and safe in a baboon model for Hb F induction. In this Phase II application, we propose to conduct the preclinical development studies necessary to obtain Investigational New Drug status for a new lead compound (ST-20) for human clinical trials. The goals of this proposal are: I) To prepare a stable medicinal formulation of a sodium salt of ST20, a synthetic SCFAD which stimulates Hb F production; ii) To refine oral dosing-regimens for ST20 for application to patients; iii) To prepare an IND Application for ST20; iv) To evaluate additional SCFADs for activity in induction of Hb F expression, as back-up compounds. PROPOSED COMMERCIAL APPLICATION: Sickle cell disease and thalassemia are the two most common genetic diseases in the world, killing millions of people. No safe definitive therapy exists for these diseases. The applicant organization has developed an oral version of a first-generation therapeutic, which must be given intravenously. Upon completion of preclinical studies, Investigational New Drug status will be obtained and the new therapeutic agent will be tested in human clinical trials.

Thesaurus Terms:
drug design /synthesis /production, drug screening /evaluation, hemoglobin F, hemoglobinopathy, oral administration, short chain fatty acid butyrate, chemical stability, fatty acid, gene expression, pharmacokinetics, transcription factor baboon