ORAL THERAPEUTIC FOR INDUCING FETAL HEMOGLOBIN

DESCRIPTION (provided by applicant): 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.