Hepcidin Mimetics for the Treatment of Iron Overload Diseases

Abstract The goal of this SBIR phase I is to develop new therapeutics for treatment of various iron overload diseases that involves the use of hepcidin mimetics and to identify an Investigational New Drug IND candidate that is effica cious in the disease model of thalassemia There are two predominant diseases hemochromatosis and tha lassemia that are characterized with iron overload In both diseases low hepcidin levels increase intestinal iron absorption and increase release of recycled iron from the reticuloendothelial system which causes depletion of macrophage iron relatively lower levels of serum ferritin increase in liver iron concentration and release into the circulation of free iron that causes target organ damage Without treatment iron continues to accumulate and a considerable proportion of patients eventually reach toxic iron overload levels Patients are treated by phlebotomy blood transfusions and or iron chelators depending on the disease Chelation therapy is associated with considerable toxicity and currently existing chelators used for treating iron overload lack significant patient compliance or are associated with toxicity renal impairment hepatic impairment and gastrointestinal hemor rhage Thus there is significant need for new treatments that are safer and better tolerated Because of hepcidins complicated disulfide structure hepcidin mimetics have been proposed as a potential therapeutic To over come the physicochemical limitations of hepcidin more potent stable soluble and efficacious alternate scaffolds than hepcidin were engineered by using a purposefully built structure based drug environment Vectrix A lead compound PN was identified after optimizing and profiling engineered scaffolds identified by Vec trix In this SBIR phase I we plan to synthesize and characterize compounds with variable serum protein binding groups on a single position of PN select the best two compounds in a PD model and test the best two compounds in a PD model in diseased mice and test the best compound in a week disease model and finally undertake a PK PD study of the best compound to predict human dose A strong scientific team and consultants experienced in the field of iron overload diseases and biological drug development will lead us to select a drug development candidate that can be taken into nonclinical safety studies and then Phase I clinical trials Project Narrative Overload of toxic iron is a significant threat to the health of patients with Hemochromatosis and thalassemia Current treatments are insufficient and have other associated toxicities Therefore it is the goal of this study to develop new therapeutics for treatment of various iron overload disease and to identify an Investigational New Drug IND candidate