Designing safe, potent, and cost-effective small peptide erythropoietin analogs

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Recombinant human erythropoietin (rhEpo) has proven to be an effective treatment of anemias, primarily those secondary to renal disease and malignancy. The cost of rhEpo therapy, the need for frequent parenteral administration, the development in some patients of anti-Epo antibodies, and an associated increase in thromboembolic events (relative risk ratio of 1.67) suggest a real need for a cheaper, safer, and more conveniently deliverable therapeutic. Therefore, we have developed and preliminarily tested with in vivo model, a short peptide epo analog based on peginesatide, a previously FDA approved peptide epo agonist. Our new lead molecules have been optimized to avoid any immunogenicity. This Phase 1 SBIR proposal will further develop this therapeutic by identifying the best compound tuned for weekly dosing and establishing its therapeutic in vivo proof of concept. This work will be articulated around 3 aims: (Aim 1) Determine the structural scaffold to attain in vitro stability and optimization of the weak metabolic centers by modifying lead molecules. (Aim 2) Determine the structural features that will provide in vitro and in vivo PK profiles to enable weekly delivery as our minimum benchmark. (Aim 3) Confirm the in vivo PK profile matching the goal of weekly administration and in vivo efficacy in mice treated weekly with vehicle vs. drugs selected from Aims 1 and 2. When these milestones are accomplished, new compounds will be ready to enter the pre-IND phase of therapeutic development.