Polymer Epithelial Lining for the Oral Delivery of Macromolecules

PROJECT SUMMARY Macromolecule drugs, specifically peptides, are an attractive therapeutic class given they are more potent and target specific than small molecules yet demonstrate superior tissue permeation and manufacturability compared to large proteins. As such, they are one of the most clinically and commercially viable therapeutic modalities for treating chronic conditions such as metabolic disease, ageing, infectious disease, and inflammatory disorders. Peptides however are also highly biodegradable, poorly absorbed in the GI tract, and rapidly cleared from the body which has necessitated administration via repeated injections. These constant injections create significant burden for patients, especially those managing chronic disease, and thus result in poor adherence. While molecular structural modifications, enteric coatings and permeation enhancing excipients (PEs) have marked major advances in oral delivery technologies, the critical challenge of sufficient GI absorption has not been solved. A key hurdle has been the dynamic intestinal environment, where variable contents and rapid gastric emptying result in insufficient co-localization of the target therapeutic agent and PE excipients. Consequently, the addition of large amounts of PEs to current oral macromolecule formulations results in only a minor improvement in absorption. Syntis’ Gastrointestinal Synthetic Epithelial Lining (GSEL) technology is synthetic tissue platform that enterically delivers a mucoadhesive polydopamine (PDA) lining to the small intestine. When GSEL is co- formulated with therapeutic agents, these compounds are incorporated into the PDA lining to create an evenly distributed drug depot that lasts between 18-24 hours, significantly increasing GI residence time and thus systemic absorption of the target drug compound. In pigs, GSEL has demonstrated the ability to increase the half-life of anti-parasitic drug praziquantel tenfold, and total absorption (AUC) fourfold. In this SBIR Fast-Track proposal. we propose to build on the previous oral delivery work achieved with praziquantel to enable peptide macromolecule compounds. To demonstrate the broad applicability of the GSEL platform, we propose to identify GSEL-compatible formulations of model peptide drugs and permeation enhancers, optimize composition for co- localization and depot formation in the small intestine, and create tablets of lead formulations for oral delivery. At the successful conclusion of the work described herein, the next steps will be to finalize raw materials sourcing for GMP manufacturing, initiate GLP toxicity studies with a CRO, and finalize a clinical plan for a first-in-human single ascending dose study.