Employing an integrated approach towards developing orally bioavailable peptide therapeutics
Stephen Timothy Buckley
Vice President, Novo Nordisk
Peptides and proteins have reshaped the possibilities for effectively treating diseases; however, their rapid degradation and poor absorption in the gastrointestinal tract challenge their ability to be delivered orally. Owing to these challenges, an integrated approach is required, which combines tailoring both the peptide and its formulation to achieve optimal in vivo performance and thereby, the desired therapeutic effect. Peptide analogues can be designed to offer improved stability and prolonged half-life while a formulation approach can facilitate improved absorption. Specifically, molecular engineering approaches designed to provide enhanced proteolytic stability with the requisite receptor affinity and strong albumin binding, which in turn lead to significantly improved bioavailability and ultra-long plasma half-life will be discussed. Additionally, a bespoke formulation approach is necessitated, which exhibits suitable compatibility for the co-formulated peptide. Strategies to delineate the relative contributions of structural traits of permeation enhancers to their capacity to promote enhanced drug absorption will be discussed. Herein, a machine learning-derived quantitative structural activity relationship (QSAR) model will be presented, which provides for a trained and reliable tool for modelling the potency of these complex pharmaceutical excipients and can be applied for both in silico screening of novel permeation enhancers, in addition to optimization of their surfactant-derived enhancing properties. Lastly, mechanistic insights into the performance of oral peptide-based formulations in human subjects will be shared, with a specific focus on the influence of ingested food and fluid on their performance.
Dr. Stephen T. Buckley is Scientific Vice President of Advanced Drug Delivery at Novo Nordisk A/S, Denmark. In addition to his leadership responsibilities, he is responsible at Novo Nordisk for a cross-organizational team of scientific experts tasked with identifying and evaluating novel drug delivery technologies. He holds a degree in Pharmacy from Trinity College Dublin (Ireland), and a Ph.D in Biopharmaceutics and Cell Physiology from the same university. During this time, he also worked as a Visiting Fellow at the University of Southern California (USA). Prior to joining Novo Nordisk A/S, Dr. Buckley was a Postdoctoral Research Fellow at the University of Southern Denmark (Denmark). He is the recipient of honors and awards from the American Association of Pharmaceutical Scientists (AAPS) and the Scandinavian and German Physiological Societies. He is (co-) author of 25+ articles in peer-reviewed journals (including Science, Science Translational Medicine and Nature Biotechnology), 1 book chapter and 30+ abstracts, and has been invited to give numerous presentations at research institutions, international conferences and workshops