Development of a Three-Fragment Hybrid SPPS/LPPS Synthesis for Retatrutide
Michael Kopach
Associate Vice President, Eli Lilly and Company
Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. It comprises a specific, defined sequence of 41 amino acids, including a backbone of 39 alpha amino acids and a second chain with one residue each of gamma-glutamate and 8-amino-3,6-dioxaoctanoic acid (ADO). Retatrutide, an investigational molecule by Lilly, is under study for treating obesity. In a phase 2 clinical study, retatrutide demonstrated a mean weight reduction of up to 24.2% (~58 lb) after a 48-week treatment duration.
To enhance clinical supply, a novel hybrid SPPS/LPPS three-fragment synthesis approach has been developed. Hybrid techniques involve coupling shorter peptide fragments in the liquid phase to achieve higher purities and minimize challenging sequence errors due to mass transfer resistances, which tend to increase for longer amino acid sequences. These hybrid coupling methods often entail the precipitation, washing, and isolation of amorphous solid intermediates after fragment assembly. This innovative synthetic approach and improved control strategy have been successfully demonstrated at a multi-kilogram scale for Retatrutide. Furthermore, this presentation will highlight sustainability improvements made during the project lifecycle.
Dr. Kopach earned a Ph. D. in Organic chemistry from the University of Virginia in 1995 under the guidance of Prof. W.D. Harman. He then completed postdoctoral studies in natural product synthesis at Colorado State University with Prof. A. I. Meyers. Dr. Kopach began his industrial career in 1997 at Roche where his primary responsibilities included development and implementation of commercial processes for Nelfinavir, Xenical and Enfuvirtide - the first synthetic peptide produced on tonnage scale. In 2001, Dr. Kopach joined Eli Lilly and Company and has led several small molecule API projects. After a fifteen year career within Lilly Small Molecule R&D, Dr. Kopach established a synthetic peptide development group at Lilly in 2016. His research teams have had responsibility for process development and successful launch of T2D synthetic peptide Mounjaro and he presently leads the phase 3 Retatrutide drug substance team. Additionally, Dr. Kopach is leading efforts to advance sustainability practices in the synthetic peptide field and has recently promoted to Associate Vice President.