ESPE Yearbook of Paediatric Endocrinology

PerspectBiol Med 2024; 67:325-336. PMID: 39247927 https://muse.jhu.edu/pub/1/article/936213

In Brief: This perspective paper discusses the lessons to be learnt from the history of GLP-1 based medication development, which is now a multi-billion dollar effective therapeutic approach, but was abandoned in 1990 despite promising early data.

Comment: The author, Jeffrey Flier, was closely involved in the early development of GLP-1 agonists. In 1987, he cofounded Metabolic Biosystems (MetaBio) and obtained from Joel Habener at Harvard University the exclusive worldwide license to their patents for GLP-1 as a therapy for diabetes. They rapidly obtained major funding from Pfizer in return for exclusive rights to the work, and went on to show that GLP-1 infusion enhanced insulin secretion, slowed gastric emptying and reduced hunger. Sadly, none of that work was ever presented publicly or published. The approach of major pharma companies at that time was to keep such data confidential.

MetaBio did not have sufficient time to answer the next challenge, how to overcome the very short half-life of GLP-1, which is only several minutes. Pfizer terminated support for the programme, concluding that injectable approaches were infeasible and that it would need a trans-nasal or other route of delivery (others would later identify and inhibit the responsible enzyme DPP-4). Furthermore, MetaBio’s parent company, CalBio, also decided they could not continue the work due to their need to focus as a small company on another emerging treatment for heart failure.

The success story of GLP-1 agonists is told by Lotte Knudsen at Novo Nordisk (1), which began studying GLP-1 in 1992 and acquired the rights to Habener’s patents after MetaBio relinquished them. Their key breakthrough was to attach an acylated fatty acid to GLP-1 to enable binding to albumin to prolong its half-life. Both the successes and failures of drug development provide relevant lessons for today.

Reference: 1. Knudsen, L. B. 2019. "Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity." ACS Pharmacol Transl Sci 2 (6): 468–84.