BPS 2023
A High Potency Protein that Normalizes Body Weight in DIO Mice through Triple Agonism at the FGF21, GLP-1 and GIP Receptors
Florence Brunel
Senior Principal Scientist, Novo Nordisk
ABSTRACT
Obesity is endemic throughout much of the world and obesity-related morbidities include heart disease, stroke, non-alcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). Glucagon-Like Peptide 1 (GLP-1) agonists have emerged as highly effective treatment for T2D and more recently for management of obesity. Glucose-dependent Insulinotropic Polypeptide (GIP) agonists when combined with GLP-1 agonism strengthen the pharmacology and yield further decreases in hyperglycemia, body weight and adiposity. The unimolecular GLP-1/GIP coagonist peptide named Tirzepatide recently received regulatory approval for the treatment of T2D, with significant associated loss of body weight. Fibroblast Growth Factor 21 (FGF21) is also an endocrine hormone that has received appreciable attention for treatment of the metabolic syndrome. It has demonstrated profound reductions in serum lipids including triglycerides, LDL, total cholesterol, and hepatic fat fraction, but less impressive relative to incretin-based drugs in control of hyperglycemia. Efruxifermin, an Fc-FGF21 agonist is being studied in the clinic for NASH. It has shown regression in hepatic fibrosis and normalization of liver fat in 12 weeks of treatment. Collectively the clinical studies with incretin and FGF-21 analogs have demonstrated the complimentary nature of these mechanisms to address the full spectrum of diseases associated with the metabolic syndrome. As such we designed, synthesized, and biologically characterized a long-acting protein that is highly potent and balanced in activity at the GLP-1, GIP and FGF21 receptors. This first-in-class triple agonist showed exquisite efficacy at reversing diet-induced obesity in mice and simultaneously provides the precedent-setting glycemic and weight benefits of GLP-1 and GIP coagonism with the enhanced lipid lowering properties of FGF21 agonism.
BIO
Florence was born and raised in France. She obtained a MS from the Ecole Nationale Superieure de Chimie De Montpellier, and then moved to the US. She obtained her Ph.D. with Prof. Arno Spatola at the University of Louisville, where her love of and career in peptides started. She then moved to San Diego to pursue her postdoctoral training with Dr. Phil Dawson at Scripps Research where she continued working with peptides while learning new methodologies such as chemical ligation. Florence then took her interest in turning peptides into drugs to the biotech and pharmaceutical industry at companies like Amylin Pharmaceuticals, Pfizer/CovX and Vertex Pharmaceuticals. Florence is now an employee of Novo Nordisk where her role has evolved into a strategy & portfolio position reviewing new technologies, project prioritization and external collaborations to meet Novo Nordisk’s strategy. Florence remains very active in the peptide community as an elected council member for the American Peptide Society, a board member for TIDES and the elected chair of the 2026 Chemistry and Biology of Peptides Gordon Research Conference.