Matthias Tschöp

Helmholtz Munich, Technical University of Munich, Germany

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Title

Overcoming obesity: the discovery of multi receptor drugs

Abstract 

On our mission to overcome the obesity pandemic by discovering highly effective medicines, we hypothesized that chemistry based on more than one endocrine factor may be required to significantly reduce body fat without causing severe side effects. We selected combinations of afferent gut hormones acting in the CNS as the most likely path toward efficacy comparable to bariatric surgery benefits. Over the last 20 years, we combined advanced in vivo preclinical biology with state-of-the-art peptide chemistry to achieve such synergistic gastrointestinal hormone pharmacology. What proved successful was the unprecedented approach of fully integrating two and three mechanisms of biological action at a potency that matched the individual native hormones into single molecules. The resulting peptides are analogous to master keys, structurally nearly identical to natural gut hormones, but delivering multiple metabolic action profiles. We discovered multiple dual and triple hormone-like chimeric peptides from a set of intestinal hormones and chemically refined these for medicinal purposes to possess suitable time action and physical properties to support infrequent subcutaneous dosing. This new class of drugs was then validated by showing unprecedented improvements in glycemic control and body weight reduction in multiple rodent models of obesity and insulin resistance. Aiming at efficient translation into clinical medicine, we designed and supervised the validation of the rodent observation with first-generation forms of these poly-agonists in non-human primate studies and subsequently in the first clinical trials. The results triggered numerous pharmaceutical interests and led to multiple competitive dual and triple agonist versions now advancing in mid and late-stage clinical trials, reflecting medicinal importance of the discovery and validating the reproducibility of their pioneering science. Tirzepatide/Mounjaro/Zepbound (Eli Lilly & Co) represents one of the initial members of the newly discovered class of dual agonist drugs and was FDA-approved last year for treating type 2 diabetes. It synergistically integrates GIP and GLP-1 receptor agonist pharmacology into a single molecule, as we had first discovered and reported in 2013. The GIP/GLP-1 dual agonist Tirzepatide/Mounjaro/Zepbound has been approved for treatment of obesity and diabetes by the regulatory agencies and achieves an average of 22.5% weight loss in clinical obesity, a milestone achievement previously thought to be impossible. Multiple other versions of such dual and triple agonist classes of drugs are successfully underway including several in clinical phase III trials.

Biosketch

Matthias Tschöp is the CEO of Helmholtz Munich, Vice President of the German Helmholtz Association and Alexander-von-Humboldt Professor at the Technical University of Munich. Tschöp unraveled fundamental gut-brain signals to discover the first highly effective drugs for human obesity in collaboration with the chemist Richard DiMarchi - the dual and triple gut hormone multi-agonists. A first representative is FDA-approved, others are successfully progressing through clinical trials. Tschöp has received numerous honors and awards, including the Banting Medal (2023), the Heinrich Wieland Prize (2023), the Schering Prize (2023), the EASD-Lilly Centennial Prize (2022) and the Ernst Jung Prize (2021). He holds an adjunct professorship at Yale University and an honorary doctorate at Leipzig University. He was elected a member of the German, Bavarian, and European Academies of Sciences, the American Society for Clinical Investigation and the Association of American Physicians.