Novel Therapeutics:
LEAP2 Switch Therapeutics: Bidirectional Control of Ghrelin Signaling for Obesity/MASLD and Cachexia
Jeffrey M. Zigman, M.D., Ph.D.
- Department of Internal Medicine (Division of Endocrinology), with a secondary appointment in the Department of Psychiatry, UT Southwestern Medical Center
LEAP2 Switch Therapeutics is developing a single, unifying platform enabling bidirectional control of ghrelin signaling to treat both obesity/MASLD and cancer cachexia. The platform is centered on LEAP2, a natural antagonist and inverse agonist of the ghrelin receptor (GHSR), which functions as a molecular "switch": turning the switch ON by enhancing LEAP2 activity suppresses ghrelin signaling to drive meaningful weight loss and improve liver pathology in obesity and MASLD, while turning the switch OFF by blocking or neutralizing LEAP2 disinhibits ghrelin's protective effects to counteract cancer-associated cachexia. The pipeline includes a LEAP2-based “switch ON” peptide–peptide conjugate supported by proof-of-principle mouse data demonstrating superior weight-loss efficacy versus either peptide alone, as well as a deliberately multimodal, "switch OFF" cachexia program (anti-LEAP2 aptamers, shRNA, humanized antibodies, and small molecules) supported by early functional neutralization data and a defined path to IND.
