Engineering of an Ultralong-Acting and Nonaggregating Dual Amylin and Calcitonin Receptor Agonist with Durable Efficacy in Obesity and Diabetes

Synergistic activation of amylin and calcitonin receptors represents a distinct strategy for the treatment of obesity and diabetes. However, the inherent fibrillogenic aggregation propensity and short half-life pose significant challenges for their therapeutic translation. Here, we disclose the discovery and preclinical studies of TPM004, an ultralong-acting and nonaggregating dual amylin and calcitonin receptor agonist, endowed with balanced bioactivity. TPM004 displayed an extended half-life compatible with once-biweekly dosing in humans. In the DIO rat models, TPM004 produced robust and durable weight loss with preferential fat reduction while attenuating post-treatment adiposity rebound. TPM004 also demonstrated a prominent glucose-lowering efficacy and improved glucose homeostasis in the ZDF rats. Toxicology studies demonstrated broad safety margins for supratherapeutic exposures. Overall, these findings not only establish TPM004 as a novel DACRA preclinical candidate with strong translational promise but also represent a new paradigm for challenging peptide modifications through a long-acting helical stapling strategy.