Comprehensive Analysis of Anamorelin (DB06645): A Ghrelin Receptor Agonist for Cancer Anorexia-Cachexia Syndrome

Executive Summary

Anamorelin is a first-in-class, orally bioavailable, small-molecule, selective ghrelin receptor agonist developed to address the profound unmet medical need of cancer anorexia-cachexia syndrome (CACS).[1] CACS is a debilitating multifactorial condition characterized by loss of appetite and a progressive wasting of skeletal muscle and adipose tissue, which is associated with poor prognosis, reduced tolerance to cancer therapies, and diminished quality of life.[4] The therapeutic rationale for Anamorelin is rooted in its ability to mimic the physiological actions of ghrelin, an endogenous peptide often termed the "hunger hormone".[7]

The core mechanism of Anamorelin involves potent and specific stimulation of the growth hormone secretagogue receptor type 1a (GHSR-1a).[7] This action initiates a dual-pronged physiological response. Centrally, it stimulates hypothalamic pathways to increase appetite and food intake (orexigenic effect). Concurrently, it triggers the pulsatile release of growth hormone (GH) from the pituitary gland, which in turn stimulates hepatic production of insulin-like growth factor-1 (IGF-1). This activation of the GH/IGF-1 axis promotes anabolism, leading to the synthesis of muscle protein and an increase in lean body mass (LBM).[7]

Pivotal clinical evidence for Anamorelin is derived from the global, Phase III ROMANA 1 and ROMANA 2 trials. These studies unequivocally demonstrated that Anamorelin treatment in patients with non-small cell lung cancer (NSCLC) and cachexia resulted in a statistically significant increase in LBM compared to placebo over 12 weeks. However, the program failed to meet its co-primary functional endpoint, showing no significant improvement in handgrip strength (HGS).[12]