Anamorelin HCl (ONO‐7643), a novel ghrelin receptor agonist, for the treatment of cancer anorexia‐cachexia syndrome: preclinical profile

Abstract

BackgroundAnamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.MethodsFluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.ResultsANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.ConclusionANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.

Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

“…Furthermore, it has better half life (7-12 h) compared to ghrelin (0.5 h) [69][70][71]. Though results of this drug are quite promising for cachexia treatment, further controlled studies with large sample size are still required to understand its efficacy and safety.…”

The wasting continuum in heart failure: from sarcopenia to cachexia

“…Therapeutic effects included increases in lean mass as well as in fat mass (114) . Ghrelin receptor agonists such as anamorelin are currently also undergoing clinical testing and can achieve increases in body weight as well as appetite, but studies have so far focused on cancer cachexia, and large-scale studies are still missing (115)(116)(117)(118) . Besides, several myostatin antibodies are currently in development and are being tested in clinical trials.…”

Ghrelin for the management of cachexia associated with cancer

“…Ghrelin, a novel orexigenic gut hormone, is primarily secreted by the endocrine X/A-like cells of the stomach mucosa and also by intestinal mucosa, arcuate nucleus of the hypothalamus, pituitary gland, pancreatic islets, and other tissues (Khatib 2015b). Studies have shown that this 28-amino acid peptide hormone is an endogenous ligand for the growth hormone secretagogue receptor and can be a potential therapeutic agent for cachexia-associated cancer (Chen 2015;Garcia 2015;Pietra 2014;Tsubouchi 2014;Zhang 2015). It has shown promising results in randomised clinical trials (Garcia 2007;Garcia 2013;Garcia 2015;Khatib 2014b;Khatib 2014e;Madeddu 2015b).…”

“…Ghrelin agonists are being developed and tested for the treatment of anorexia/cachexia. Anamorelin, a first-in-class, potent orallyactive and highly-specific ghrelin receptor agonist, increases food intake, body weight and lean body mass (Northrup 2013;Pietra 2014). It is well tolerated with no dose-limiting toxicities (Zhang 2015).…”