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

Journal of Cachexia, Sarcopenia and Muscle

Pietra Claudio¹  Takeda Yasuhiro³  Tazawa-Ogata Naoko³  Minami Masashi³  Yuanfeng Xia⁴  Duus Elizabeth Manning² 

[1] Helsinn Healthcare SA, Research and Preclinical Department, Lugano;Helsinn Therapeutics Inc., Bridgewater, NJ;ONO Pharmaceutical Co., Ltd, Discovery Research Laboratories, Osaka;HD Biosciences, Shanghai

关键词: Anamorelin HCl;    Ghrelin receptor agonist;    Cancer anorexia-cachexia syndrome;    Body weight;    Growth hormone;   

DOI  :  10.1007/s13539-014-0159-5

来源: Wiley

【 摘 要 】

Abstract

Background

Anamorelin 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.

Methods

Fluorescent 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.

Results

ANAM 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.

Conclusion

ANAM 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.

【 授权许可】

CC BY-NC   
© 2014 The Authors. Published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders

Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.