465P - The preclinical pharmacological profile of anamorelin/ONO-7643, a new ghrelin receptor agonist for the treatment of cancer cachexia

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Claudio Pietra
Authors C. Pietra1, Y. Takeda2, N. Tazawa-Ogata2, M. Minami2, X. Yuanfeng3, E. Duus4, R. Northrup4
  • 1Research And Preclinical, Helsinn Healthcare SA, 6915 - Pambio Noranco/CH
  • 2Discovery Research Laboratories, ONO Pharmaceutical, Osaka/JP
  • 3In Vitro Assay, HDB Biosciences, Shanghai/CN
  • 4Rd, Helsinn Therapeutics Inc., Bridgewater, NJ/US

Abstract

Introduction

Ghrelin is the only known circulating orexigenic hormone which acts as the endogenous ligand for the ghrelin receptor (GRLN), and is considered a potential agent to treat cancer cachexia/anorexia. The aim of this study was to evaluate the in vitro and in vivo pharmacological activities of Anamorelin/ONO-7643 (ANA), a new synthetic ghrelin receptor agonist, on food intake (FI), body weight (BW) and GH in rats.

Material and methods

HEK293 cells expressing human recombinant ghrelin receptor were utilized in a Fluorescent Imaging Plate Reader (FLIPR), along with Fluo-8 dye to signal intracellular calcium. Ghrelin and ANA were incubated (0.001-1000 nM) to generate a concentration-response increase of Ca++. Binding experiments were also performed by using [125I]Ghrelin. In vivo experiments were performed on male SD rats after oral treatment of ANA or vehicle. FI and BW were measured daily from Day 1 up to Day 7 of once-daily treatment. In other experiments, blood samples were collected at different time interval up to 6 hours post single dose for GH measurements.

Results

Ghrelin and ANA showed a significant agonist activity on the ghrelin receptor in the FLIPR assay, with EC50 values of 0.67 nM and 0.74 nM, respectively. No significant antagonist activity was observed with ANA up to 1000 nM. In binding experiments, the affinity of ghrelin and ANA for ghrelin receptors were evaluated and resulted in a Ki of0.58 nM and 0.70 nM, respectively. In the in vivo experiments, ANA (3, 10, 30 mg/kg p.o.) significantly (p < 0.05 vs vehicle ) increased FI and BW gain.The effect on FI was stable from Day 2 to Day 7 of treatment. ANA at the same doses increased GH AUC0-6h and induced an increase in plasma GH levels. The effect was dose-dependent, and GH AUC0-6h at 10 and 30 mg/kg p.o. were significantly higher (p < 0.05) than vehicle-treated animals.

Conclusions

Anamorelin is a potent ghrelin agonist endowed with significant orexigenic activity demonstrating both an increase of FI and BW after subchronic treatment in rats. Plasma GH levels were increased after a single administration of ANA. These results support the continued investigation of Anamorelin as a potential treatment of cancer cachexia/anorexia.

Disclosure

C. Pietra: Employee of Helsinn SA.

Y. Takeda: Ono employee.

N. Tazawa-Ogata: ONO employee.

M. Minami: ONO Employee.

E. Duus: Helsinn Therapeutics employee.

R. Northrup: Helsinntheraputics employee.

All other authors have declared no conflicts of interest.