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

ABSTRACT: 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.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.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.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.

SUBMITTER: Pietra C

PROVIDER: S-EPMC4248409 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Pietra Claudio C Takeda Yasuhiro Y Tazawa-Ogata Naoko N Minami Masashi M Yuanfeng Xia X Duus Elizabeth Manning EM Northrup Robert R

Journal of cachexia, sarcopenia and muscle 20140930 4

<h4>Background</h4>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.<h4>Methods</h4>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 AN ...[more]

PMID: 25267366

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Project description:BackgroundCancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI).MethodsThis multicenter, open-label, single-arm study enrolled Japanese patients with non-small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI < 20 kg/m2 , involuntary weight loss > 2% in the last 6 months, and anorexia). Patients were administered 100 mg of anamorelin once daily for up to 24 weeks. The primary end point was a composite clinical response (CCR) at 9 weeks, which was defined as an increase in body weight of ≥5% from the baseline, an increase of ≥2 points in the score of the 5-item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia Therapy, and being alive.ResultsOne hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/m2 , respectively. The CCR rate at 9 weeks was 25.9% (95% confidence interval [CI], 18.3%-35.3%), which met the primary end point with a lower 95% CI exceeding the prespecified minimum of 8%. Improvements in body weight and anorexia were durable and were accompanied by improvements in patients' global impression of change for appetite/eating-related symptoms and overall condition. Adverse drug reactions occurred in 37 of 101 treated patients (36.6%), with the most common being glycosylated hemoglobin increases, constipation, and peripheral edema.ConclusionsAnamorelin improved body weight and anorexia-related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability.Lay summaryAnamorelin is a drug that stimulates appetite and promotes weight gain. This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss. Anamorelin was found to improve body weight and anorexia-related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated. These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index.

Project description:Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia.This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100?mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results.The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38?±?0.18 and -0.17?±?0.17?kg in the anamorelin and placebo groups, respectively (P?<?.0001). Changes from the baseline in LBM, body weight, and anorexia symptoms showed significant differences between the 2 treatment groups at all time points. Anamorelin increased prealbumin at weeks 3 and 9. No changes in HGS or 6MWT were detected between the groups. Twelve weeks' treatment with anamorelin was safe and well tolerated in NSCLC patients.Anamorelin significantly increased LBM and improved anorexia symptoms and the nutritional state, but not motor function, in Japanese patients with advanced NSCLC. Because no effective treatment for cancer cachexia is currently available, anamorelin can be a beneficial treatment option. Cancer 2018;124:606-16. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Dataset Information

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

Publications

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

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