Randomized Controlled Phase Ib Study of Ghrelin Agonist, RM-131, in Type 2 Diabetic Women With Delayed Gastric Emptying

Shin, Andrea; Camilleri, Michael; Busciglio, Irene; Burton, Duane; Stoner, Elizabeth; Noonan, Patrick K.; Gottesdiener, Keith; Smith, Steven A.; Vella, Adrian; Zinsmeister, Alan R.

doi:10.2337/dc12-1128

Cited by 99 publications

(100 citation statements)

References 41 publications

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“…This observation highlights the unresolved question of whether the low-fat, EggBeaters meal is even the optimal solid meal substrate; indeed, significantly different emptying between the EggBeaters meal and a radiolabeled liver at 3 h was reported in the original report ''validating'' the EggBeaters meal [1]. GES also has utility in the evaluation of the motility effects of drugs, such as has been reported for studies utilizing the 2 % fat EggBeaters meal [7,8] and with the higher-calorie (296 kcal) and 32 % fat scrambled eggs meal [9,10].…”

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confidence: 95%

Novel and Validated Approaches for Gastric Emptying Scintigraphy in Patients with Suspected Gastroparesis

Camilleri

Shin

2013

Dig Dis Sci

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Controversy exists regarding the relation of upper gastrointestinal symptoms to gastroparesis, which centers on the reportedly weak correlation between symptoms and gastric emptying (GE) measurements. Appropriate management of patients with suspected gastroparesis thus requires the use of validated assessments of GE.GE scintigraphy (GES) using a low-fat EggBeaters (chicken egg white) meal (ConAgra Foods Inc., Omaha, NE, USA) [1] is regarded as the gold standard due to standardized procedures, methods, and well-established normal values. Although this meal has the advantage of good tolerability by the majority of symptomatic patients, there are potential drawbacks: a few patients may not tolerate any solid meal, or the low fat and caloric content may not be able to adequately stress the system, failing to identify impaired gastric motor function in a subset of individuals. Therefore, identification of an alternative, appropriate test meal may be important for clinical and research applications.In this issue, Sachdeva et al.[2] compared GE of the low-fat EggBeaters solid meal (255 kcal containing 2 % fat, 24 % protein, 72 % carbohydrate, and 2 % fiber) to an Ensure Plus (Abbott Laboratories, North Chicago, IL, USA) liquid meal (350 kcal containing 28 % fat, 15 % protein, 57 % carbohydrate, and no fiber) to identify a valid alternative for patients unable to consume the standard low-fat egg-white meal. On separate days, 20 healthy volunteers participated in a well-designed prospective study comparing GES with these two meals; simultaneously, the authors evaluated gastric contractility using a wireless motility capsule (WMC) during both assessments.The objectives were to demonstrate feasibility and to provide hypothesis-generating data (e.g., definition of coefficient of variation [COV; standard deviation/mean] to facilitate the design of future studies).The conclusion that GE of a liquid nutrient meal is similar to that of low-fat egg-white meal (of similar calorie content) is valid, at least in healthy subjects. Nevertheless, as acknowledged by the authors, their results will require replication in a larger cohort, and in subjects with suspected gastroparesis who might differ from a healthy population in terms of having differential GE of solid versus liquid meals. Jones et al. [3] previously reported a significant but weak (r = 0.42, p \ 0.01) correlation between GE of solids and nutrient-containing liquids among 86 patients with diabetes mellitus. In the study by Sachdeva et al. [2], the correlation between the GE T 1/2 of the two meals was similarly weak (r = 0.53) among healthy subjects, suggesting that there are significant intraindividual differences in the emptying of the two meals, and that less than 30 % of the variance is attributable to the same mechanisms for emptying of the two types of meals.It is also necessary to clarify the inter-individual COV with the EggBeaters and the liquid nutrient meal. Diagnostic interpretation of GE T 1/2 by GES in an individual patient requires robust definition of the i...

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confidence: 95%

Novel and Validated Approaches for Gastric Emptying Scintigraphy in Patients with Suspected Gastroparesis

Camilleri

Shin

2013

Dig Dis Sci

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“…Improvements in in GE Tlag, GE T1/2 liquids, and colonic filling at 6 hours were observed, although not statistically significant. No significant effects was observed for total GCSI-DD score or composite scores for nausea, bloating postprandial fullness and pain; however, the study was not powered for these endpoints and baseline symptom severity was not a criterion for study eligibility [86].…”

Section: Current Clinical Trials Of Ghrelin Agonists In Gastroparesismentioning

confidence: 99%

“…In pre-clinical studies prior to acquisition of RM-131 by Rhythm Pharmaceuticals, RM-131 has been shown to cause a dose-dependent increase in food intake and weight gain (both fat and lean mass) with greater potency than human ghrelin [85]. In a rat models, RM-131 was successful in reversing postsurgical, opiate-induced gastric ileus while in normal, nonsurgical primates, RM-131 increased the GE rate [86]. RM-131 also displayed anti-inflammatory effects and increased survival in models of inflammatory bowel disease.…”

Section: Current Clinical Trials Of Ghrelin Agonists In Gastroparesismentioning

confidence: 99%

“…RM-131 was found to be safe and well tolerated in both trials, with no serious adverse events reported and no clinically significant impact on physical examination, ECG parameters, vital signs, or routine hematology and chemistry laboratory tests [86,87]. Although results of initial clinical trials with RM-131 have been promising, larger scale studies will be required to address generalizability and establish medium and long-term efficacy of this agent.…”

Section: Current Clinical Trials Of Ghrelin Agonists In Gastroparesismentioning

confidence: 99%

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Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Shin

2015

Curr Gastroenterol Rep

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There remains an unmet need for effective pharmacologic treatments for gastroparesis.Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101 initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131 was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis.

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“…36,37 Moreover, RM-131 exerts improved stability, greater potency, and longer plasma half-life. 36,38 RM-131 may be used in the treatment of gastroparesis, since in gastroparesis RM-131 accelerates gastric emptying without causing severe adverse effects.…”

Section: Relamorelinmentioning

confidence: 99%

Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

Mosińska

Zatorski

Storr³

et al. 2017

J Neurogastroenterol Motil

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There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients' quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation.

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Randomized Controlled Phase Ib Study of Ghrelin Agonist, RM-131, in Type 2 Diabetic Women With Delayed Gastric Emptying

Cited by 99 publications

References 41 publications

Novel and Validated Approaches for Gastric Emptying Scintigraphy in Patients with Suspected Gastroparesis

Novel and Validated Approaches for Gastric Emptying Scintigraphy in Patients with Suspected Gastroparesis

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

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