title: Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131.
abstract: OBJECTIVE
  The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease.
  
  
  METHODS
  We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131.
  
  
  RESULTS
  The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies.
  
  
  CONCLUSIONS
  RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans.
authors.affiliation: Rhythm Pharmaceuticals Inc., United States. Electronic address: lvanderploeg@rhythmtx.com.
authors.forename: Lex
authors.initials: L
authors.lastname: Van der Ploeg
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Haley
authors.initials: H
authors.lastname: Laken
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Shubh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Ipsen, France.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Datta
authors.affiliation: Ipsen, France.
authors.forename: Heather
authors.initials: H
authors.lastname: Halem
authors.affiliation: Ipsen, France.
authors.forename: Jesse
authors.initials: J
authors.lastname: Dong
authors.affiliation: Ipsen, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Touvay
authors.affiliation: Ipsen, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Teillot
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Noonan
authors.affiliation: Third Rock Ventures, United States.
authors.forename: Lou
authors.initials: L
authors.lastname: Tartaglia
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Liz
authors.initials: L
authors.lastname: Stoner
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Bart
authors.initials: B
authors.lastname: Henderson
authors.affiliation: Rhythm Pharmaceuticals Inc., United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.affiliation: Ipsen, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Culler
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use; D048909:Diabetes Complications / Q000188:drug therapy; D004285:Dogs; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000737:chemistry* / Q000627:therapeutic use*; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D005769:Gastrointestinal Motility / Q000187:drug effects; D018589:Gastroparesis / Q000188:drug therapy; D054439:Ghrelin / Q000737:chemistry* / Q000627:therapeutic use*; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D045823:Ileus / Q000188:drug therapy; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D054439:Ghrelin; D013006:Growth Hormone
keywords: Diabetic gastroparesis; Gastrointestinal; Ghrelin; Inflammatory bowel disease; Prokinetic