Relamorelin

Relamorelin (RM-131, BIM-28131) is a synthetic pentapeptide analog of ghrelin that activates the growth hormone secretagogue receptor type 1a (GHSR-1a) with approximately three- to sixfold greater binding affinity and functional potency than native human ghrelin, and with substantially enhanced plasma stability and a terminal elimination half-life of approximately 4.5 to 19.4 hours depending on dose and measurement interval. The compound was originally synthesized by Ipsen as BIM-28131 and subsequently developed by Rhythm Pharmaceuticals (as RM-131), Motus Therapeutics, Allergan, and AbbVie for gastrointestinal motility disorders, principally diabetic gastroparesis, chronic idiopathic constipation, and anorexia nervosa. Relamorelin accelerates gastric emptying through activation of ghrelin receptors expressed on enteric neurons, interstitial cells of Cajal, and gastric smooth muscle, producing dose-dependent increases in antral contractile frequency and propagated colonic contractions without inhibition of gastric accommodation or induction of early satiation. In nonclinical studies, the compound reversed morphine-induced gastroparesis in Sprague-Dawley rats at potencies approximately 100-fold greater than native ghrelin and stimulated gastrointestinal transit throughout the small and large intestine. In clinical trials, relamorelin administered subcutaneously at 10 to 100 micrograms once or twice daily significantly accelerated gastric emptying half-time (mean difference of approximately 8 to 11 minutes versus placebo), reduced vomiting frequency by approximately 60 to 75 percent in diabetic gastroparesis populations with documented delayed gastric emptying, and improved composite symptom scores for nausea, bloating, abdominal pain, and early satiety. A Phase 2 trial in chronic idiopathic constipation demonstrated significant acceleration of colonic transit at 32 and 48 hours and increased spontaneous bowel movement frequency over 14 days of treatment. A proof-of-concept randomized trial in outpatient women with anorexia nervosa demonstrated significant reduction in gastric emptying time (median 58 versus 85 minutes) and a trend toward weight gain after four weeks of treatment. The principal adverse events observed across clinical programs were hyperglycemia (reflecting accelerated nutrient delivery to the small intestine in diabetic populations), diarrhea, headache, and dizziness, with no clinically significant injection site reactions. Growth hormone, prolactin, and cortisol elevations were observed as expected pharmacodynamic consequences of GHSR-1a activation. Allergan initiated a Phase 3 program (PLEDGE) comprising two pivotal 12-week randomized controlled trials in diabetic gastroparesis beginning in 2018; however, in September 2020, the program was terminated following the AbbVie acquisition of Allergan, and the compound is not currently in active clinical development. Relamorelin is not approved by any regulatory authority. It remains available as a research-grade compound from multiple chemical suppliers and is the subject of ongoing academic interest as both a pharmacological tool for ghrelin receptor biology and a potential therapeutic candidate for gastrointestinal dysmotility syndromes. This monograph reviews the chemistry, structure, and synthesis of relamorelin; the molecular pharmacology at the GHSR-1a receptor; comprehensive pharmacokinetics; preclinical gastrointestinal pharmacology; the clinical evidence base across diabetic gastroparesis, chronic constipation, and anorexia nervosa indications; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety signals; and a comparative assessment of five gastroparesis therapeutic candidates against relamorelin on five competency standards.