The hormone ghrelin plays a vital role in the function of the digestive system, being involved in GI motility, digestion and the absorption of nutrients. Previous drugs targeting the dopamine and serotonin receptors that were designed to have an effect in motility disorders had safety issues, and while small molecule ghrelin agonists have been developed in the past, their efficacy and potency were limited.
An alternative, relamorelin, is being investigated by Rhythm Pharmaceuticals.1 It is a pentapeptide that retains ghrelin’s specificity and functionality, but is more potent than both previous drugs and ghrelin itself.
Several early stage trials have been carried out. In one, the safety and efficacy of single doses of relamorelin on gastric emptying and upper gastrointestinal symptoms were evaluated in patients with Type I diabetes who were experiencing delayed gastric emptying.2 In the double blind, cross-over study, 10 patients were given a single 100µg subcutaneous dose of relamorelin or placebo, followed 30 minutes later by a radiolabelled solid–liquid meal. They then underwent four hours of gastric emptying and six hours of colonic filling analyses, with measurements made by scintigraphy. After dosing with the active, the median time to solid gastric emptying was just over half an hour faster than with placebo. Upper gastrointestinal symptoms were also improved. However, the numeric differences in half-life for gastric emptying of liquids and colonic filling after six hours were not significant.
Similar results were also seen in another Phase Ib trial in 10 female diabetic women with delayed gastric emptying, this time designed to investigate its pharmacokinetics, pharmacodynamics and safety compared with healthy volunteers.3 In addition to a significant improvement in gastric emptying, there was no significant difference in pharmacokinetics between the diabetic and healthy volunteer groups, and only light-headedness as a side-effect was reported by more of those given the drug.
As ghrelin receptors are also present in the colon, its effects on the bowel have also been investigated, in a Phase II randomised, double blind, parallel group, placebo controlled trial.4 The 48 female patients in the study had chronic constipation, with four or fewer spontaneous bowel movements a week. Subjects were given 100µg daily subcutaneous doses of relamorelin or placebo every day for 14 days, following on from a single-blind phase in which all patients were given a placebo dose. Those given the drug had accelerated gastric emptying, small bowel transit and colonic transit, as measured during the final two days of the trial dosing. It also increased the number of spontaneous bowel movements, and accelerated the time to first bowel movement after the first dose was given. Side-effects resulting from the drug included fatigue, headache and an increased appetite.
Trials continue, both in these indications and in the treatment of anorexia nervosa. A trial is also underway for refractory chronic constipation in patients with Parkinson’s disease. It has been given fast track status by the FDA for diabetic gastroparesis.
References
1. M. Camilleri and A. Acosta, Neurogastroenterol. Motil. 2015, 27, 324
2. A. Shin et al. Clin. Gastroenterol. Hepatol. 2013, 11, 1453
3. A. Shin et al. Diabetes Care. 2013, 36, 41
4. A. Acosta et al. Clin. Gastroenterol. Hepatol. 2015, May, epub ahead of print
