Overall safety of relamorelin in adults with diabetic gastroparesis: Analysis of phase 2a and 2b trial data

Abstract

Background: Relamorelin, a pentapeptide ghrelin receptor agonist, accelerated gastric emptying significantly and improved symptoms in adults with diabetic gastroparesis in phase 2 trials. Aim:To assess the safety and tolerability of relamorelin across phase 2 trials. Methods: Safety assessments in patients aged 18-75 years (weight, adverse events [AEs] and laboratory tests) from two randomised, double-blind phase 2 trials (NCT01571297, NCT02357420; results published previously) were reviewed descriptively. Analysis of covariance assessed treatment effect on glycated haemoglobin (HbA1c) and blood glucose post hoc. Phase 2a and 2b trial durations were, respectively, 4 weeks (relamorelin 10 µg once or twice daily [b.d.] or placebo b.d.) and 12 weeks (relamorelin 10, 30 or 100 µg or placebo b.d.) with 1-and 2-week, singleblind placebo run-ins.Results: Among 204 phase 2a and 393 phase 2b patients, respectively, 67% and 62% were female, and 88% and 89% had type 2 diabetes. Proportions of patients reporting serious AEs were similar across treatment groups, as were those with ≥1 treatment-emergent AE (TEAE). TEAE-related discontinuations were proportionally higher in relamorelin groups than placebo. Of 12 serious TEAEs in phase 2a, none occurred in >1 patient. In phase 2b, five serious TEAEs were reported in >1 patient, and one (100 µg) died (urosepsis), all unrelated to relamorelin. In phase 2b, increased HbA1c and fasting blood glucose levels were dose-related (P < 0.0001 and P = 0.0043, respectively). Conclusions:Relamorelin showed acceptable safety and tolerability in phase 2 trials. Relamorelin may elevate blood glucose: this should be managed proactively in relamorelin-treated patients.

Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double‐blind, randomised, placebo‐controlled, phase 2 study

“…1,9,12,16,19,[29][30][31] Relamorelin-a pentapeptide ghrelin receptor agonist with prokinetic properties that significantly accelerated GE and improved symptoms in phase 2 trials-is under development only in patients with diabetic gastroparesis. 32,33 In this study, velusetrag was generally well tolerated in subjects with gastroparesis, with no new safety or tolerability findings relative to previous studies of velusetrag and the specific 5-HT 4 agonist prucalopride in subjects with chronic constipation. 20,34,35 As expected, most TEAEs were GI-related.…”

“…Metoclopramide is not approved in the EU for gastroparesis treatment and is approved by the FDA only for short‐term treatment of diabetic gastroparesis; domperidone, erythromycin and prucalopride may be used off‐label for their prokinetic properties for symptom relief but are not approved in the US or EU for gastroparesis treatment 1,9,12,16,19,29‐31 . Relamorelin—a pentapeptide ghrelin receptor agonist with prokinetic properties that significantly accelerated GE and improved symptoms in phase 2 trials—is under development only in patients with diabetic gastroparesis 32,33 …”

Editorial: a need for glucose monitoring on prokinetic treatment with a ghrelin agonist in diabetic gastroparesis?

“…We acknowledge that less potent prokinetics may not significantly affect glycaemic control; cisapride, for example, was not associated with significant glycaemic disturbances over a 28-day period. 3 However, the literature indicates that the rate of gastric emptying is a major determinant of both early and overall postprandial glycaemia, 4 and faster gastric emptying (induced by erythromycin) was associated with greater postprandial glucose measurements in 30 patients with type 1 diabetes mellitus treated with an insulin pump. 5 Moreover, after adjusting for carbohydrate intake and insulin consumption, faster gastric emptying was associated with increased postprandial hyperglycaemia but lower glucose values across the study overall.…”

New Developments in Prokinetic Therapy for Gastric Motility Disorders

“…Relamorelin also increased distal antral contraction frequency without impeding gastric accommodation or altering postprandial satiation in healthy volunteers Figure 2 ( Nelson et al, 2016 ), which differentiates its effects from those of the macrolide antibiotic, erythromycin. In phase 2A and 2B, randomized, controlled trials in patients with diabetic gastroparesis, relamorelin improved clinical symptoms and appears to be safe, other than the induction of (typically postprandial) hyperglycemia which is attributable to the acceleration of gastric emptying ( Lembo et al, 2016 ; Camilleri et al, 2017 ; Camilleri et al, 2020 ). It has therefore been recommended that proactive steps should be taken to control postprandial glycemia in diabetics receiving relamorelin ( Camilleri et al, 2020 ).…”