Relamorelin in patients with diabetic gastroparesis: Efficacy and safety results from a phase 2B randomized, double-blind, placebo-controlled, 12-week study (RM-131-009)

Background: Gastroparesis is a serious complication of diabetes mellitus (DM) with few treatment options. Relamorelin (RM-131) [RM] is a selective ghrelin agonist with potent prokinetic properties. Aims: To evaluate the efficacy of RM on symptoms and gastric emptying (GE) in patients with moderate to severe diabetic gastroparesis (DG). Methods: This was a 12-week, randomized, double-blind, placebo (PBO)-controlled, parallel-group study, with a 2-week single-blind PBO run-in. Eligible DG patients had 13C-spirulina GE breath test T1/2 values ≥79 min, a history of recent vomiting, and a Gastroparesis Cardinal Symptom Index score ≥2.6 (actual range 2.6 to 4.9), and were randomized to twice daily subcutaneous injections of PBO or RM: 10 μg, 30 μg, or 100 μg. Patients completed the Diabetic Gastroparesis Symptom Severity Diary (DGSSD), a daily e-Diary designed to collect patient-reported vomiting frequency and symptoms of nausea, abdominal pain, post-prandial fullness (PPF), and bloating on a 0-10 scale. The primary endpoint was change from baseline in vomiting frequency; a key secondary endpoint was change from baseline in a 4-symptom composite of DGSSD symptoms. Weekly normalized DG symptom scores were analyzed for change from baseline through Week 12. A longitudinal, mixed-effects model using repeated measures, with baseline and baseline-by-week interaction values as covariates, was used to assess treatment effects over time. Safety was evaluated by vital signs, adverse events, and laboratory assessments. Results: A total of 393 DG patients (male: 37.7%; age: 57.0 ± 11.3 years; BMI: 32.4 ± 7.3 kg/m2; mean HbA1c: 7.7 ± 1.4%; Type 1 DM: 9.9%) were randomized at clinic sites in the US, Israel, and Europe. RM led to ∼75% reduction in vomiting frequency compared to baseline (primary endpoint) across all doses tested; however, no significant difference vs. PBO was observed due to a high PBO response. RM demonstrated substantial efficacy at all 3 doses tested, with reductions in key DG symptoms of nausea, PPF, abdominal pain, and bloating measured as a composite endpoint (Table). DG symptoms improved vs. PBO for all RM doses over the entire 12-week study period (Figure); these composite scores reflect the individual results in nausea, PPF, abdominal pain, and bloating.RM also accelerated GE at all 3 doses compared to PBO (Table). RM was generally safe and well tolerated with high compliance and study completion rates. Worsening of glycemic control was noted as an adverse event in some RM patients after treatment initiation. Conclusions: The prokinetic RM demonstrated clinically meaningful reductions in core DG symptoms and overall composite score, and was generally safe and well tolerated. A high PBO response limited the ability to show efficacy of RM vs. PBO for the vomiting frequency endpoint. Table. Change from baseline to Week 12 in DGSSD (4-symptom composite scorea) and GEBTb (Table presented) Full analysis set aNausea, post-prandial fullness, abdominal pain, bloating; composite score in total numeric points; bGEBT (Tin min); cAnalysis done on change-from-baseline data for sum of weekly averages of 4 individual symptom scores (nausea, abdominal pain, postprandial fullness, and bloating); dTwo-sided p-value from longitudinal, mixed-effects model with repeated measures, including fixed effects for treatment, week, and treatment-by-week interaction, as well as baseline and baseline-by-week interaction values as the covariates with unstructured variance-covariance correlation matrix being common to all subjects for the repeated measures over treatment weeks BID, twice daily; DGSSD, Diabetic Gastroparesis Symptom Severity Diary; GEBT, gastric emptying breath test; LS, least squares; PBO, placebo; RM, relamorelin; SD, standard deviation.