Phase 2b, randomized, double-blind 12-week studies of TZP-102, a ghrelin receptor agonist for diabetic gastroparesis

BackgroundTZP-102, a potent, oral, ghrelin receptor agonist, improved diabetic gastroparesis symptoms in Phase 2a. MethodsPatients with type 1 or 2 diabetes, delayed gastric half-emptying (T-1/2), and 3months gastroparesis symptoms randomized 1:1:1 to double-blind placebo, 10-mg, or 20-mg TZP-102 once daily for 12weeks (Study TZP-102-CL-G003). Study TZP-102-CL-G004 patients randomized 1:1 to 10-mg TZP-102:placebo three-times-daily. Primary endpoint was change-from-baseline through Weeks 11-12 in Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) via electronic Patient Recorded Outcome device: worst severity of nausea, early satiety, bloating, and upper abdominal pain in 24h (0=none-to-5=very severe). GSDD Composite Score for eligibility was 2.5 (Day-14-to-baseline). Patient Overall Treatment Evaluation (OTE) provided an anchor-based minimal clinically important difference (MCID) for GSDD Composite Score. Key ResultsStudy TZP-102-CL-G003 enrolled 201 outpatients: females 72%; Caucasians 87%; type 2 diabetes 61%; insulin-dependent 65%; age meanSD 53 +/- 11.3years; HbA1c 7.8 +/- 1.5%; GCSI 3.4 +/- 0.7; GSDD Composite 3.6 +/- 0.6; gastric T-1/2 131 +/- 32min; n=69 (10-mg), n=66 (20-mg), n=66 (placebo). Primary endpoint (GSDD): significant improvement in all arms, although not for TZP-102 vs placebo: mean change-from-baseline -1.7, -1.4, -1.5 (10-mg, 20-mg, placebo); Gastroparesis Cardinal Symptom Index -1.8, -1.6, -1.5, respectively. The OTE (all patients) at Week-12 was: Patient 3.7 +/- 3.2 and Physician 3.6 +/- 3.0 with median score for both of 5.0=important on scale of improvement; individual MCID was 1.61 and 0.94 for group analyses, greater than expected. Study TZP-102-CL-G004 with similar demographic/disease characteristics was prematurely terminated for efficacy futility (n=64 with Week-4 assessments). Conclusions & InferencesEfficacy of TZP-102 was not demonstrated compared with placebo in diabetic gastroparesis; however, there was substantial symptom improvement in all arms (ClinicalTrials.gov NCT01452815/NCT01664637).