BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.
“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.
Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).
Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.
During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).
Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).
One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.
Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.
TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.
Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.