Novel Drug Relieves Carcinoid Syndrome Symptoms


Telotristat etiprate, a novel serotonin synthesis inhibitor, helped reduce daily bowel movements for patients with carcinoid syndrome no longer responding to standard-of-care therapies.

Matthew H. Kulke, MD

Telotristat etiprate, a novel serotonin synthesis inhibitor, helped reduce daily bowel movements for patients with carcinoid syndrome no longer responding to standard-of-care therapies, an encouraging signal for an emerging class of drugs, according to research presented at the 2015 North American Neuroendocrine Tumor Society (NANETS) Symposium.

In the phase III TELESTAR study, telotristat etiprate decreased mean daily bowel movements by 35% among participants who received 500 mg of the drug three times a day and 29% among those who took 250 mg three times a day, compared with 17% for individuals who received a placebo. The results, measured from baseline to 12 weeks, were statistically significant (P <.001).

“These results clearly show telotristat etiprate represents a potentially promising new class of treatment for patients with carcinoid syndrome," said Matthew H. Kulke, MD, director of the Program in Neuroendocrine and Carcinoid Tumors at Dana-Farber Cancer Institute in Boston.

Telotristat etiprate is a small-molecule inhibitor of tryptophan hydroxylase (TPH), which is overexpressed in carcinoid tumor cells and is involved in serotonin biosynthesis. Blockade of TPH reduces peripheral serotonin production (5-HT), resulting in fewer serotonin-mediated gastrointestinal effects, such as diarrhea.

Patients who develop carcinoid syndromes are typically treated with somatostatin analogs (SSAs) and, although these therapies are initially effective, responses may become diminished over time, Kulke and colleagues wrote in a research report.1 He said new therapies are needed for these patients.

The TELESTAR study accrued 135 patients with well-differentiated metastatic neuroendocrine tumors and a documented history of carcinoid syndrome experiencing ≥4 bowel movements per day.2 To be eligible, patients had to be receiving stable-dose SSA therapy.

The co-primary endpoints were the change in the number of daily bowel movements and the incidence of treatment-emergent adverse events from baseline to 12 weeks. Secondary measures included change in urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, cutaneous flushing episodes, and abdominal pain from baseline to 12 weeks.

Patients were randomized to receive telotristat etiprate at either 250 mg or 500 mg three times a day or placebo, with 45 patients in each arm. Patients in all arms continued to receive SSA therapy throughout the study.

The durable response rate, defined as at least a 30% reduction in daily bowel movements over at least half the days of the study period, was 44% for the 250-mg group, 42% for the 500-mg group, and 20% for the placebo cohort.

Using the Hodges-Lehmann estimator of treatment difference, the results showed a strong statistically significant reduction versus placebo, of 0.81 bowel movements daily for the 250-mg group and 0.69 daily for the 500-mg group, Kulke said.

Especially from a patient's perspective, reducing daily bouts of diarrhea from 6 to 4 is a significant improvement, said Kjell Öberg, MD, PhD, a professor of endocrine oncology at Uppsala University Hospital in Sweden.

Telotristat etiprate also significantly reduced urinary 5-HIAA. The levels decreased almost 58% in the 500-mg group and 40% in the 250-mg group, but increased more than 11% in the placebo group. Kulke said the decreases are consistent with the drug's suggested mechanism of action, which is inhibition of intratumoral TPH.

Comparing the two doses, Öberg said both produced fewer bowel movements. However, the lower dose had a better durable response. "So why use the higher dose?" Öberg said.

Öberg said both doses of the drug were well tolerated with no significant side effects. However, 17% of the high-dose group had depression. This issue needs further study but physicians already should be on the lookout for depression.

During his presentation, Kulke noted that telotristat etiprate, at both doses, had a safety profile similar to that of the placebo. He added that the few occasions of nausea and depression were "areas of potential interest" that needed watching and further study.

The incidence of treatment-related adverse events for patients in the placebo, 250-mg, and 500-mg groups was 26.7%, 33.3%, and 68.9%, respectively, Kulke said. However, the rate of serious treatment-related adverse events were low in all arms: 2.2% in the placebo group, 0% in the 250-mg arm, and 4.4% in the 500-mg group. Discontinuations were very low and were similar in all three groups.

Secondary endpoints, which did not reach statistical significance, show reduced flushing in the few patients who had it. Abdominal pain also improved. Kulke said the study's size may have limited researchers' ability to detect such problems.

Other studies will address efficacy and safety issues the 12-week TELESTAR study was not able to cover due to its size and time limitations, Kulke said. Lexicon Pharmaceuticals, based in Texas, is developing the drug under a Fast Track designation from the FDA.


  1. Kulke MH, O’Dorisio T, Phan A, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide [published online July 10, 2014]. Endocr Relat Cancer. 2014;21(5):705-714.
  2. NIH Clinical Trials Registry. Identifier: NCT01677910.


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