Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide.

Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.