422PD - Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome

Abstract

Telotristat etiprate (TE) is an oral tryptophan hydroxylase inhibitor in development for the treatment of carcinoid syndrome (CS). During the placebo-controlled, 12-week double-blind treatment (DBT) periods of 2 Phase 3 studies, TELESTAR and TELECAST, TE significantly reduced bowel movement (BM) frequency compared to placebo. Objective: To examine the safety of TE vs placebo, a combined analysis of safety data from the DBT periods of TELESTAR and TELECAST was performed. 211 patients (pts) with CS were randomly assigned (1:1:1) to placebo or TE 250 mg or 500 mg, each given 3x/day (tid). At entry, pts on stable-dose long-acting somatostatin analog (SSA) therapy had ≥4 (TELESTAR) or <4 (TELECAST) BMs/day, while pts not on SSAs had ≥4 BMs/day (TELECAST). Antidiarrheals and short-acting rescue SSAs were allowed. Treatment-emergent adverse event (TEAE), serious adverse event (SAE), and adverse event of special interest (AESI) data were pooled. AESIs related to depression, hepatic enzyme elevation, and gastrointestinal (GI) symptoms were identified by prespecified preferred terms. 71 pts on placebo and 70 pts each on TE 250 mg or 500 mg tid were analyzed. At entry, 47% of pts were female, all pts had metastatic neuroendocrine tumors with mean disease duration of 7 yrs, mean BM frequency was 5.7 (TELESTAR) and 2.5 (TELECAST) BMs/day, and mean urinary 5-hydroxyindoleacetic acid was 84 mg/day. DBT period completion rates were similar between TE (88%) and placebo (87%) pts, as were incidences of SAEs and treatment withdrawal due to TEAE. Hepatic enzyme elevations were no greater than Drug-Induced Liver Injury Network Grade 1 (mild; on a scale up to 5). Slightly higher rates of nausea, constipation, and depression were reported with TE. There were no serious AESIs related to depression. Integrated safety analyses of placebo-controlled data support the proposed use of TE for the treatment of CS in patients receiving SSA therapy.Tabled 1TE# of pts with:Placebo n = 71250 mg tid n = 70500 mg tid n = 70≥1 TEAE606263≥1 SAE12810Death311Drug withdrawal due to TEAE12159AESIs- Depression related558- Hepatic enzymes0108- Any GI303232- Nausea9916- Vomiting536- Constipation245 Open table in a new tab