The FDA has approved telotristat ethyl (Xermelo) for use in combination with somatostatin analog (SSA) as a treatment for carcinoid syndrome diarrhea in patients with metastatic neuroendocrine tumors (NETs) that cannot be adequately controlled by SSA therapy alone.
According to a statement from the FDA, the safety and efficacy of telotristat ethyl were established in a 12-week, double-blind, placebo-controlled trial in 90 adult participants with well-differentiated metastatic NETs and carcinoid syndrome diarrhea. Despite the use of SSA at a stable dose for ≥3 months, the patients continued to have 4 to 12 daily bowel movements.
Patients continued SSA therapy and were randomized to telotristat ethyl or placebo 3 times daily. In the telotristat ethyl arm, 33% of patients had an average reduction of 2 bowel movements per day compared with 4% of patients on the placebo arm.
“Today’s approval will provide patients whose carcinoid syndrome diarrhea is not adequately controlled with another treatment option,” Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said in a statement.
The application for telotristat ethyl submitted by Lexicon Pharmaceuticals was based on data from the phase III TELESTAR trial, which enrolled 135 patients with metastatic NETs and a documented history of inadequately controlled carcinoid syndrome (defined as ≥4 daily bowel movements). Patients were randomized to receive oral telotristat ethyl three times per day at 250 mg (n = 45), 500 mg (n = 45), or placebo (n = 45). Treatment with a somatostatin analog was maintained throughout the trial. Telotristat ethyl was approved at the 250 mg dose.
Patient characteristics were similar across arms, with a mean age of 64 years. The primary endpoint of the study was a reduction in the mean number of daily bowel movements over a 12-week double-blind period. Secondary outcome measures included cutaneous flushing episodes, abdominal pain, and changes in urinary 5-hydroxyindoleacetic acid (u5-HIAA), which is the primary metabolite of serotonin.
After 12 weeks of follow-up, average daily bowel movements were reduced by 29% and 35% with the 250 mg and 500 mg doses of telotristat ethyl, respectively. The 12-week decline in bowel movements was 17% with placebo. At least a 30% reduction in bowel movement frequency for ≥50% of the study was achieved for 44% of patients in the 250 mg arm and for 42% in the 500 mg group compared with 20% with placebo (P
In the 250 mg arm, patients experienced 1.71 fewer average daily bowel movements compared with a reduction of 0.87 in the placebo arm (P
<.001). Those treated with a 500 mg dose of telotristat ethyl experienced 2.11 fewer average daily bowel movements compared with baseline.
At the 12-week analysis, the 250 mg dose reduced u5-HIAA levels by 30.1 mg per 24 hours compared with placebo (P
<.001). The 500 mg dose of telotristat ethyl reduced u5-HIAA levels by 33.8 mg per 24 hours compared with placebo (P
<.001). In the placebo arm, u5-HIAA levels increased from baseline by 11 mg/24 hours.
Patients treated with telotristat ethyl did not experience a statistically significant reduction in flushing and abdominal pain.
The therapy was well tolerated, with fewer adverse events (AEs) seen in the 250 mg arm compared with placebo. Those in the 500 mg arm experienced a higher rate of AEs compared with the placebo and 250 mg arms. All-grade treatment-related AEs occurred in 82% of patients treated with the 250 mg dose of telotristat ethyl compared with 93% with the 500 mg dose and 87% with the placebo. AEs led to treatment discontinuation for 7% of patients in each telotristat ethyl arm compared with 13% with placebo.
Eight patients (18%) treated with the 500 mg dose of the therapy experienced depression versus 3 (6.7%) with placebo and 2 with the 250 mg dose (4.4%). Mild to moderate nausea was experienced by 6 patients in the 250 mg arm (13.3%) versus 13 (28.9%) and 5 (11.1%) with the 500 mg dose and placebo, respectively. At the time of the analysis, 87% of patients were receiving open-label telotristat ethyl at 500 mg.
“The approval of Xermelo establishes a new treatment option for patients with carcinoid syndrome diarrhea that is inadequately controlled by SSA therapy,” Matthew H. Kulke, MD, TELESTAR primary investigator, director of the Program in Neuroendocrine and Carcinoid Tumors at Dana Farber Cancer Institute and Professor of Medicine, Harvard Medical School said in a statement. “Inhibition of tumoral serotonin production represents a novel approach for patients with this condition. Studies have shown that Xermelo can reduce the debilitating effects of carcinoid syndrome diarrhea and has a favorable efficacy and safety profile in patients who currently have limited treatment options.”