The US Food and Drug Administration (FDA) has approved telotristat ethyl (Xermelo) tablets in combination with the current standard of care, somatostatin analogs, for the treatment of patients with carcinoid syndrome diarrhea that has not responded to somatostatin analogs alone.
“Today’s approval will provide patients whose carcinoid syndrome diarrhea is not adequately controlled with another treatment option,” said Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, in a press release.
Carcinoid tumors, a type of neuroendocrine tumor, develop most frequently in the gastrointestinal (GI) tract or lungs. Carcinoid syndrome occurs in less than 10% of patients with these GI tumors, usually after the tumor has spread to the liver and excess amounts of serotonin are released, causing diarrhea. Other symptoms of carcinoid syndrome include flushing, palpitations, asthma, cutaneous vasodilation, dizziness, and fatigue.
The trial that led to the approval of telotristat ethyl, TELESTAR, was a placebo-controlled phase III trial that enrolled 135 patients with carcinoid syndrome. Patients included had four or more bowel movements per day despite being treated with somatostatin analogs, and were randomized 1:1:1 to somatostatin analogs plus 250-mg oral telotristat ethyl, 500-mg oral telotristat ethyl, or placebo three times per day. The primary endpoint of the trial was change in bowel movement frequency from the start of the trial.
Results of the 12-week double-blind portion of the trial and a 36-week open-label extension were published last year in the Journal of Clinical Oncology.
Compared with placebo, the study showed a statistically significant reduction from baseline in the average number of daily bowel movements for patients in both telotristat ethyl arms. The estimated differences in daily bowel movement frequency were –0.81 for patients receiving 250-mg telotristat ethyl (P < .001) and –0.69 for those on 500-mg telotristat ethyl over the 12 weeks of the study (P < .001). At week 12, mean reductions in daily bowel movement frequency were –0.9, –1.7, and –2.1 with placebo, 250-mg telotristat ethyl, and 500-mg telotristat ethyl, respectively.
Responses were defined as a reduction in bowel movement frequency of 30% or greater from baseline for at least half of the 12-week treatment period. In patients given placebo, 250-mg telotristat ethyl, and 500-mg telotristat ethyl, responses were observed in 20%, 44%, and 42%, respectively.
In both telotristat ethyl arms, a statistically significant reduction in urinary 5-hydroxyindoleacetic acid levels, the main metabolite of serotonin, was also observed during the 12-week portion of the trial.
Treatment with telotristat ethyl was generally well tolerated. The most common adverse events were fever, nausea, headache, depression, peripheral edema, increased levels of gamma-glutamyl transferase, flatulence, and decreased appetite. The drug may cause constipation, with a possible increased risk for patients with less than four bowel movements per day. In trials, patients treated with a higher than recommended dose of telotristat ethyl developed severe constipation, with one patient requiring hospitalization and two developing intestinal perforation or obstruction complications.
The 36-week open-label extension of the study included 85% of the patients who had originally enrolled in TELESTAR. These patients opted to continue on the study, receiving telotristat ethyl treatment at the 500-mg dose. Results from this portion of the study showed sustained reductions in bowel movement frequency and no additional safety signals.