A TRYPTOPHAN HYDROXYLASE INHIBITOR APPROVED FOR CARCINOID SYNDROME

On February 28, the U.S. Food and Drug Administration(FDA) approved telotristat ethyl (Xermelo) tablets in combination with somatostatin analog therapy for the treatment of adults with carcinoid syndrome diarrhea that somatostatin analog therapy alone has inadequately controlled.

About Carcinoid Tumors and Carcinoid Syndrome

Carcinoid syndrome is a cluster of symptoms sometimes seen in people with carcinoid tumors. These tumors are rare and often slow-growing. Most carcinoid tumors are found in the gastrointestinal tract.

Carcinoid syndrome occurs in less than 10% of patients with carcinoid tumors, usually after the tumor has spread to the liver. The tumors in these patients release excess amounts of the hormone serotonin, resulting in diarrhea. Complications of uncontrolled diarrhea include weight loss, malnutrition, dehydration, and electrolyte imbalance.

“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.

Telotristat ethyl, in a regimen with somatostatin analog therapy, is approved in tablet form to be taken orally 3 times daily with food. Telotristat ethyl inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea.

Study Findings

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 neuroendocrine tumors and carcinoid syndrome diarrhea. These patients were having between 4 and 12 daily bowel movements despite the use of a somatostatin analog at a stable dose for at least 3 months. Participants remained on their somatostatin analog treatment, and were randomized to add placebo or treatment with telotristat ethyl 3 times daily.

Those receiving telotristat ethyl added on to their somatostatin analog treatment experienced a greater reduction in average bowel movement frequency than those on a somatostatin analog and placebo. Specifically, 33% of participants randomized to add telotristat ethyl to a somatostatin analog experienced an average reduction of 2 bowel movements per day compared to 4% of patients randomized to add placebo to a somatostatin analog.

The most common side effects of telotristat ethyl include nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, depression, peripheral edema, flatulence, decreased appetite, and fever. Telotristat ethyl may cause constipation, and the risk of developing constipation may be increased in patients whose bowel movement frequency is less than four bowel movements per day.

Patients treated with a higher-than-recommended dosage of telotristat ethyl developed severe constipation in clinical trials. One patient required hospitalization, and two other patients developed complications of either intestinal perforation or intestinal obstruction. Patients should be monitored for severe constipation. If a patient experiences severe constipation or severe, persistent, or worsening abdominal pain, they should discontinue telotristat ethyl and contact their health-care provider.

The FDA granted this application Fast Track designation and priority review. Telotristat ethyl also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.