General Information

Xermelo (telotristat ethyl) is a tryptophan hydroxylase inhibitor. Xermelo targets the overproduction of serotonin inside mNET cells. 

Xermelo is specifically indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.

Mechanism of Action

Xermelo (telotristat ethyl) is a tryptophan hydroxylase inhibitor. Tryptophan hydroxylase mediates the rate limiting step in serotonin biosynthesis. The in vitro inhibitory potency of telotristat toward tryptophan hydroxylase is 29 times higher than that of telotristat ethyl. Serotonin plays a role in mediating secretion, motility, inflammation and sensation of the gastrointestinal tract and is overproduced in patients with carcinoid syndrome. Through inhibition of tryptophan hydroxylase, telotristat and telotristat ethyl reduce the production of peripheral serotonin and the frequency of carcinoid syndrome diarrhea.

Side Effects

Adverse effects associated with the use of Xermelo may include, but are not limited to, the following: 

• Nausea
• Headache
• Increased GGT
• Depression
• Flatulence
• Decreased appetite
• Peripheral edema
• Pyrexia.

Dosing/Administration

Xermelo is supplied as a tablet for oral administration. The recommended dosage of Xermelo in adults is 250 mg three times daily for patients whose diarrhea is inadequately controlled by an SSA therapy. Xermelo should be ingested with food. When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo. Discontinue Xermelo if severe constipation develops.

Clinical Trial Results

FDA Approval

The FDA approval of Xermelo was based on a 12-week double-blind, placebo-controlled, randomized, multicenter trial conducted in adult patients with a well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea who were having between four to 12 daily bowel movements despite the use of SSA therapy at a stable dose for at least three months. Patients were randomized to placebo or treatment with Xermelo 250 mg three times daily. Study medication was administered within 15 minutes before or within one hour after a meal or snack. All patients were required to stay on their baseline SSA regimen and were allowed to use rescue medication (short-acting octreotide) and antidiarrheals for symptomatic relief. Ninety patients were evaluated for efficacy. The primary efficacy end point was the change from baseline in the number of daily bowel movements averaged over the 12-week treatment period. In the 12-week study, a difference in average weekly reductions in bowel movement frequency between Xermelo and placebo was statistically significant and was observed as early as one to three weeks, and persisted for the remaining nine weeks of the study.