Lexicon Pharmaceuticals, Inc., a biopharmaceutical company focused on discovering breakthrough treatments for human disease, announced positive, top-line proof-of-concept data from its recently completed phase II study in carcinoid syndrome with LX1032, telotristat etiprate.

Carcinoid syndrome is a chronic condition caused by neuroendocrine tumours that usually originate from the gastrointestinal tract. It is characterized by severe diarrhoea and flushing episodes with long-term consequences including malnutrition, heart disease, and death. Symptoms of carcinoid syndrome have been linked to excess production of serotonin by metastatic tumour cells. Telotristat etiprate is designed to reduce serotonin production.

“Telotristat etiprate is our third drug candidate to demonstrate proof of concept in patients in phase II,” said Dr Arthur T Sands, Lexicon's president and CEO. “Based on the positive results of this US study, as well as encouraging observations from our clinical trial in Europe, we intend to discuss a phase III development plan for carcinoid syndrome with the FDA.”

The randomized, double-blind, placebo-controlled study was conducted in the United States in 23 patients with carcinoid syndrome who were refractory to currently available therapy. Patients in the study had metastatic carcinoid disease and were experiencing an average of about six bowel movements per day at baseline. Patients received either placebo (n=5) or one of four doses of telotristat etiprate (n=18) daily for 28 days. The primary endpoint of the study was safety and tolerability. Efficacy measures included change in bowel movement frequency, relief of symptoms, and reduction in serotonin synthesis.

Telotristat etiprate was well tolerated, and adverse events in the study were usually mild to moderate with similar frequencies overall between treatment groups and placebo. Five telotristat etiprate patients achieved clinical responses characterized by reductions of at least 30% in the number of bowel movements per day for two weeks or more during the study. Six telotristat etiprate patients reported adequate relief of carcinoid symptoms at the end of the study. There were nine telotristat etiprate patients with a complete biochemical response defined as a reduction of at least 50% in urinary 5-HIAA, a biomarker of serotonin synthesis.

No patients on placebo experienced a clinical response, adequate relief of symptoms, or biochemical response during the study. The difference between telotristat etiprate and placebo in bowel movement frequency ranged between 1.6 and 2.9 bowel movements/day across telotristat etiprate doses, all favouring telotristat etiprate treatment. Also of note, all eligible patients elected to continue treatment with telotristat etiprate under an extension protocol.

Preliminary data were also reported from a separate, ongoing, open-label, single-arm study of telotristat etiprate in Europe. To date, 5 out of 6 patients with refractory carcinoid syndrome have experienced sustained reductions of at least 30% in bowel movement frequency when treated with telotristat etiprate. Two of these responses were within the first 4 weeks of therapy, while three more occurred between 4 and 8 weeks of treatment under the 12-week protocol.

“The phase II data clearly show a reduction in bowel movements and symptom relief in a population that has exhausted all standard-of-care treatment options,” said Dr Pablo Lapuerta, senior vice president and chief medical officer at Lexicon. “The phase II data are also consistent with preliminary results from the European study, where there appear to be some early responses and additional benefit with continued treatment. We look forward to presenting detailed results at a scientific meeting later this year.”

Telotristat etiprate was discovered and developed at Lexicon to reduce serotonin production by inhibiting tryptophan hydroxylase (TPH), a key enzyme in the synthesis of serotonin. Excessive levels of serotonin have been implicated in symptoms associated with carcinoid syndrome, especially diarrhoea and carcinoid heart disease. Serotonin’s breakdown product, 5-HIAA, is a biomarker used in the diagnosis of the condition. In preclinical studies, telotristat etiprate reduced peripheral serotonin in several different species without affecting serotonin levels in the brain. In phase I clinical studies, telotristat etiprate reduced serotonin levels and urinary 5-HIAA in healthy volunteers consistent with preclinical results.

Telotristat etiprate is being developed under Fast Track designation from the US Food and Drug Administration and orphan drug designation from the European Medicines Agency. It is a member of a new class of oral drugs invented by Lexicon, the serotonin synthesis inhibitors, which are being developed in a spectrum of gastrointestinal indications. Lexicon is also currently planning a phase II trial of telotristat etiprate in mild to moderate ulcerative colitis.

Carcinoid syndrome is a chronic condition caused by metastatic neuroendocrine tumours that usually originate from the gastrointestinal tract. These tumours secrete large amounts of serotonin, which can cause a variety of symptoms including severe diarrhoea and abdominal discomfort.  Patients with carcinoid syndrome currently have limited therapeutic options, and the standard of care includes chronic therapy with somatostatin analogues, which are delivered by injection. With current therapy, the gastrointestinal symptoms return over time in most patients, hence the need for new agents.