Telotristat etiprate, or LX1032, is an orally-delivered small molecule compound that we are developing for the treatment of carcinoid syndrome. Telotristat etiprate was internally generated by our medicinal chemists and inhibits tryptophan hydroxylase, or TPH, the rate-limiting enzyme for serotonin production found primarily in enterochromaffin, or EC, cells of the gastrointestinal tract. Our scientists found that mice lacking the non-neuronal form of this enzyme, TPH1, have virtually no serotonin in the gastrointestinal tract, but maintain normal levels of serotonin in the brain. Telotristat etiprate was specifically designed to achieve systemic exposure to address disorders such as carcinoid syndrome that require regulation of serotonin levels beyond the EC cells in the gastrointestinal tract without impacting brain serotonin production.
Telotristat etiprate reduces peripheral serotonin production by inhibiting the enzyme TPH in metastatic carcinoid tumors.
We reported top-line data in August 2015 from our pivotal TELESTAR Phase 3 clinical trial of telotristat etiprate evaluating the safety and tolerability of telotristat etiprate and its activity in carcinoid syndrome. The trial enrolled 135 patients with inadequately controlled carcinoid syndrome on background somatostatin analog therapy, the current standard of care, in a randomized, double-blind, placebo-controlled study of 250mg three times daily and 500mg three times daily doses of telotristat etiprate over a 12-week treatment period, followed by a 36-week, open-label extension where all patients receive 500mg three times daily doses of telotristat etiprate. The primary efficacy endpoint under evaluation in the trial was the number of daily bowel movements, with secondary efficacy endpoints including changes in urinary 5-HIAA, the primary metabolite of serotonin and a biomarker for serotonin synthesis, flushing episodes, abdominal pain and quality of life measures. Top-line data from the study showed that patients who added telotristat etiprate to the standard of care at both the 250mg and 500mg doses experienced a statistically significant reduction from baseline compared to placebo in the average number of daily bowel movements over the 12-week study period, meeting the study’s primary endpoint. A substantially greater proportion of patients on telotristat etiprate achieved a durable response (44 percent and 42 percent in the 250mg and 500mg treatment arms, respectively), defined as at least a 30 percent reduction in daily bowel movements over at least half the days of the study period, as compared to 20 percent response on placebo (p<0.040). Patients who received 250mg of telotristat etiprate experienced a 29 percent reduction in the average number of daily bowel movements during the final week (week 12) of the study period compared to baseline, and those in the 500mg arm experienced a 35 percent reduction, while the placebo group showed a 17 percent reduction. The proportion of patients with treatment-emergent adverse events, serious adverse events and discontinuation due to adverse events were generally similar in all three treatment arms. The tolerability profile of the 250mg dose appeared similar to placebo and somewhat better than the 500mg dose with respect to gastrointestinal discomfort and mood. The overall incidence and nature of adverse events in TELESTAR were consistent with those reported in previous studies.
We reported top-line data in November 2015 from our additional TELECAST Phase 3 clinical trial of telotristat etiprate, which was designed as a companion to our pivotal TELESTAR Phase 3 clinical trial to provide additional safety exposure while further evaluating telotristat etiprate’s activity in carcinoid syndrome. The trial enrolled 76 patients in a randomized, double-blind, placebo-controlled study of 250mg three times daily and 500mg three times daily doses of telotristat etiprate over a 12-week treatment period. Patients qualified for the trial based on at least one symptom of carcinoid syndrome, such as at least two episodes of flushing per day, elevated urinary 5-HIAA at baseline or nausea present on at least one out of five days at baseline. Most enrolled patients were on background somatostatin analog therapy. Patients who were not on background somatostatin analog therapy could also qualify for the trial based on experiencing at least four bowel movements per day as their symptom of carcinoid syndrome. The primary efficacy endpoint under evaluation in the trial was the change in urinary 5-HIAA, with secondary endpoints including the number of daily bowel movements. Top-line data from the study showed that patients treated with telotristat etiprate at both the 250mg and 500mg doses experienced a statistically significant reduction from baseline compared to placebo in urinary 5-HIAA at week 12, (p<0.001), meeting the study’s primary efficacy endpoint. Patients treated with telotristat etiprate at both the 250mg and 500mg doses also experienced a statistically significant percent reduction from baseline compared to placebo in the average number of daily bowel movements over the 12-week study period (p=0.004 and p<0.001 for the 250mg and 500mg arms, respectively). The proportion of patients with treatment-emergent adverse events, serious adverse events and discontinuation due to adverse events were generally similar in all three treatment arms, with patients receiving telotristat etiprate experiencing a slightly higher rate of treatment-emergent adverse events. In general, the tolerability profile of both doses of telotristat etiprate appeared similar to placebo and the overall incidence and nature of adverse events in TELECAST were consistent with those reported in previous studies.
We previously completed two Phase 2 clinical trials in carcinoid syndrome patients, in which telotristat etiprate provided evidence of efficacy across multiple endpoints, including bowel movement frequency, stool consistency and decreased levels of urinary 5-HIAA. Telotristat etiprate was well tolerated in the studies, with no dose-limiting toxicity observed.
We have filed an application for regulatory approval to market telotristat etiprate in the United States and are presently preparing for the commercial launch of telotristat etiprate in the United States, if approved. We have entered into a license and collaboration agreement with Ipsen Pharma SAS under which we granted Ipsen an exclusive, royalty-bearing right and license to commercialize telotristat etiprate outside of the United States and Japan.
Telotristat etiprate has received Fast Track status and Orphan Drug designation from the United States Food and Drug Administration, or FDA, for the treatment of gastrointestinal symptoms associated with carcinoid syndrome in patients who no longer respond to the standard care. Telotristat etiprate has also received Orphan Drug designation from the Committee for Orphan Medical Products of the European Medicines Agency for the treatment of carcinoid tumors.
About Carcinoid Syndrome
Carcinoid tumors are a type of neuroendocrine tumor (NET) that typically form in the gastrointestinal system. Carcinoid NETs may arise from multiple different organ systems, including the small bowel, appendix, rectum, stomach, and lung, but most are derived from enterochromaffin (EC) cells of the midgut, and often produce and release large amounts of serotonin (5-HT). Carcinoid syndrome is a combination of symptoms, including severe diarrhea, bronchial restriction, facial flushing and rapid heartbeat, caused by the release of excessive serotonin and other substances into the blood stream from metastatic carcinoid tumors.
Carcinoid syndrome is a combination of symptoms caused
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* Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.