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 enhanced 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.
Phase 3 Clinical Trial
In August 2015, we announced positive top-line results for our pivotal Phase 3 study of telotristat etiprate in patients with carcinoid syndrome (“TELESTAR”). Top-line results from TELESTAR showed that patients who added telotristat etiprate to the standard of care, somatostatin analog depot injection (“SSA”), at both 250 mg and 500 mg 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 (p<0.001), meeting the study’s primary endpoint.
In a key secondary measure, a substantially greater proportion of patients on telotristat etiprate achieved a durable response (44 percent and 42 percent in the 250 mg and 500 mg 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 250 mg 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 500 mg arm experienced a 35 percent reduction, while the placebo group showed a 17 percent reduction. The proportion of patients with treatment-emergent adverse events (AEs), serious AEs and discontinuation due to AEs were generally similar in all three treatment arms. The tolerability profile of the telotristat etiprate 250 mg dose appeared similar to placebo and somewhat better than the 500 mg dose with respect to gastrointestinal discomfort and mood. The overall incidence and nature of AEs in TELESTAR was consistent with those reported in previous studies.
TELESTAR was a double-blind Phase 3 study that enrolled 135 patients with carcinoid syndrome which was not adequately controlled on SSA therapy. The three-arm study evaluated two doses of oral telotristat etiprate – 250 mg and 500 mg, each taken three times daily – against placebo over a 12-week period and measured the reduction from baseline in the average number of daily bowel movements. Patients in both the treatment and placebo arms continued their SSA therapy throughout the study.
Phase 2 Clinical Trials
We reported top-line data in October 2012 from an open-label Phase 2 clinical trial evaluating the safety and tolerability of telotristat etiprate and its effects on symptoms associated with carcinoid syndrome. The trial enrolled 15 patients with metastatic carcinoid syndrome who were refractory to or could not tolerate somatostatin analog therapy in an open-label study of ascending doses of 150mg, 250mg, 350mg and 500mg of telotristat etiprate, administered three times daily, for 14 days on each dose until reaching the maximal dose, which was then continued until the completion of 12 weeks of therapy. The primary efficacy endpoint under evaluation in the trial was the reduction of bowel movements from baseline to week 12, with secondary endpoints including relief of symptoms and reduction in serotonin synthesis. Top-line data from the study showed that patients experienced a 46.4% median reduction from baseline at week 12, with the number of daily bowel movements steadily decreasing over time. All observed changes from baseline were statistically significant at p<0.001. This change corresponded with an increased proportion of patients reporting adequate relief of their carcinoid symptoms, a global assessment which also improved over time, with 75% of the patients with data at week 12 reporting improvement. Clinically relevant decreases from baseline were likewise seen for a number of key secondary endpoints, including statistically significant improvements in stool consistency (p<0.001) and trends of reductions which did not achieve statistical significance in abdominal pain and the number of cutaneous flushing episodes. The median percentage reductions from baseline of urinary 5- HIAA, a biomarker of serotonin synthesis, at weeks 8 and 12 were 68.3% and 72.7%, respectively (each, p<0.05). Telotristat etiprate was well tolerated in the study, with no dose-limiting toxicity observed. Three patients reported serious adverse events, none of which were related to telotristat etiprate, and no patient discontinued from the study due to an adverse event.
We reported top-line data in August 2011 from a Phase 2 clinical trial evaluating the safety and tolerability of telotristat etiprate and its effects on symptoms associated with carcinoid syndrome. The trial enrolled 23 patients with symptomatic carcinoid syndrome who were refractory to octreotride therapy in a double-blind, randomized, placebo-controlled study of 150mg, 250mg, 350mg and 500mg doses of telotristat etiprate, each administered three times daily over a 28-day treatment period in combination with octreotide therapy. The efficacy endpoints under evaluation in the trial included the number of daily bowel movements, stool form, urgency, a global assessment of symptoms associated with carcinoid syndrome, flushing episodes and an assessment of pain and discomfort. Top-line data from the trial showed evidence of efficacy across multiple endpoints, including improvements in bowel movement frequency, decreased levels of urinary 5-HIAA, the primary metabolite of serotonin and a biomarker for serotonin production, and improvements in the assessment of pain and discomfort. Telotristat etiprate demonstrated a favorable safety profile in the trial, with no dose-limiting toxicity observed. Adverse events were generally mild to moderate and similarly distributed across all groups, including the placebo group.
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 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 Fast Track Designation
Telotristat etiprate has received Fast Track designation from the United States Food and Drug Administration (FDA) for the treatment of symptoms associated with carcinoid syndrome in certain patients. FDA’s Fast Track program facilitates the development of potential new drugs and expedites the review of new drugs intended to serve unmet medical needs in serious or life-threatening conditions. Fast Track status also provides formal mechanisms for sponsors to communicate with the FDA on product development issues, including clinical trial design. Fast Track benefits include eligibility for an early review process that may significantly shorten FDA approval times by allowing for the possibility of a “rolling submission” for marketing authorization.
About Orphan Designation
Telotristat etiprate has received orphan drug designation from both the FDA and the European Medicines Agency (EMA). The goal of the FDA and EMA orphan drug programs are to promote the development of drugs intended for the prevention or treatment of life-threatening or chronically debilitating conditions that affect limited populations. Incentives for developing new drugs under orphan drug designation in the U.S. and E.U. include 7 and 10 years of marketing exclusivity, respectively, regulatory assistance, reduced regulatory fees associated with applying for marketing approval and assistance with clinical trial design.
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.