Date: 2016-10-31
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the Journal of Clinical Oncology (JCO)
Company: Ipsen (France) Lexicon Pharmaceuticals (USA - TX)
Product: telotristat etiprate
Action
mechanism: enzyme inhibitor.Telotristat etiprate is an oral, small-molecule inhibitor of tryptophan hydroxylase (TPH) that reduces peripheral serotonin production without affecting brain serotonin levels. In October 2014, Ipsen and Lexicon announced that they had entered into an exclusive licensing agreement for Ipsen to commercialize telotristat etiprate, excluding the US and Japan, with a focus on the symptomatic treatment of carcinoid syndrome inadequately controlled with SSAs. Lexicon retains sole rights to commercialize telotristat etiprate in the United States and Japan. Telotristat etiprate has received Fast Track and Orphan Drug designation from the FDA.
Disease: carcinoid syndrome patients with metastatic neuroendocrine tumor (NET) inadequately controlled by somatostatin analog (SSAs)
Therapeutic area: Cancer - Oncology
Country: Australia, Belgium, Canada, France, Germany, Israel, Italy,The Netherlands, Spain, Sweden, UK, USA
Trial
details: The double-blind Phase 3 study known as TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) enrolled 135 patients with carcinoid syndrome who were not adequately controlled on SSA therapy, the current standard of care. 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. (NCT01677910) Telotristat Etiprate for Carcinoid Syndrome Therapy (TELECAST) is a phase 3, randomized, placebo-controlled, multicenter, double-blind study to evaluate the safety and efficacy of telotristat etiprate (LX1606) in patients with carcinoid syndrome. (NCT02063659)
Latest
news: * On October 31, 2016, Lexicon Pharmaceuticals announced that the Journal of Clinical Oncology published detailed results from Lexicon’s pivotal Phase 3 TELESTAR clinical study of telotristat ethyl in patients with carcinoid syndrome. This global double-blind Phase 3 study enrolled 135 patients from 12 countries with carcinoid syndrome whose symptoms were not adequately controlled on somatostatin analog therapy (SSA), the current standard of care. Data show that patients who added telotristat ethyl to SSA therapy at both the 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. There was also a statistically significant reduction in the levels of urinary 5-hydroxyindole acetic acid (5-HIAA), the main metabolite of serotonin, from baseline to week 12 with a reduction of 40 mg/24 hours (250 mg arm) and 58 mg/24 hours (500 mg arm) versus an increase of 11 mg/24 hours in the placebo arm (p<0.001). Treatment with telotristat ethyl was generally well tolerated during the double-blind treatment period. Eighty-five percent of the patients originally enrolled in TELESTAR opted to continue study participation, receiving treatment with 500 mg telotristat ethyl in a 36-week open-label extension (OLE) study. Results from the OLE showed sustained bowel movement responses to treatment and no additional safety signals. Additional results detailed in the publication showed evidence that telotristat ethyl may also improve stool consistency, reduce the urgency to defecate and reduce the use of rescue short-acting octreotide. Inhibition of tryptophan hydroxylase with telotristat ethyl represents a novel approach to reducing tumoral serotonin production in patients with carcinoid tumors,” said TELESTAR primary investigator and lead author, Matthew H. Kulke, M.D., Director, Program in Neuroendocrine and Carcinoid Tumors and Senior Physician, Dana Farber Cancer Institute, and Professor of Medicine, Harvard Medical School. The article, titled “Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome,” is available online at the Journal of Clinical Oncology website. * On December 1, 2015, Lexicon Pharmaceuticals announced that top-line data from its TELECAST Phase 3 study showed results of telotristat etiprate in treating carcinoid syndrome in cancer patients with metastatic neuroendocrine tumors consistent with the clinical benefit observed in its pivotal TELESTAR study. The TELECAST study was designed as a companion to TELESTAR primarily to provide additional safety exposure while further evaluating telotristat etiprate’s activity in carcinoid syndrome. TELECAST mostly enrolled patients treated with somatostatin analog (SSA) therapy, the current standard of care, with carcinoid syndrome characterized by less severe bowel movement frequency than those patients in the TELESTAR study, together with a smaller number of carcinoid syndrome patients not treated with SSA therapy. The double-blind TELECAST study enrolled 76 patients with or without concomitant SSA therapy provided they qualified based on at least one sign/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. Patients who were not receiving SSA therapy could also qualify for the study based on experiencing at least four bowel movements per day as their sign/symptom. 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 with primary outcome measures consisting of safety and the percent change from baseline in urinary 5-HIAA, and secondary outcome measures including change from baseline in the number of daily bowel movements. Patients in both the treatment and placebo arms who were on SSA therapy at baseline continued their SSA therapy throughout the study. Data showed that patients treated with telotristat etiprate at both the 250 mg and 500 mg doses experienced a statistically significant percent reduction from baseline compared to placebo in urinary 5-HIAA, the main metabolite of serotonin, at week 12, the final week of the double-blind treatment portion of the study (p<0.001), meeting the study’s primary efficacy endpoint. In addition, data showed that patients treated with telotristat etiprate at both the 250 mg and 500 mg doses experienced a statistically significant percent reduction from baseline compared to placebo in the average number of daily bowel movements over the 12 weeks of the study (p=0.004 for the 250 mg dose arm and p Treatment with telotristat etiprate was well tolerated during the double-blind treatment period. The proportions of patients with treatment-emergent adverse events (AEs) were 100% in the 250 mg arm, 84% in the 500 mg arm and 81% in the placebo group during the 12-week study period. The proportions of patients with serious AEs (none of which were deemed related to treatment) were 4% in the 250 mg arm, 8% in the 500 mg arm and 19% in the placebo group. The proportions of patients who discontinued treatment due to AEs were 8% in the 250 mg arm, 0% in the 500 mg arm and 4% in the placebo group. Notably, in terms of pre-defined AEs of special interest, both doses of telotristat etiprate appeared similar to placebo, with three patients experiencing nausea in the 250 mg arm, two in the 500 mg arm and four in the placebo group, and one patient experiencing depression or depressed mood in each of the 250 mg and 500 mg arms and two in the placebo group. Results from Lexicon’s pivotal TELESTAR Phase 3 study were presented earlier this year at the European Cancer Conference and the annual symposium of the North American Neuroendocrine Tumor Society. * On August 3, 2015, Ipsen announced that its partner, Lexicon Pharmaceuticals disclosed positive results from the pivotal Phase 3 TELESTAR study. TELESTAR evaluated the efficacy and safety of telotristat etiprate for carcinoid syndrome patients with metastatic neuroendocrine tumor (NET) inadequately controlled by somatostatin analog (SSAs), the current standard of care. The double-blind Phase 3 study known as TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) enrolled 135 patients with carcinoid syndrome who were not adequately controlled on SSA therapy. Patients in both the treatment and placebo arms continued their SSA therapy throughout the study. Top-line results from TELESTAR show that patients who added telotristat etiprate to SSA therapy at both the 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 another key finding, 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 had a 35 percent reduction, while the placebo group showed a 17 percent reduction. These results are consistent with those seen in the 12-week Phase 2 study of telotristat etiprate. 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 telotristat etiprate 250 mg tid appeared similar to placebo and somewhat better than 500 mg tid with respect to gastrointestinal discomfort and mood. Further in depth analysis of safety and tolerability data will be conducted. Complete results from the Phase 3 TELESTAR study will be presented at an upcoming scientific conference. The 12-week double-blind study period is being followed by a 36-week open-label extension where all patients receive telotristat etiprate 500 mg three times daily.
Top-line results from the Phase 3 study show that patients who added telotristat etiprate to the standard of care at both the 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.
