We reported top-line data in August 2015 from our pivotal Phase 3 TELESTAR clinical trial of telotristat ethyl evaluating the safety and tolerability of telotristat ethyl 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 ethyl 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 ethyl. 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 ethyl 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 ethyl 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 ethyl 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. 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).

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. 

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.

Detailed results from the pivotal Phase 3 TELESTAR were published in the Journal of Clinical Oncology in an article titled, “Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome,” which is available online at the Journal of Clinical Oncology website at ascopubs.org/journal/jco.

 

Phase 3 TELECAST Study

 

We reported top-line data in November 2015 from our additional Phase 3 TELECAST clinical trial of telotristat ethyl, which was designed as a companion to our pivotal Phase 3 TELESTAR clinical trial to provide additional safety exposure while further evaluating telotristat ethyl’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 ethyl 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. 

Telotristat ethyl met the study’s primary efficacy endpoint, the percent change from baseline in urinary 5-hydroxyindoleacetic acid (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 for both telotristat ethyl arms compared to placebo).  The placebo-adjusted change in 5-HIAA was -54.0% and -89.7% for the 250 mg and 500 mg treatment arms, respectively.

In addition, despite the lower baseline bowel movement frequency than in TELESTAR, telotristat ethyl achieved statistically significant reductions in daily bowel movement frequency over the 12 weeks of the study (p=0.004 for the 250 mg treatment arm and p<0.001 for the 500 mg treatment arm compared to placebo).  Baseline mean daily bowel movement frequency was 2.2, 2.5 and 2.8 in the placebo, 250 mg and 500 mg arms.  Patients in the 250 mg and 500 mg dose arms experienced noteworthy reductions in daily bowel movement frequency early in the study that tended to increase over time.  The placebo-adjusted reduction in daily bowel movement frequency over the entire 12-week period was -0.45 and -0.54 for the 250 mg and 500 mg treatment arms, respectively. 

Notably, 40% of patients in each of the telotristat ethyl treatment arms achieved a ≥30% reduction in BM frequency for at least 50% of the days in the double-blind treatment period, while not a single patient in the placebo arm achieved that result (p=0.001 for both doses compared to placebo).

Safety and tolerability was one of the primary objectives of the TELECAST study, and telotristat ethyl was well tolerated during the double-blind treatment period. Across all three treatment arms (placebo, 250 mg, 500 mg, each taken three times daily), the incidence of treatment-emergent adverse events (AEs) were 80.8%, 100% and 84.0%, respectively; the incidence of serious AEs (SAEs) were 19.2%, 4.0% and 8.0%, respectively; and discontinuation due to AEs were 3.8%, 8.0% and 0%, respectively.  AEs of depression or depressed mood were seen in two patients (7.7%) in the placebo arm and one (4.0%) in each of the telotristat ethyl treatment arms. Gastrointestinal AEs were seen in 57.7%, 64.0% and 36.0% of patients in the placebo, 250 mg and 500 mg treatment arms, respectively.