Telotristat Etiprate Application for Carcinoid Syndrome Submitted to FDA

The application was based on data from two phase III trials, both of which demonstrated significant reductions in the frequency of daily bowel movements with telotristat etiprate versus placebo. In the first study, TELESTAR, telotristat etiprate reduced daily bowel movements by up to 35%. In the second study, TELECAST, there was also a significant reduction in bowel movements (P≤.004), although the exact data were not yet released.

The FDA will review the NDA within 60 days of submission, at which point the agency will assign a review deadline under the Prescription Drug User Fee Act. Lexicon requested a priority review for the NDA, which would provide a 6-month deadline if the designation is granted.

“The filing of the NDA for telotristat etiprate brings us one step closer to the possibility of bringing this innovative new investigational treatment to the market to improve the lives of the community of patients and caregivers who live with carcinoid syndrome on a daily basis,” Lonnel Coats, president and chief executive officer of Lexicon, said in a statement. “We look forward to working closely with the FDA during the review process.”

The phase III TELESTAR study enrolled 135 patients with metastatic NETs and a documented history of inadequately controlled carcinoid syndrome (defined as ≥4 daily bowel movements). Patients were randomized to receive oral telotristat etiprate three times per day at 250 mg (n = 45), 500 mg (n = 45), or placebo (n = 45). Treatment with a somatostatin analog was maintained throughout the trial.

Patient characteristics were similar across arms, with a mean age of 64 years. The primary endpoint of the study was a reduction in the mean number of daily bowel movements over a 12-week double-blind period. Secondary outcome measures included cutaneous flushing episodes, abdominal pain, and changes in urinary 5-hydroxyindoleacetic acid (u5-HIAA), which is the primary metabolite of serotonin.

After 12 weeks of follow-up, average daily bowel movements were reduced by 29% and 35% with the 250 mg and 500 mg doses of telotristat etiprate, respectively. The 12-week decline in bowel movements was 17% with placebo. At least a 30% reduction in bowel movement frequency for ≥50% of the study was achieved for 44% of patients in the 250 mg arm and for 42% in the 500 mg group compared with 20% with placebo (P≤.02).

In the 250 mg arm, patients experienced 1.71 fewer average daily bowel movements compared with a reduction of 0.87 in the placebo arm (P<.001). Those treated with a 500 mg dose of telotristat etiprate experienced 2.11 fewer average daily bowel movements compared with baseline.

At the 12-week analysis, the 250 mg dose reduced u5-HIAA levels by 30.1 mg per 24 hours compared with placebo (P<.001). The 500 mg dose of telotristat etiprate reduced u5-HIAA levels by 33.8 mg per 24 hours compared with placebo (P<.001). In the placebo arm, u5-HIAA levels increased from baseline by 11 mg/24 hours.

Patients treated with telotristat etiprate did not experience a statistically significant reduction in flushing and abdominal pain.

The therapy was well tolerated, with fewer adverse events (AEs) seen in the 250 mg arm compared with placebo. Those in the 500 mg arm experienced a higher rate of AEs compared with the placebo and 250 mg arms. All-grade treatment-related AEs occurred in 82% of patients treated with the 250 mg dose of telotristat etiprate compared with 93% with the 500 mg dose and 87% with the placebo. AEs led to treatment discontinuation for 7% of patients in each telotristat etiprate arm compared with 13% with placebo.

Eight patients (18%) treated with the 500 mg dose of the therapy experienced depression versus 3 (6.7%) with placebo and 2 with the 250 mg dose (4.4%). Mild to moderate nausea was experienced by 6 patients in the 250 mg arm (13.3%) versus 13 (28.9%) and 5 (11.1%) with the 500 mg dose and placebo, respectively. At the time of the analysis, 87% of patients were receiving open-label telotristat etiprate at 500 mg.

In the TELECAST study, 76 patients with at least one symptom of carcinoid syndrome were randomized to telotristat etiprate three times per day at 250 mg, 500 mg, or placebo. Prior treatment with a somatostatin analog was not part of the inclusion criteria. The primary endpoint of the study was the percent change in u5-HIAA levels at 12 weeks.

The u5-HIAA levels were significantly reduced with both doses of telotristat etiprate compared with placebo (P<.001), although exact numbers have not yet been released. Telotristat etiprate also demonstrated a significant reduction in daily bowel movements compared with placebo for the 250 mg dose (P= .004) and the 500 mg dose (P<.001). Both dose levels were included in the NDA.

All-grade AEs occurred in 100% of patients in the 250 mg arm and in 84% and 81% of those in the 500 mg and placebo arms, respectively. Serious AEs occurred in 4% of patients in the 250 mg arm, 8% in the 500 mg arm, and in 19% of those in the placebo arm, although none were related to treatment. Nausea was experienced by 3 patients in the 250 mg arm, 2 in the 500 mg arm, and by 4 in the placebo group. One patients experienced depression in each of the telotristat etiprate arms versus 2 in the placebo group.

&ldquo;TELECAST was intended to complement our pivotal phase III trial, TELESTAR,&rdquo; Pablo Lapuerta, MD, executive vice president and chief medical officer of Lexicon, said in a statement when the data were released. &ldquo;We now have experience in more than 200 patients with carcinoid syndrome, with TELECAST contributing consistent efficacy data and favorable safety results. The data further support that the compound is acting directly on the cause of carcinoid syndrome, by reducing serotonin production within tumor cells.&rdquo;

A third phase III study, TELEPATH, is exploring expanded treatment with telotristat etiprate at the 250 mg and 500 mg thrice daily for patients with carcinoid syndrome. Treatment-related AEs are the primary endpoint of this study (NCT02026063).

References

1. Kulke MH, H&ouml;rsch D, Caplin M, et al. Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 37LBA.