Matthew H. Kulke, MD
Telotristat etiprate significantly reduced the average number of daily bowel movements compared with placebo for patients with carcinoid syndrome that was not adequately controlled by a somatostatin analog, according to top-line results from the phase III TELESTAR trial released by the developer of the tryptophan hydroxylase inhibitor, Lexicon.
In the TELESTAR trial, oral telotristat etiprate was administered at 250 mg or 500 mg 3 times daily with a somatostatin analog. Both doses were superior to placebo with a somatostatin analog for the primary endpoint of reducing average daily bowel movements at 12 weeks (P
Full data from the trial are being submitted for presentation at an upcoming meeting. Additionally, Lexicon is working with the FDA to submit data from the TELESTAR trial for regulatory approval, according to the statement.
"The TELESTAR results are promising, and the community of patients and caregivers who live and deal with carcinoid syndrome are excited about the prospect of a new treatment becoming available," principal investigator Matthew H. Kulke, MD, director, Program in Neuroendocrine and Carcinoid Tumors and Senior Physician, Dana-Farber Cancer Institute, said in a statement.
The phase III study enrolled 135 patients with well-differentiated metastatic neuroendocrine tumors and a documented history of carcinoid syndrome. All patients were receiving a minimum dose of octreotide of 30 mg every 4 weeks or a minimum dose of lanreotide of 120 mg every 3 weeks upon entering trial.
At baseline, the average daily bowel movements per patient were ≥4. The dual primary endpoints of the study were change from baseline in the number of bowel movements at 12 weeks and the incidence of treatment-related adverse events (AEs). Secondary endpoints focused on changes in urinary 5-hydroxyindoleacetic acid, cutaneous flushing episodes, and abdominal pain.
In the 250 mg arm, treatment with telotristat etiprate demonstrated a 29% reduction in the average number of daily bowel movements at week 12 compared with baseline. In the 500 mg arm, there was a 35% reduction. Those in the placebo arm experienced a 17% reduction in average daily bowel movements.
A greater than 30% reduction in daily bowel movements was experienced by 20% of patients in the placebo arm compared with 44% and 42% of those treated with telotristat etiprate in the 250 and 500 mg arms, respectively (P
<.04). Based on the promise of these results, a 36-week open-label extension arm was opened to allow all patients to receive telotristat etiprate at 500 mg 3 times daily dose. This arm has fully recruited (NCT01677910).
In the study, patients experienced similar AEs in the placebo and investigational arms. Those receiving the 250 mg dose experienced gastrointestinal (GI) discomfort and mood-related AEs that were similar to placebo. GI and mood-related AEs were better in the 250 mg arm compared with the 500 mg dose, according to Lexicon. Treatment discontinuations due to serious AEs were similar across all arms.
"Carcinoid syndrome is severely debilitating, preventing many patients from leading active and predictable lives, and unfortunately, a majority of patients will not be adequately controlled over time with the current standard of care," Lonnel Coats, president and chief executive officer at Lexicon, said in a statement. "We are committed to working closely with the FDA to file our first new drug application and to bring this innovative new treatment to patients whose lives are already impacted by the challenges of cancer."
Telotristat etiprate was granted a fast track designation in 2008 and a subsequent orphan drug designation in 2012. The TELESTAR trial is the first successful phase III trial completed by Lexicon. If approved, telotristat etiprate would be the first therapy approved for carcinoid syndrome in more than 16 years.
"We are extremely pleased with these top-line results," Coats said.
Telotristat etiprate is an oral bioavailable, small-molecule inhibitor of tryptophan hydroxylase (TPH), which is overexpressed in carcinoid tumor cells and is involved in serotonin biosynthesis. Blockade of TPH reduces peripheral serotonin production (5-HT), resulting in fewer serotonin-mediated GI effects, like diarrhea.
A second 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).