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Lexicon's phase 3 trial of telotrista...
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Lexicon’s phase 3 trial of telotristat etiprate in cancer patients with carcinoid syndrome meets primary endpoint
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Lexicon Pharmaceuticals, Inc., a fully integrated biopharmaceutical company, announced that the pivotal TELESTAR phase 3 clinical trial met its primary endpoint, showing the benefit of oral telotristat etiprate in treating cancer patients with carcinoid syndrome that is not adequately controlled by the current standard of care.

Telotristat etiprate was discovered using Lexicon’s gene science, based on Nobel Prize-winning technology, and is the company’s first discovery to complete a pivotal phase 3 clinical trial. If approved, telotristat etiprate would be the first oral treatment successfully developed for carcinoid syndrome and the first addition to the standard of care in more than 16 years.

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.

“We are extremely pleased with these top-line results. 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. We are committed to working closely with the US Food and Drug Administration (FDA) to file our first new drug application (NDA) and to bring this innovative new treatment to patients whose lives are already impacted by the challenges of cancer,” said Lexicon president and chief executive officer Lonnel Coats.

“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,” said principal investigator Matthew H. Kulke, M.D., director, programme in neuroendocrine and carcinoid tumours and senior physician, Dana Farber Cancer Institute, and associate professor of medicine, Harvard Medical School.

Lexicon received Fast Track designation and Orphan Drug status for telotristat etiprate from FDA in 2008 and 2012, respectively. The company plans to announce complete results from the phase 3 TELESTAR study at an upcoming scientific conference.

Carcinoid syndrome is a rare disease affecting thousands of patients with neuroendocrine tumours that originate in the gastrointestinal tract and metastasize or spread to the liver or other organs. Overproduction of serotonin within these metastatic neuroendocrine tumour (mNET) cells is a driver of carcinoid syndrome, which is characterized by debilitating diarrhea, facial flushing, abdominal pain, heart valve damage and other serious consequences. The severe and unpredictable diarrhea associated with carcinoid syndrome has a profound impact on cancer patients’ lives, often preventing them from participating in daily activities.

The current standard of care for carcinoid syndrome is somatostatin analog depot injection (SSA), first approved in 1998. SSA therapy fails to maintain adequate control of carcinoid syndrome for most patients, with many becoming not adequately controlled within the first two years after the therapy is initiated. Patients with carcinoid syndrome can live for many years with metastatic cancer, requiring the need for long-term treatment options to effectively manage their disease.

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 which was 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.

Top-line results from TELESTAR 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.

In a key secondary measure, a substantially greater proportion of patients on telotristat etiprate achieved a durable response (44 percent and 42 per cent in the 250 mg and 500 mg arms, respectively), defined as at least a 30 per cent reduction in daily bowel movements over at least half the days of the study period, as compared to 20 per cent response on placebo (p<0.040).

Patients who received 250 mg of telotristat etiprate experienced a 29 per cent 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. 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 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. Further in depth analysis of safety and tolerability data will be conducted.

The 12-week study period is being followed by a 36-week open-label extension where all patients receive telotristat etiprate 500 mg three times daily.

Discovered using Lexicon’s unique approach to gene science, telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase (TPH), an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome. While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumour cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells. By specifically inhibiting serotonin production, telotristat etiprate seeks to control this important driver of carcinoid syndrome and, in turn, provide patients with more control over their disease.

Lexicon retains rights to market telotristat etiprate in the US and Japan, and is building the in-house commercial infrastructure to serve the US market. The company has a license and collaboration agreement with Ipsen to commercialise telotristat etiprate in Europe and other countries outside the US and Japan.

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