telotristat and Malignant-Carcinoid-Syndrome

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient's quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.

Topics: Humans; Malignant Carcinoid Syndrome; Phenylalanine; Pyrimidines; Serotonin; Signal Transduction; Tryptophan Hydroxylase

Many patients with neuroendocrine tumour-related carcinoid syndrome treated with somatostatin analogues (SSA) won't achieve adequate symptom relief with the SSA alone; new treatment options are required. Telotristat ethyl is a tryptophan hydroxylase inhibitor, developed for the treatment of carcinoid syndrome. Areas covered: This review summarises the evidence supporting the role of telotristat ethyl in the management of carcinoid syndrome. Rationale, pharmacodynamics, pharmacokinetics, metabolism, clinical experience, efficacy and toxicity profiles are covered. Expert opinion: The efficacy of telotristat ethyl in producing a statistically-significant and clinically-meaningful reduction in daily bowel movements has been confirmed in phase III clinical trials. Two pivotal trials, TELESTAR and TELECAST, explored the role of telotristat ethyl in the management of patients with carcinoid syndrome refractory to SSAs focusing on patients with ≥4 and <4 daily bowel movements, respectively. In addition, benefit was confirmed in patient-reported outcomes. Based on activity and safe toxicity profile, telotristat ethyl is pending regulatory agencies evaluation and is likely to add to the armamentarium used to treat carcinoid syndrome. Long-term safety and efficacy data will be available from the ongoing TELEPATH study. The impact on carcinoid heart disease, mesenteric fibrosis and other long-term complications of carcinoid syndrome as well as its role earlier in patients' pathways remain investigational.

Topics: Animals; Carcinoid Tumor; Clinical Trials as Topic; Humans; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Phenylalanine; Pyrimidines; Somatostatin; Tryptophan Hydroxylase

Telotristat etiprate, a tryptophan hydroxylase inhibitor, was previously evaluated in a Phase II randomized, placebo-controlled clinical trial in patients with carcinoid syndrome (CS) and diarrhea not adequately controlled by octreotide. The objective of the current study was to characterize the symptom experiences of patients participating in that trial.. Consenting patients participated in one-on-one, qualitative interviews focused on eliciting symptoms they had experienced in association with their CS diagnosis and recollection of symptom changes they experienced while participating in the Phase II trial.. Among the 23 patients who participated in the previous 4-week dose-escalation study, 16 were eligible for interviews and 11 participated in the present study. The median time from study completion to the interview was 31 months; 4 of 11 patients were receiving telotristat etiprate in a follow-up, open-label trial at the time of interview. All of the patients (100%) described diarrhea as a symptom of CS, with effects on the emotional, social, and physical aspects of their lives. Improvement in diarrhea during the study was described by 82% of participants, and was very impactful in several patients. Results led to the design and implementation of a larger interview program in Phase III and helped to establish a definition of clinically meaningful change for the clinical development program.. The diarrhea associated with CS can have a large impact on daily lives, and patient interviews can characterize and capture clinically meaningful improvements with treatment. ClinicalTrials.gov Identifier: NCT00853047.

Topics: Aged; Antineoplastic Agents; Diarrhea; Female; Humans; Interviews as Topic; Male; Malignant Carcinoid Syndrome; Middle Aged; Phenylalanine; Pyrimidines; Treatment Outcome

Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed.. To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin).. A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses.. A multicenter study.. Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed.. TE, a novel oral inhibitor of peripheral serotonin synthesis.. Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA.. Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated.. TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Female; Flushing; Gastrointestinal Transit; Humans; Hydroxyindoleacetic Acid; Male; Malignant Carcinoid Syndrome; Middle Aged; Phenylalanine; Pyrimidines; Treatment Outcome

Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Diarrhea; Female; Gastrointestinal Agents; Humans; Hydroxyindoleacetic Acid; Male; Malignant Carcinoid Syndrome; Middle Aged; Octreotide; Phenylalanine; Pyrimidines; Serotonin Antagonists; Treatment Outcome

Telotristat ethyl (Xermelo™) is a peripheral tryptophan hydroxylase (TPH) inhibitor that was developed by Lexicon Pharmaceuticals, Inc. for the treatment of carcinoid syndrome. Many neuroendocrine tumours secrete serotonin (5-HT) into the blood stream, resulting in a number of symptoms, notably diarrhoea. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT. In February 2017, telotristat ethyl was approved in the USA for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. This article summarizes the milestones in the development of telotristat ethyl leading to this first global approval.

Topics: Animals; Diarrhea; Drug Approval; Drug Therapy, Combination; Humans; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Somatostatin; Tryptophan Hydroxylase; United States; United States Food and Drug Administration