lx1032 and Diarrhea

Telotristat ethyl (Xermelo

Topics: Diarrhea; Drug Interactions; Drug Therapy, Combination; Humans; Malignant Carcinoid Syndrome; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Signal Transduction; Somatostatin; Treatment Outcome; Tryptophan Hydroxylase

Telotristat ethyl (Xermelo), developed by Lexicon Pharmaceuticals, is an oral tryptophan hydroxylase inhibitor blocking peripheral conversion of tryptophan to serotonin (5-hydroxytryptamine [5-HT]). It was approved by the U.S. Food and Drug Administration (FDA) in February 2017 and by the European Commission in September 2017 for patients with carcinoid syndrome in whom diarrhea is not adequately controlled by somatostatin analogues (SSAs). Diarrhea, secondary to the release of serotonin, is the predominant gastrointestinal symptom in patients with carcinoid syndrome and has a significant impact on patients' quality of life. Telotristat is not meant for all patients with diarrhea and carcinoid syndrome. Prescribing of telotristat for patients with diarrhea refractory to SSAs requires careful consideration and an approach that involves identifying and ruling out other common causes of diarrhea in patients with carcinoid syndrome. Delineating the timing of diarrhea and whether it occurs in patients with stable disease versus cancer progression can help identify the right drug candidates for therapy.

Topics: Clinical Trials as Topic; Diarrhea; Humans; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Phenylalanine; Pyrimidines; Somatostatin

Metastatic neuroendocrine tumors (NETs) are associated with carcinoid syndrome that is typically characterized by diarrhea, cutaneous flushing and bronchospasm. Treatment with somatostatin analogues (SSA) improves the symptom burden but a significant proportion of patients stop responding to SSA therapy eventually. Novel agents with the potential to effectively control the symptoms are urgently needed.. This article reviews an in-depth analysis of the phase I-III clinical trials determining the clinical rationale for the use of tryptophan hydroxylase inhibitor, telotristat ethyl in patients with well-differentiated metastatic NETs and uncontrolled carcinoid syndrome.. Telotristat ethyl has already been approved for the treatment of inadequately controlled carcinoid syndrome symptoms in metastatic NET patients on SSA therapy. Results from multiple phase I-III clinical studies of telotristat ethyl therapy have reported a significant decrease in the daily bowel movement frequency, increase in quality of life and the subsequent decrease in annual health costs related to carcinoid syndrome symptoms in NET patients.. The associated decrease in urinary 5-hydroxyindoleacetic acid (u5-HIAA) provides evidence that telotristat ethyl effectively decreases serotonin production, and therefore, offers a rationale to investigate this agent to mitigate serotonin-mediated complications in this patient population, especially cardiac valvular disease or mesenteric fibrosis.

Topics: Administration, Oral; Diarrhea; Female; Humans; Male; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Phenylalanine; Pyrimidines

When carcinoid syndrome (CS) diarrhea (CSD) is inadequately controlled with long-acting somatostatin analogs (SSAs), clinical practice guidelines recommend addition of the tryptophan hydroxylase inhibitor telotristat ethyl (TE). In a 12-week multinational, randomized controlled trial, TE added to SSA reduced peripheral serotonin and the frequency of CSD. We evaluated real-world effectiveness of TE using patient-reported data from a nurse support program over 3 months.. This study used a deidentified data set of patients initiating TE who opted into a nurse support program between March and November 2017 and reported CS symptom burden at baseline and at least one follow-up time point at months 1, 2, and 3. Patients reported demographic and medical history information as well as frequency of bowel movements (BMs) and flushing episodes, severity of nausea, urgency and abdominal pain (0 "no/not at all" to 100 "worst imaginable/very urgent"), and stool form (1 "very hard" to 10 "watery"). Mean changes from baseline in CS symptom burden were reported using paired-sample. Most patients initiating TE enrolled in the nurse program (791/898, 88%), of whom 369 (47%) were included in the analysis. Patients treated with TE reported significant reductions in CSD and other CS symptoms (all. Patients taking SSA therapy showed substantial burden of disease before initiating TE and significant improvements with the addition of TE treatment in this real-world effectiveness study.. Patients with carcinoid syndrome diarrhea uncontrolled by high doses of long-acting somatostatin analogs may be candidates for additional therapy with the tryptophan hydroxylase inhibitor telotristat ethyl. Understanding the real-world prevalence of uncontrolled symptoms and the effectiveness of telotristat ethyl in clinical practice may further support clinical and policy decisions for these patients. This study investigated self-reported carcinoid syndrome symptom burden and improvements among patients initiating telotristat ethyl and participating in a voluntary nurse support program. Disease burden and off-label somatostatin analog treatment before initiating telotristat ethyl were high, and symptoms improved markedly over 1, 2, and 3 months of treatment.

Topics: Aged; Cohort Studies; Diarrhea; Female; Follow-Up Studies; Humans; International Agencies; Male; Malignant Carcinoid Syndrome; Patient Reported Outcome Measures; Phenylalanine; Prognosis; Pyrimidines

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (

Topics: Adult; Aged; Aged, 80 and over; Diarrhea; Double-Blind Method; Female; Humans; Hydroxyindoleacetic Acid; Male; Malignant Carcinoid Syndrome; Middle Aged; Phenylalanine; Pyrimidines; Somatostatin; Treatment Outcome

In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m. Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan.. In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.. Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.

Topics: Aged; Body Weight; Diarrhea; Double-Blind Method; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Phenylalanine; Pyrimidines; Treatment Outcome; Tryptophan Hydroxylase

Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL.. Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48.. At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs.. These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.

Topics: Aged; Diarrhea; Double-Blind Method; Female; Humans; Male; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Phenylalanine; Pyrimidines; Quality of Life; Treatment Outcome; Tryptophan Hydroxylase

Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful.. Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment.. All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo.. Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl.

Topics: Diarrhea; Double-Blind Method; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Phenylalanine; Pyrimidines; Treatment Outcome

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Topics: Aged; Antineoplastic Agents, Hormonal; Defecation; Diarrhea; Double-Blind Method; Female; gamma-Glutamyltransferase; Gastrointestinal Agents; Humans; Hydroxyindoleacetic Acid; Male; Malignant Carcinoid Syndrome; Middle Aged; Nausea; Octreotide; Peptides, Cyclic; Phenylalanine; Pyrimidines; Somatostatin; Tryptophan Hydroxylase

We evaluated carcinoid syndrome (CS) symptoms and the real-world effectiveness of telotristat ethyl (TE) among patients with ≤3 bowel movements (BM) per day.. Patients with CS initiating TE between March and November 2017 could participate in a nurse support program collecting demographic and CS symptom data before TE initiation (baseline) and during ≥1 monthly follow-up within 3 months. Symptoms for patients averaging ≤3 BM/d at baseline were evaluated using pre/post-Student t tests.. Sixty-eight patients reported ≤3 BM/d at baseline. Symptom burden was high and similar to participants with higher daily BM frequency. After 3 months of TE, most patients reported stable or improved symptoms with significant improvements in urgency (88%; mean [SD], -13.2 [32.2]), stool consistency (88%; -1.3 [2.0]), BMs per day (81%; -0.2 [1.2]), abdominal pain (86%; -13.7 [25.8]), nausea (85%; -30.9 [35.7]), and daily flushing episodes (83%; -1.7 [4.4]; all except BMs per day, P < 0.05).. This analysis illustrates high CS symptom burden among patients with relatively low daily BM frequency. After initiating TE, patients reported significant improvements in urgency, stool consistency, abdominal pain, nausea, and flushing episodes. Clinicians and population health managers should consider CS symptom burden beyond daily BM frequency when evaluating treatment selection.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Child; Child, Preschool; Defecation; Diarrhea; Female; Flushing; Humans; Infant; Infant, Newborn; Male; Malignant Carcinoid Syndrome; Middle Aged; Nausea; Patient Reported Outcome Measures; Phenylalanine; Pyrimidines; Recovery of Function; Time Factors; Treatment Outcome; Young Adult

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.. Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.. Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.. Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome.. Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarrhea; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Patient Safety; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome

This study evaluated the cost-effectiveness of telotristat ethyl (TE) added to somatostatin analog octreotide (SSA + TE) compared to octreotide alone (SSA) in patients with carcinoid syndrome diarrhea (CSD) whose symptoms remain uncontrolled with SSA alone.. A deterministic Markov model evaluated the costs and quality-adjusted life-years (QALY) gained with SSA + TE vs SSA per a third-party US payer perspective. The model reflected clinical practice and resource use estimates based on current standards of care, with utility estimates based on similar symptoms from ulcerative colitis. Treatment efficacy was based on the phase III clinical trial of SSA + TE vs SSA alone [TELESTAR, NCT01677910]. According to TELESTAR, 44% of SSA + TE and 20% of SSA patients responded to therapy after 12 weeks. At each 4-week assessment period, SSA patients not adequately controlled received increasing doses of SSA and SSA + TE patients discontinued TE and moved to SSA only. Drug costs for adequately and not adequately controlled patients were $4,291.75 and $5,890.57 for SSA, respectively, and $9,456.07 and $5,890.57 for SSA + TE, respectively.. The base-case analysis demonstrated lifetime QALYs of 1.67 at a cost of $495,125 for the SSA cohort and 2.33 ($590,087) for SSA + TE with an incremental QALY for SSA + TE of 0.66 for an additional $94,962. The incremental cost per QALY gained was $142,545. Sensitivity analyses demonstrated high probability (>99%) of SSA + TE being cost-effective at thresholds for rare diseases and orphan drugs of $300,000-$450,000.. The recent availability of TE precluded the incorporation of clinical and economic inputs based on real-world practice patterns. The scarcity of epidemiology and utility information for this rare condition required the use of some proxy estimates.. This analysis demonstrated TE is a cost-effective treatment option when used on top of standard of care in CSD patients.

Topics: Adult; Aged; Cost-Benefit Analysis; Diarrhea; Drug Costs; Drug Therapy, Combination; Female; Health Resources; Humans; Male; Malignant Carcinoid Syndrome; Markov Chains; Middle Aged; Phenylalanine; Pyrimidines; Quality-Adjusted Life Years; Somatostatin; Treatment Outcome; United States

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.

Topics: Diarrhea; Humans; Malignant Carcinoid Syndrome; Phenylalanine; Prevalence; Pyrimidines; Quality of Life; Somatostatin; Treatment Outcome; Tryptophan Hydroxylase

Topics: Carcinoid Tumor; Clinical Trials, Phase III as Topic; Diarrhea; Humans; Malignant Carcinoid Syndrome; Phenylalanine; Pyrimidines

Topics: Antidiarrheals; Diarrhea; Drug Therapy, Combination; Humans; Malignant Carcinoid Syndrome; Octreotide; Phenylalanine; Pyrimidines; Treatment Outcome

Telotristat ethyl (TE) was recently approved for carcinoid syndrome diarrhea (CSD) in patients not adequately controlled with somatostatin analog long-acting release (SSA LAR) therapy alone. A budget impact model was developed to determine the short-term affordability of reimbursing TE in a US health plan.. A budget impact model compared health care costs when CSD is managed per current treatment patterns (SSA LAR, reference drug scenario) versus when TE is incorporated in the treatment algorithm (SSA LAR + TE, new drug scenario). Prevalence of CSD, proportion of patients not adequately controlled on SSA LAR, monthly treatment costs (pharmacy and medical), and treatment efficacy were derived from the literature. In the reference drug scenario, an escalated monthly dose of SSA LAR therapy of 40 mg was assumed to treat patients with CSD not adequately controlled on the labeled dose of SSA LAR. In the new drug scenario, TE was added to the maximum labeled monthly dose of SSA LAR therapy of 30 mg. The incremental budget impact was calculated based on an assumed TE market uptake of 28%, 42%, and 55% during Years 1, 2, and 3, respectively. One-way sensitivity analyses were conducted to test model assumptions.. A hypothetical health plan of 1 million members was estimated to have 42 prevalent CSD patients of whom 17 would be inadequately controlled on SSA LAR therapy. The monthly medical cost per patient not adequately controlled on SSA LAR in addition to pharmacotherapy was estimated to be $3946 based on the literature. Based on the observed treatment response in a clinical trial of 20% and 44% for the base case reference and new drug scenarios, total per patient per month costs were estimated to be $7563 and $11,205, respectively. Total annual costs in the new drug scenario were estimated to be $2.3 to $2.5 million during the first 3 years. The overall incremental annual costs were estimated to be $154,000 in Year 1, $231,000 in Year 2, and $302,000 in Year 3. This translated to an incremental per patient per month cost of $0.013, $0.019, and $0.025 for Years 1, 2, and 3. These results remained robust in 1-way sensitivity analyses.. The availability of TE for patients not adequately controlled on SSA LAR therapy provides a novel treatment option for CSD. This model showed that providing access to this first-in-class oral agent would have a minimal budget impact to a US health plan.

Topics: Antidiarrheals; Budgets; Diarrhea; Health Care Costs; Humans; Insurance, Health; Malignant Carcinoid Syndrome; Models, Economic; Phenylalanine; Pyrimidines; Somatostatin; United States