Carcinoid Syndrome Diarrhea Research Articles

Real-World Clinical and Patient-Reported Outcomes from the Longitudinal Telotristat Ethyl Treatment Registry of Patients with Neuroendocrine Tumors.

BackgroundTelotristat ethyl (TE) is an oral tryptophan hydroxylase inhibitor approved for the treatment of carcinoid syndrome diarrhea (CSD) in combination with somatostatin analogs (SSAs).MethodsThis prospective, observational, single-arm study evaluated long-term patient-reported outcomes for adults initiating TE in US clinical practice from 2017 through January 2022. The primary objective was satisfaction with overall CS symptom control 6 months after initiating TE. Secondary objectives evaluated satisfaction with control of CSD, flushing, and CS symptoms, as well as work productivity/activity impairment, SSA use, and weight. All analyses were descriptive in nature.ResultsA total of 223 patients completed the baseline survey; 56% also completed the 6-month follow-up survey. Mean age was 61 years and 61% were women. After 6 months of TE treatment, the majority of patients (76%, n=95/125) reported being satisfied with control of their CS symptoms which was markedly improved from baseline (41%, n=91). Similarly, the majority of patients (78%, n=97/125) were satisfied with control of their CSD after 6 months of TE, markedly improved from baseline (36%).ConclusionThis longitudinal observational study showed improvements in real-world clinical and humanistic outcomes for patients with CS and at least 6 months of TE treatment.

Randomized, parallel arm, phase II study of telotristat (Xermelo) in combination with lutetium Lu 177 dotatate (Lutathera) in well-differentiated neuroendocrine tumors (NETs).

TPS516 Background: PRRT using Lutetium Lu 177 Dotatate, has been approved by the FDA for metastatic, progressive gastroenteropancreatic neuroendocrine tumors (GEPNETs). Despite an impressive progression-free survival noted in NETTER-1 study, most patients will eventually progress after PRRT treatment. Increased serotonin secretion is found in a number of slow-growing NETs of the diffuse neuroendocrine system. Serotonin stimulates proliferation in cell lines of a typical (NCI-H727), an atypical (NCI-H720) bronchopulmonary NET, a small intestinal NET (KRJ-I), and a functioning human pancreatic carcinoid cell line (BON). This stimulation of growth by serotonin can be performed in an autocrine manner. Telotristat ethyl is a novel oral inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. In 2017, results of placebo-controlled phase III study (Telestar) evaluating Telotristat ethyl confirmed that 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 bowel movement frequency and urinary 5- hydroxy indoleacetic acid (u5-HIAA). Based on results of the Telestar trial, FDA approved 250 mg PO TID dosage of Telotristat for control of carcinoid syndrome diarrhea. Of note, 500 mg TID arm showed increased decline in urinary 5-HIAA as compared to 250 mg TID arm. Study Hypotheses: We hypothesize that inhibition of serotonin production will lead to cytostatic effect on neuroendocrine tumors and will complement anti-tumor activity of lutetium 177 dotatate. We anticipate our proposed combination will result in improved treatment efficacy as reflected by improved 20-month PFS as compared to historical control (NETTER-1). Methods: This is a single center, open label, randomized, parallel arm, phase II study evaluating two dose levels of Telotristat (Xermelo; 250 mg vs 500 mg) in combination with Lutetium Lu 177 Dotatate (Lutathera) in 70 well-differentiated neuroendocrine tumor patients. Study is currently enrolling patients and is expected to complete accrual in 3 years. Clinical trial information: NCT04543955.

Comparative theoretical analysis using DFT & MP2 calculations, ADMET profiling and docking studies of the drug telotristat ethyl

The title drug, Ethyl(2S)-2-amino-3-(4{2-amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl) phenyl]-2,2,2-trifluoroethoxy] pyrimidin-4-yl}phenyl)propanoate was reported for carcinoid syndrome diarrhea and approved by FDA in the year 2017. DFT (B3LYP) and Moller-Plesset Second Order (MP2) quantum chemical calculations in the 631G basis set were used to optimize the drug and evaluate the global and local reactivity descriptors. Molecular docking was performed against the tryptophan hydroxylase-1 inhibitor protein to study the binding interactions of the drug with the protein and rationalize the structure-activity relationship. The bond length between drug and protein established the presence of good binding with more interaction or reactivity. Fukui functions were invoked to describe the reactivity and stability of the drug molecule. ADMET profiling of the drug molecule predicts poor solubility and limited absorption in the gastrointestinal tract. BOILED Egg representation displayed low absorption, impermeability to the Blood-Brain barrier, and induced P-gp Substrate. Descriptor parameters were compared between DFT and MP2 optimized structures for each atom, and the most reactive and stable atoms were reported. The current research focuses on the structural and bioactive properties of the title molecule. The study was conducted further to find suitable reactivity centers. This aspect would help to evaluate more reactivity patterns of such types of molecules in future.

Changes in Carcinoid Syndrome Symptoms Among Patients Receiving Telotristat Ethyl in US Clinical Practice: Findings from the TELEPRO-II Real-World Study.

BackgroundInadequately controlled symptoms incur a substantial burden on patients with neuroendocrine tumors and carcinoid syndrome (CS). The effectiveness of telotristat ethyl (TE) with a somatostatin analog for uncontrolled CS diarrhea has been demonstrated in clinical trials and observational studies. TELEPRO-II was a prospective observational study evaluating TE’s effectiveness in clinical practice over the first 3 months of treatment.MethodsPatients initiating TE in 2018 participated in an optional nurse support program reporting CS symptoms during interviews at baseline and 1, 2, and 3 months after TE initiation. Eligible patients received TE for ≥3 months and reported symptom burden at baseline and ≥1 follow-up visit within the first 3 months. Daily bowel movement (BM) frequency and flushing episodes were reported as events/episodes per day. Stool consistency, nausea severity, urgency severity, and abdominal pain were reported on a severity scale (1–10). Symptom changes were evaluated using paired-sample t-tests and Wilcoxon signed-rank tests. Analysis of symptoms based on achievement of <30% or ≥30% reduction in daily BM frequency was conducted using a cumulative distribution function.ResultsA total of 684/1603 (43%) patients were eligible for analysis. At baseline, patients reported a mean of 6.3 BM/day, nausea severity of 8.4/10 and stool urgency of 8.2/10. Significant improvements in all CS symptoms were observed after 3 months of TE. Mean daily BMs were reduced 64% after 3 months of TE (mean reduction [SD], –3.99 [3.8]; P<0.0001). Most patients (74%, n=503) reported ≥30% reduction in daily BM frequency; these patients also reported improvements in other symptoms (76–87%). Patients with <30% reduction in daily BMs also reported improvements in nausea severity (62%, n=24), daily flushing episodes (66%, n=98), abdominal pain (50%, n=60), urgency severity (38%, n=64), and stool consistency (24%, n=44).ConclusionPatients treated with TE in a real-world setting experienced significant, clinically meaningful improvements in CS symptoms.

Long-Term Treatment with Telotristat Ethyl in Patients with Carcinoid Syndrome Symptoms: Results from the TELEPATH Study

Introduction: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed. Objectives: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS. Methods: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients’ QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms. Results: In 124 patients exposed to telotristat ethyl for a mean of 102.6 ± 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study. Conclusions: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores (NCT02026063).

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome

BackgroundTelotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods.MethodsFirst occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial.ResultsIn TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3–4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2–3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6–11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7–11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR.ConclusionThe time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency.Trial RegistrationClinicalTrials.gov Identifiers: NCT01677910, NCT02063659

Direct costs of carcinoid syndrome diarrhea among adults in the United States

BACKGROUNDThe burden of carcinoid syndrome (CS) among patients with neuroendocrine tumors is substantial and has been shown to result in increased healthcare resource use and costs. The incremental burden of CS diarrhea (CSD) is less well understood, particularly among working age adults who make up a large proportion of the population of patients with CS.AIMTo estimate the direct medical costs of CSD to a self-insured employer in the United States.METHODSCS patients with and without CSD were identified in the IBM® MarketScan® Database, including the Medicare Supplemental Coordination of Benefits database. Eligible patients had ≥ 1 medical claim for CS with continuous health plan enrollment for ≥ 12 mo prior to their first CS diagnosis and for ≥ 30 d after, no claims for acromegaly, and no clinical trial participation during the study period (2014-2016). Baseline demographic and clinical characteristics, including comorbidities and treatment, were analyzed using descriptive statistics. Measures of healthcare resource use and costs were compared between patients with and without CSD, including Emergency Department (ED) visits, hospital admissions and length of stay, physician office visits, outpatient services, and prescription claims, using univariate and multivariate analyses to evaluate associations of CSD with healthcare resource use and costs, controlling for baseline characteristics.RESULTSOverall, 6855 patients with CS were identified of which 4,043 were eligible for the analysis (1352 with CSD, 2691 with CS only). Baseline demographic and clinical characteristics were similar between groups with the exception of age, underlying tumor type, and health insurance plan. Patients with CSD were older, had more comorbidities, and received more somatostatin analog therapy at baseline. Patients with CSD required greater use of healthcare resources and incurred higher costs than their peers without CSD, including hospitalizations (44% vs 25%) and ED visits (55% vs 31%). The total adjusted annual healthcare costs per patient were 50% higher (+ $23865) among those with CSD, driven by outpatient services (+ 56%), prescriptions (+ 48%), ED visits (+ 26%), physician office visits (+ 21%), and hospital admissions (+ 11%).CONCLUSIONThe economic burden of CSD is greater than that of CS alone among insured working age adults in the United States, which may benefit from timely diagnosis and management.

Optimizing the Management of Carcinoid Syndrome to Reduce the Impact of Diarrhea.

Diarrhea is often a presenting symptom in patients with neuroendocrine tumors (NETs). Frequently diagnosed in advanced stages, carcinoid syndrome diarrhea negatively impacts patients’ well-being and quality of life. This article will review the diagnostic work-up for neuroendocrine tumors and etiology and management of NET-related carcinoid syndrome diarrhea and provide guidance for advanced practitioners, including nurse practitioners, physician assistants, pharmacists, and dieticians, focusing on their role in patient and caregiver education regarding disease, symptom monitoring and management, development of patient-specific treatment, and survivorship plans.

Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea

ABSTRACT Objectives: We estimated the indirect costs of work productivity burden from carcinoid syndrome diarrhea (CSD) among employed, insured adults in the United States. Methods: Retrospective cohort study of patients ≥18 years old with CS who did and did not have CSD (2014–2016). Eligible patients had continuous health plan enrollment for ≥12 months prior to their first CS claim and for ≥30 days after. Univariate analyses of clinical and work productivity outcomes and indirect costs were conducted. Multivariate analyses examined associations of CSD with work productivity measures, controlling for baseline characteristics. Results: A total of 1,880 patients with CS were eligible, including 577 with CSD and 1,303 with CS only. Baseline characteristics were generally similar. Patients with CSD missed half of eligible workdays (median 56%, 146/260); those with CS-only missed one-third (38%, 100/260). Work productivity was lower and the associated costs were higher in the presence of CSD. Patients with CSD had more absenteeism, short-term disability, and lost workdays which translated into incremental mean costs of $16,679 greater than those with CS only. Conclusion: Indirect costs related to work productivity losses among adults with CSD are significant, which further add to the burden of CSD to society.

Management of Diarrhea in Patients With Carcinoid Syndrome.

Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.

&lt;p&gt;Spotlight on telotristat ethyl for the treatment of carcinoid syndrome diarrhea: patient selection and reported outcomes&lt;/p&gt;

Neuroendocrine tumors (NETs) are rare cancers with an associated prolonged survival in some patients. A proportion of patients diagnosed with NETs will present with carcinoid syndrome symptoms, characterized by diarrhea, flushing and/or wheezing. This review summarizes the current treatment options for carcinoid syndrome, focusing on the latest novel treatment option, telotristat ethyl. In addition, information on patient-reported outcomes and impact of carcinoid syndrome on quality of life (QOL) and improvement of following treatment with telotristat ethyl are reviewed. This article also provides an overview of the current QOL questionnaires for patients with NETs and addresses unmet needs in this field of patient-reported outcomes.

TELEPRO: Patient-Reported Carcinoid Syndrome Symptom Improvement Following Initiation of Telotristat Ethyl in the Real World.

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 t tests and Wilcoxon signed-rank tests. 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 p < .001). At least half of patients treated with TE experienced ≥30% improvement from baseline in BM frequency and an average reduction of at least two BMs per day within 3 months. 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.

Systemic Therapy for Neuroendocrine Neoplasms

AbstractNeuroendocrine neoplasms (NENs) are heterogeneous malignancies which are becoming more common. Systemic treatment is considered for patients with advanced disease, and treatment decisions are often driven by the histological grade of the tumor and the site of primary. Somatostatin analogues are the first-line option of choice for gastroenteropancreatic NENs but subsequent options may include the targeted agents everolimus and sunitinib as well as peptide receptor radionuclide therapy. Telotristat is a new option for the treatment of refractory carcinoid syndrome diarrhea. Chemotherapy is infrequently used for Grade 1 to 2 NENs (except for the combination of capecitabine and temozolomide) but is the mainstay of therapy for Grade 3 neuroendocrine carcinomas. Bronchial NENs are graded differently and there are few proven options for systemic treatment. Optimal integration of available systemic therapies, the timely recognition of tumor heterogeneity, and the use of nuclear medicine are areas of ongoing research. Finally, the patient experience is impacted by factors such as delayed diagnosis and symptoms of carcinoid syndrome. Clinicians need to account for patient priorities and disease characteristics to individualize therapy choices for patients with advanced NEN.

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.

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.

FDA approves Xermelo for carcinoid syndrome diarrhea

FDA approves Xermelo for carcinoid syndrome diarrhea

Time to sustained improvement in bowel movement frequency with telotristat ethyl: Analysis of the phase III telecast study.

395 Background: Telotristat ethyl (TE) is approved to treat inadequately controlled carcinoid syndrome (CS) diarrhea in combination with somatostatin analog (SSA) therapy. Understanding the time to onset of sustained BM frequency improvement is important when considering the use of TE in patients with CS diarrhea. We present data on time to sustained improvement and worsening in BM frequency during the double-blind treatment (DBT) period of TELECAST, a phase 3, randomized, placebo-controlled, double-blind study in patients with CS that required additional treatment, primarily due to gastrointestinal symptoms. Methods: Stable dose SSA was not required. Patients were treated with TE 250 mg 3 times per day (tid), TE 500 mg tid, or placebo tid. Sustained response was defined as the time from the first double-blind dose date to the first day of 2 consecutive weeks with BM frequency change of at least 30% from baseline. The time to the first sustained response in the TELECAST study was examined among treatment groups and analyzed using Cox regression. Results: There were 26 patients on placebo and 25 patients on either 250 mg or 500 mg telotristat groups. Sustained improvement in BM frequency over the 12-week DBT period was achieved in 6, 16, and 16 patients on placebo, TE 250 mg, and TE 500 mg treatment groups. Median time to sustained ≥ 30% improvement was 4-5 weeks with TE at both dosing levels, with no median reached on placebo. First occurrence of sustained improvements in BM frequency occurred within 4-68 days. Time to sustained worsening was delayed on the 500-mg dose of TE (no percentile reached) and is statistically significant (p = 0.021, HR: 0.25) Conclusions: Treatment with telotristat ethyl may provide sustained BM frequency reduction within 4-5 weeks (median) of initiating therapy. No median was reached on placebo due to fewer patients with sustained improvement. Additionally, TE 500 mg tid may also offer additional clinical benefit by reducing sustained BM worsening. Clinical trial information: NCT02063659.

Developments in the treatment of carcinoid syndrome - impact of telotristat.

Carcinoid syndrome occurs in 20% of patients with neuroendocrine tumors, and serotonin is usually the main causative hormonal peptide. Carcinoid syndrome, and particularly diarrhea, can significantly impact patients’ quality of life. Somatostatin analogs (SSAs) are the mainstay of treatment, but are unable to ameliorate symptoms in all patients due to dose-limiting side effects and tachyphylaxis. Telotristat is a novel oral inhibitor of tryptophan hydroxylase, which is the rate-limiting enzyme in serotonin synthesis. A Phase III placebo-controlled trial of telotristat etiprate (orally at 250 mg three times a day) showed a significant decrease in the frequency of bowel motions in treated patients with diarrhea from carcinoid syndrome. The main side effects were gastrointestinal symptoms, deranged liver function tests and depression. Treatment with 500 mg three times a day also decreased stool frequency, but was associated with more nausea and mood disturbances. Telotristat, therefore, represents a valuable option in the management of carcinoid syndrome diarrhea refractory to SSAs, and the US Food and Drugs administration approved its use for this indication in March 2017. However, its role in somatostatin-naïve patients and in the treatment of other carcinoid syndrome symptoms (flushing and abdominal pain) remains unknown. Further research should focus on these issues as well as the safety of continuing telotristat in the context of other systemic antineoplastic therapies.

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea.

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.

Telotristat ethyl for the treatment of carcinoid syndrome diarrhea not controlled by somatostatin analogues.

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.

Budgetary Impact of Telotristat Ethyl, a Novel Treatment for Patients with Carcinoid Syndrome Diarrhea: A US Health Plan Perspective

PurposeTelotristat 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. MethodsA 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. FindingsA 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. ImplicationsThe 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.