Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors.

Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.

One Key and Multiple Locks: Substrate Binding in Structures of Tryptophan Dioxygenases and Hydroxylases.

Since its discovery at the beginning of the past century, the essential nutrient l-Tryptophan (l-Trp) and its catabolic pathways have acquired an increasing interest in an ever wider scientific community for their pivotal roles in underlying many important physiological functions and associated pathological conditions. As a consequence, enzymes catalyzing rate limiting steps along l-Trp catabolic pathways - including IDO1, TDO, TPH1 and TPH2 - have turned to be interesting drug targets for the design and development of novel therapeutic agents for different disorders such as carcinoid syndrome, cancer and autoimmune diseases. This article provides a fresh comparative overview on the most recent advancements that crystallographic studies, biophysical and computational works have brought on structural aspects and molecular recognition patterns of these enzymes toward l-Trp. Finally, a conformational analysis of l-Trp is also discussed as part of the molecular recognition process governing the binding of a substrate to its cognate enzymes.

Gastric Serotonin Biosynthesis and Its Functional Role in L-Arginine-Induced Gastric Proton Secretion.

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.

Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease.

Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.

RNA-Seq reveals inflammatory mechanisms of Xiao-Ban-Xia-Tang decoction to ameliorate cisplatin-induced emesis in a rat pica model.

OBJECTIVES: Xiao-Ban-Xia-Tang decoction (XBXT), an antiemetic formula in traditional Chinese medicine, has been proved to be a potential treatment for chemotherapy-induced nausea and vomiting (CINV), but the underlying mechanisms are not adequately understood. This study aimed to investigate changes in the ileum transcriptome after cisplatin and XBXT treatment and to reveal whether the antiemetic mechanisms of XBXT are related to its anti-inflammatory effect. METHODS: The pica model was established by a single intraperitoneal injection of 6 mg/kg cisplatin in Wistar rats. Tissues from the gastric antrum and ileum were stained with hematoxylin-eosin to observe gastrointestinal tract pathological changes. Based on the differentially expressed genes (DEGs) which were altered by cisplatin and reversed by XBXT, the transcriptome data of rat ileum were analyzed by GO, KEGG, and PPI analyses. Several inflammatory DEGs were validated by RT-PCR. RESULTS: XBXT could reduce kaolin intake up to 72 h after modeling and alleviate the inflammatory damage of gastric antrum and ileum induced by cisplatin. According to the transcriptome profile, there were 75 DEGs down-regulated by cisplatin and up-regulated by XBXT and 343 DEGs up-regulated by cisplatin and down-regulated by XBXT. XBXT could blunt the overexpression of tryptophan hydroxylase 1 (the rate-limiting enzyme of serotonin synthesis) in ileum. Enrichment analysis showed that inhibiting overexpression of several conventional inflammation pathways and pro-inflammation cytokines were related to the antiemetic effectiveness of XBXT. CONCLUSIONS: This study implies that inhibiting inflammatory signaling pathways and synthesis of serotonin might be potential mechanisms of XBXT's antiemetic effect against CINV.

Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis.

Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation. Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound 1 (2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 ± 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of 1 showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of 1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed. Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.

Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications.

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.

Effects of Thryptophan Hydroxylase Blockade by P-Chlorophenylalanine on Contextual Memory Reconsolidation after Training of Different Intensity.

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval induces the plasticity, which may result in reconsolidation of the original memory and needs critical molecular events to stabilize the memory or its extinction. 4-Chloro-DL-phenylalanine (P-chlorophenylalanine-PCPA) depresses the most limiting enzyme of serotonin synthesis the tryptophan hydroxylase. It is known that PCPA reduces the serotonin content in the brain up to 10 times in rats (see Methods). We hypothesized that the PCPA could behave the similar way in snails and could reduce the content of serotonin in snails. Therefore, we investigated the effect of PCPA injection on contextual memory reconsolidation using a protein synthesis blocker in snails after training according to two protocols of different intensities. The results obtained in training according to the first protocol using five electrical stimuli per day for 5 days showed that reminding the training environment against the background of injection of PCPA led to a significant decrease in contextual memory. At the same time, the results obtained in training according to the second protocol using three electrical stimuli per day for 5 days showed that reminding the training environment against the injection of PCPA did not result in a significant change in contextual memory. The obtain results allowed us to conclude that the mechanisms of processes developed during the reconsolidation of contextual memory after a reminding depend both on the intensity of learning and on the state of the serotonergic system.

Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells.

Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating its effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2 (somatostatin receptor subtype 2)-preferring SSA should be evaluated in more detail.

Inhibition of serotonin synthesis: A novel therapeutic paradigm.

The rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase (TPH). There are two independent serotonin systems in the body characterized by two isoforms of TPH, TPH1 and TPH2. While TPH2 synthesizes serotonin in the brain, TPH1 is expressed in the gut and in other peripheral tissues and supplies platelets in the circulation with serotonin. This duality of the serotonin system is enforced by the blood-brain barrier which is impermeable for serotonin. In the brain serotonin acts as neurotransmitter and is a main target for the treatment of psychiatric disorders. In the periphery it is released by platelets at the site of activation and elicits numerous physiological effects. TPH1 deficient mice were shown to be protected from diverse diseases including hemostatic, inflammatory, fibrotic, gastrointestinal, and metabolic disorders and therefore serotonin synthesis inhibition emerged as a reasonable therapeutic paradigm. Recently the first TPH inhibitor, telotristat ethyl, came on the market for the treatment of carcinoid syndrome. This review summarizes the state of development and the therapeutic opportunities of such compounds.

Functional Inactivation of Mast Cells Enhances Subcutaneous Adipose Tissue Browning in Mice.

Adipose tissue browning and systemic energy expenditure provide a defense mechanism against obesity and associated metabolic diseases. In high-cholesterol Western diet-fed mice, mast cell (MC) inactivation ameliorates obesity and insulin resistance and improves the metabolic rate, but a direct role of adipose tissue MCs in thermogenesis and browning remains unproven. Here, we report that adrenoceptor agonist norepinephrine-stimulated metabolic rate and subcutaneous adipose tissue (SAT) browning are enhanced in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wild-type mice on a chow diet. MC reconstitution to SAT in Kitw-sh/w-sh mice blocks these changes. Mechanistic studies demonstrate that MC inactivation elevates SAT platelet-derived growth factor receptor A (PDGFRα+) adipocyte precursor proliferation and accelerates beige adipocyte differentiation. Using the tryptophan hydroxylase 1 (TPH1) inhibitor and TPH1-deficient MCs, we show that MC-derived serotonin inhibits SAT browning and systemic energy expenditure. Functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice.

Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models.

Introduction: Tryptophan hydroxylase 2 (TPH2) is the key, rate-limiting enzyme of serotonin (5-HT) synthesis in the brain. Some polymorphic variants of the human Tph2 gene are associated with psychiatric disorders. Area covered: This review focuses on the mechanisms underlying the association between the TPH2 activity and behavioral disturbances in models of psychiatric disorders. Specifically, it discusses: 1) genetic and posttranslational mechanisms defining the TPH2 activity, 2) behavioral effects of knockout and loss-of-function mutations in the mouse Tph2 gene, 3) pharmacological inhibition and the activation of the TPH2 activity and 4) alterations in the brain TPH2 activity in animal models of psychiatric disorders. We show the dual role of the TPH2 activity: both deficit and excess of the TPH2 activity cause significant behavioral disturbances in animal models of depression, anxiety, aggression, obsessive-compulsive disorders, schizophrenia, and catalepsy. Expert opinion: Pharmacological chaperones correcting the structure of the TPH2 molecule are promising tools for treatment of some hereditary psychiatric disorders caused by loss-of-function mutations in the human Tph2 gene; while some stress-induced affective disorders, associated with the elevated TPH2 activity, may be effectively treated by TPH2 inhibitors. This dual role of TPH2 should be taken into consideration during therapy of psychiatric disorders.

The journey from gene knockout to clinical medicine: telotristat and sotagliflozin.

Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood-brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

Relationship Between Symptoms and Health-related Quality-of-life Benefits in Patients With Carcinoid Syndrome: Post Hoc Analyses From TELESTAR.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Peripartum dietary supplementation of a small-molecule inhibitor of tryptophan hydroxylase 1 compromises infant, but not maternal, bone.

Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized that inhibiting nonneuronal serotonin activity by feeding a small-molecule inhibitor of the rate-limiting enzyme in serotonin synthesis [tryptophan hydroxylase 1 (TPH1)] would preserve maternal bone postweaning without affecting neonatal bone. Chow supplemented with the small-molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation, and blood was collected on days 1 and 21 of lactation. Dams returned to a common diet postweaning and were aged to 3 or 9 mo postweaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations ( P = 0.0007) and reduced bone turnover, indicated by serum NH2-terminal propeptide of type I collagen ( P = 0.01) and COOH-terminal collagen cross-links ( P = 0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at 3 or 9 mo postweaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared with pups from control dams, with fewer ( P = 0.02) and thinner ( P = 0.001) trabeculae as well as increased trabecular spacing ( P = 0.04). Additionally, cortical porosity was increased ( P = 0.007) and cortical tissue mineral density was decreased ( P = 0.005) in pups of LP778902-treated dams. Small-molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.

Crucial Roles of 5-HT and 5-HT2 Receptor in Diabetes-Related Lipid Accumulation and Pro-Inflammatory Cytokine Generation in Hepatocytes.

BACKGROUND/AIMS: Previously, we confirmed that liver-synthesized 5-HT rather than non-liver 5-HT, acting on the 5-HT2 receptor (5-HT2R), modulates lipid-induced excessive lipid synthesis (ELS). Here, we further revealed the effects of the hepatocellular 5-HT system in diabetes-related disorders. METHODS: Studies were conducted in male ICR mice, human HepG2 cells, and primary mouse hepatocytes (PMHs) under gene or chemical inhibition of the 5-HT system, key lipid metabolism, and inflammation-related factors. Protein and messenger RNA expression and levels of the factors were determined via western blotting, reverse transcription PCR, and quantitative assay kits, respectively. Hepatic steatosis with inflammation and fibrosis, intracellular lipid droplet accumulation (LDA), and reactive oxygen species (ROS) location were determined via hematoxylin and eosin, Masson's trichrome, Oil red O, and fluorescent-specific staining, respectively. RESULTS: Palmitic acid induced the activation of the 5-HT system: the activation of 5-HT2R, primarily 5-HT2AR, in addition to upregulating monoamine oxidase A (MAO-A) expression and 5-HT synthesis, by activating the G protein/ phospholipase C pathway modulated PKCε activation, resulting in ELS with LDA; the activation of NF-κB, which mediates the generation of pro-inflammatory cytokines, was primarily due to ROS generation in the mitochondria induced by MAO-A-catalyzed 5-HT degradation, and secondarily due to the activation of PKCε. These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. CONCLUSION: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target.

Telotristat Ethyl: A Review in Carcinoid Syndrome Diarrhoea.

Telotristat ethyl (Xermelo®), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

PURPOSE: 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/m2) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. METHODS: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FINDINGS: 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. IMPLICATIONS: 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.