Xermelo (telotristat etiprate) / Ipsen, Lexicon Pharma, TerSera Therap - LARVOL DELTA

5-HT prompt TPO mRNA transcription via H3Q5 serotonylation (ASH 2025) - "Subsequently, we established a 5-HT-depleted mouse model using LX1606, an inhibitor of tryptophan hydroxylase 1 (Tph1), the rate-limiting enzyme in 5-HT synthesis... This study reveals a novel mechanism for 5-HT-driven thrombopoiesis. 5-HT was transported into hepatocytes via SERT, where it was catalyzed by TGM2 to induce serotonylation of histone H3Q5, thereby facilitating transcriptional activation of the TPO gene."

Aplastic Anemia • Oncology • CD34 • TGM2

An Update on Novel Pharmacotherapies for the Treatment of Neuroendocrine Tumors. (PubMed, Int J Mol Sci) - "Therapeutic options include somatostatin analogs, multi-targeted tyrosine kinase inhibitors (e.g., sunitinib), or mammalian targets of rapamycin (mTOR) inhibitors (e.g., everolimus), telotristat ethyl, chemotherapy, and peptide-receptor radionuclide therapy. Biomarkers may assist in both the diagnosis and post-treatment follow-up in patients with GEP-NETs. The next decade of research on GEP-NETs is promising and should provide new insights into the molecular underpinnings of this disease, therapy selection, and the sequencing of the available therapies, along with the potential role of AL in NET pharmacotherapy."

Journal • Review • Neuroendocrine Tumor • Oncology • Solid Tumor • SSTR

Adverse Event Profile of Telotristat in Carcinoid Syndrome Diarrhea: Insights From the FAERS Database (ACG 2025) - "A total of 5,556 ADR reports were analyzed, including 375 deaths (6.7%) and 838 hospitalizations (15%). Gastrointestinal disorders were most common (47.6%), with diarrhea (14.1%) and constipation (10.5%) frequently reported. Intestinal obstruction occurred in 66 cases (5.7%), 42 (64%) of which were serious."

Adverse events • Carcinoid Syndrome • CNS Disorders • Constipation • Depression • Fatigue • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Insomnia • Pancreatitis • Psychiatry • Septic Shock • Sleep Disorder

Beyond the Pancreas: Two Atypical Presentations of VIPoma Requiring Multidisciplinary Care (ACG 2025) - "Postoperative persistent diarrhea was managed with lanreotide and telotristat ethyl...These painful anorectal complications required multidisciplinary intervention, including surgery evaluation, botulinum toxin injection to the internal sphincter, and bilateral pudendal nerve blocks. Persistent pelvic pain necessitated CT-guided pudendal nerve ablation, resulting in symptom improvement. These cases highlight complications of VIPoma syndromes, requiring comprehensive management with multidisciplinary care to address the multifaceted challenges, improving quality of life in this complex population.Figure: Figure 1: Large heterogeneous mass centered on the right adrenal gland measures 9.3 x 7.8 x 7.0 cm concerning for pheochromocytoma Figure: Figure 2: Positron emission tomography (PET) scan showing right-sided mesenteric soft tissue mass near the prior small bowel resection site, measuring 2.6 cm and adjacent metastatic lesions with radiotracer uptake."

Endocrine Disorders • Gastrointestinal Disorder • Gynecology • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • Musculoskeletal Pain • Neuroendocrine Tumor • Pancreatic Cancer • Short Bowel Syndrome • Solid Tumor • RET • SYP

Protective Effect of Pediococcus pentosaceus Li05 on Constipation via TGR5/TPH1/5-HT Activation. (PubMed, Microb Biotechnol) - "Following intervention with Li05 in loperamide-induced constipated mice, constipation symptoms improved...When the TGR5 gene was knocked out or the TPH1 inhibitor LX1606 was administered to suppress 5-HT synthesis in constipated mice, the beneficial effects of Li05 on gastrointestinal motility and mucus secretion were reversed. Culturing intestinal organoids demonstrated that increased bile acids such as DCA, Iso-LCA, and EALCA could enhance 5-HT levels through the TGR5/TPH1 axis. Therefore, we concluded that Li05 regulated bile acid metabolism, subsequently increasing 5-HT levels through the TGR5/TPH1 axis, thus alleviating constipation."

Journal • Constipation • Gastroenterology • Gastrointestinal Disorder • DLAT

Preventing Early Bioprosthetic Valve Deterioration in Carcinoid Heart Disease: A Case Series and Perioperative Management Strategy (NANETS 2025) - "These strategies included the initiation of telotristat ethyl, hepatic tumor embolization or cytoreductive surgeries prior to cardiac surgery...The addition personalized serotonin reduction strategies can result in stable valve function and prevent further deterioration. These findings support an individualized multidisciplinary approach to optimize surgical outcomes in CHD."

Clinical • Hepatocellular Cancer • Liver Cancer • Oncology

Stratification of Biochemical Response to Somatostatin Analogs in Carcinoid Syndrome: Implications for Risk of Carcinoid Heart Disease (NANETS 2025) - "METHODS We retrospectively analyzed patients with carcinoid syndrome initiated on standard-dose somatostatin analog (SA) therapy (lanreotide 120 mg SQ every 4 weeks or octreotide LAR 30 mg IM every 4 weeks)...Patients were included in the TELEHEART study and were randomized to SA + Placebo versus SA + Telotristat Ethyl...This approach enables timely consideration of adjunctive serotonin-lowering therapies for partial responders, who fail to suppress 5-HIAA below 123 ng/mL. Long-term studies can establish the survival impact of this approach."

Oncology

Telotristat ethyl affects tumour-fibroblast crosstalk in small intestinal neuroendocrine tumours. (PubMed, J Neuroendocrinol) - "Telotristat ethyl affects the expression of genes associated with the ECM and interferes with SI-NET-fibroblast crosstalk. Further analysis is required; however, this study represents an important step in understanding the mechanisms of telotristat ethyl when treating SI-NET patients."

Journal • Carcinoid Syndrome • Fibrosis • Immunology • Neuroendocrine Tumor • Oncology • Small Intestinal Carcinoma • Solid Tumor • ADAM12 • COL12A1 • COL6A2 • CTNNB1 • LAMA5

Impact of treatment on quality of life in neuroendocrine neoplasms survivors. (PubMed, Endocr Relat Cancer) - "In conclusion, evidence supports that SSA and RLT contribute to improve QoL, likely due to symptom control. Further research is needed to better characterize the QoL impact of other therapies using standardized assessment tools, in order to optimize therapeutic management."

HEOR • Journal • Carcinoid Syndrome • CNS Disorders • Depression • Endocrine Cancer • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Psychiatry • Solid Tumor

Selectivity and Safety Characterization of a Xanthine-Imidazothiazole Lead Structure: a Novel Tryptophan Hydroxylase Inhibitor of Peripheral Serotonin Synthesis. (PubMed, ACS Pharmacol Transl Sci) - "This study aimed to evaluate the selectivity and inhibitory potential of TPT-004, a novel TPH inhibitor, compared with Telotristat (LP778902) and its prodrug (LX1606)...Hematology parameters remained normal, with only minor liver changes observed. These results highlight TPT-004's potential as a selective and safe TPH inhibitor, offering a promising therapeutic option for serotonin-related disorders."

Journal • Hematological Disorders

THE STUDY ON THE FODMAP DIET REGULATING VISCERAL HYPERSENSITIVITY IN WATER AVOIDANCE STRESS IBS MODEL OF MICE THROUGH THE 5-HT PATHWAY AND ITS RELATED MECHANISMS (ESPGHAN 2025) - "Tryptophan hydroxylase inhibitor LX1032 was used to alter 5-HT levels, and microbiota and short-chain fatty acids were analyzed by 16S RNA and GC-MS...Conclusions HFD increased visceral hypersensitivity, reduced intestinal transit time, and induced anxiety, while LFD improved these symptoms. The FODMAP diet regulates 5-HT synthesis via TPH1, alters colonic microcirculation, and affects gut microbiota, with bacteria like Akkermansia and Bifidobacterium influencing 5-HT metabolism and SCFAs."

Preclinical • Immunology • Infectious Disease • Mood Disorders • Pain • Psychiatry

Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm (AACR 2025) - "Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl (TE) in severe cases...The combination of TE andcabozantinib, an effective tyrosine kinase inhibitor for NET, showed further improvement of tumor inhibition. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs."

Late-breaking abstract • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

AMT-PET in Monitoring Telotristat Etiprate Treatment in Participants With MetastaticNeuroendocrine Neoplasm (clinicaltrials.gov) - P2 | N=4 | Completed | Sponsor: Barbara Ann Karmanos Cancer Institute | Recruiting ➔ Completed

Trial completion • Carcinoid Syndrome • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

Burden of Comorbidities and Concomitant Medications and Their Associated Costs in Patients with Gastroenteropancreatic or Lung Neuroendocrine Tumors: Analysis of US Administrative Data. (PubMed, Adv Ther) - "Compared with people without cancer, patients with NETs had a higher prevalence of comorbidities and concomitant medication use, which was associated with a greater economic burden."

Journal • Carcinoid Syndrome • Cardiovascular • Diabetes • Endocrine Cancer • Gastrointestinal Disorder • Hypertension • Metabolic Disorders • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • Type 2 Diabetes Mellitus

Breaking the Phalanx: Overcoming Bacterial Drug Resistance with Quorum Sensing Inhibitors that Enhance Therapeutic Activity of Antibiotics. (PubMed, bioRxiv) - "Amongst explored drug combinations, 31 exhibited a synergistic effect, including mixtures involving naldemedine and telotristat, two drugs predicted by our model with previously undescribed QSI activity. Although no mixture inhibiting all the strains was found, piperacillin combined with curcumin, ketoprofen, indomethacin, and piroxicam demonstrated the broadest antimicrobial action. We anticipate that further preclinical investigation of these combinations of novel repurposed QSIs with a known antibiotic may lead to novel clinical candidates."

Journal • Infectious Disease

Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer. (ASCO-GI 2025) - P2 | "We developed a phase II trial to evaluate the impact of TE on the weight of patients with metastatic PDAC (mPDAC) receiving first-line chemotherapy Treatment-naïve pts with mPDAC who had lost at least 10% of baseline weight (Group 1) received gemcitabine and nab-paclitaxel (GnP) in combination with TE (250mg administered orally three times a day). Among pts with mPDAC and cachexia, the addition of TE to chemotherapy led to weight stabilization. These pts experienced 2% weight loss on average during the study (the upper limit of the CI just crossed -5% at -5.2%). The average weight loss was 5.6% in those who did not receive TE suggesting a signal of activity."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Inhaling arsenic aggravates airway hyperreactivity by upregulating PNEC-sourced 5-HT in OVA-induced allergic asthma. (PubMed, Ecotoxicol Environ Saf) - "Moreover, LX1032 alleviated As-evoked airway hyperreactivity in asthmatic mice. These results suggest that respiratory As exposure elevates airway hyperreactivity partially through upregulating PNEC-sourced 5-HT in OVA-induced allergic asthma, which provides significant insight about the hazards of environmental As exposure."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • IL13 • IL4 • IL5

EFFICACY OF RACECADOTRIL IN A NEN PATIENT SUFFERING FROM THERAPY-REFRACTORY VIPOMA AND CARCINOID-SYNDROM (UEGW 2024) - "Of note, hormonal excess syndromes can have a greater impact on patients` morbidity and mortality than the tumor mass itself.Case presentation: We present the case of a 49-year-old male patient suffering from an oligo-metastatic ileal NEN, concurrently demonstrating vasointestinal peptide (VIP) and serotonin excretion, complicated by pulmonary tuberculosis, using Racecadotril as ultimate ratio.After the first cycle of Lutetium-177-DOTATATE peptide-radio-receptor therapy, the patient developed a severe watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome, despite receiving high-dose somatostatin analogues, everolimus, and telotristat ethyl, without any surgical options. This case report underscores racecadotril as an individualized, off-label treatment strategy for patients with severe VIPoma and serotonin-driven WDHA syndrome, where conventional therapeutic avenues have been exhausted. Further studies are warranted to potentially expand and license the use of..."

Clinical • Carcinoid Syndrome • Endocrine Cancer • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Neuroendocrine Tumor • Oncology • Respiratory Diseases • Solid Tumor • Tuberculosis • PENK

Efficacy of Racecadotril in a Patient Affected by a Therapy-Refractory VIPoma and Carcinoid Syndrome. (PubMed, JCEM Case Rep) - "After the first cycle of Lutetium-177-DOTATATE peptide-radio-receptor therapy, the patient developed a severe watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome, despite receiving high-dose somatostatin analogues, everolimus, and telotristat ethyl, without any surgical options. After 5 days of treatment, the WDHA syndrome exhibited sufficient control, facilitating the patient's discharge from the ICU. This case report underscores racecadotril as an individualized, off-label treatment strategy for patients with severe VIPoma and serotonin-driven WDHA syndrome, where conventional therapeutic avenues have been exhausted."

Journal • Carcinoid Syndrome • Critical care • Endocrine Cancer • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Neuroendocrine Tumor • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Tuberculosis • PENK

Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients with Metastatic Neuroendocrine Tumor (clinicaltrials.gov) - P3 | N=79 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Aug 2024 ➔ Aug 2025

Biomarker • Metastases • Trial completion date • Trial primary completion date • Cardiovascular • Endocrine Cancer • Heart Failure • Neuroendocrine Tumor • Oncology • Solid Tumor

Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients with Metastatic Neuroendocrine Tumor (clinicaltrials.gov) - P3 | N=79 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=60 ➔ 79

Biomarker • Enrollment change • Enrollment closed • Metastases • Cardiovascular • Endocrine Cancer • Heart Failure • Neuroendocrine Tumor • Oncology • Solid Tumor

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models. (PubMed, J Cell Mol Med) - "Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months...Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts...Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy."

Journal • Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

RELAX: Real-world Evidence Study EvaLuating PAtient-Reported Outcomes With XERMELO (clinicaltrials.gov) - P=N/A | N=223 | Completed | Sponsor: TerSera Therapeutics LLC | N=349 ➔ 223

Enrollment change • Carcinoid Syndrome

Retifanlimab (INCMGA00012) and Telotristat Ethyl for the Treatment of Advanced Neuroendocrine Tumors and Carcinoid Syndrome (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: M.D. Anderson Cancer Center; N=20 ➔ 0; Not yet recruiting ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Carcinoid Tumor • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor

Retifanlimab (INCMGA00012) and Telotristat Ethyl for the Treatment of Advanced Neuroendocrine Tumors and Carcinoid Syndrome (clinicaltrials.gov) - P2; N=20; Not yet recruiting; Sponsor: M.D. Anderson Cancer Center

Clinical • New P2 trial • Carcinoid Tumor • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor