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

Abstract

Background Inadequately 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. Methods Patients 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. Results A 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). Conclusion Patients treated with TE in a real-world setting experienced significant, clinically meaningful improvements in CS symptoms.

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

“…The real-world TELEPRO (2019) and TELEPRO-II (2021) studies reported a high baseline burden of CSD and CS symptoms for patients receiving SSAs only, and substantial improvements in patient-reported experience and outcomes after 3 months of TE in US clinical practice. 19 , 20 TELEPRO-II showed significant improvements in overall CS symptoms, daily bowel movement frequency, stool consistency, nausea, abdominal pain, urgency, and flushing as early as 1 month through 3 months of TE treatment. 20 After 3 months of TE, approximately half (52%) of patients in the TELEPRO study reported a reduction of ≥2 bowel movements per day.…”

“… 19 , 20 TELEPRO-II showed significant improvements in overall CS symptoms, daily bowel movement frequency, stool consistency, nausea, abdominal pain, urgency, and flushing as early as 1 month through 3 months of TE treatment. 20 After 3 months of TE, approximately half (52%) of patients in the TELEPRO study reported a reduction of ≥2 bowel movements per day. 19 The majority of patients in the RELAX study reported less frequent bowel movements (82%) after 6 months of TE, underscoring the importance of continued follow-up and treatment adherence.…”

“…18 The efficacy and safety of TE has been demonstrated in Phase 3 clinical trials 16 , 17 and in the real-world TELEPRO-I and TELEPRO-II studies of patients receiving TE in US clinical practice. 19 , 20 Interim analyses from the ongoing RELAX registry (Real-world Evidence Study Evaluating Patient-Reported Outcomes With XERMELO; NCT03223428) have reported high patient satisfaction with control of CS symptoms and CSD among patients receiving TE in clinical practice. 21 , 22 This paper reports final results from completed follow-up of all patients receiving TE in the RELAX study from 2017 through January 2022.…”

Molecular factors, diagnosis and management of gastrointestinal tract neuroendocrine tumors: An update

“…Telotristat is an inhibitor of tryptophan hydroxylases (TPH 1 and TPH2) that limits serotonin biosynthesis and relieves manifestations of carcinoid syndrome. Telotristat together with a long-acting somatostatin analog is currently recommended for uncontrolled carcinoid syndrome diarrhea by the United States National Comprehensive Cancer Network (NCCN)[ 84 ].…”

Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors

“…While in TPH1-deficient mice a protection from pulmonary arterial hypertension (PAH), , inflammation, nonalcoholic steatohepatitis, , and irritable bowel disease was observed, TPH2-deficient mice suffered from neuronal dysfunction such as increased aggressive behavior, , altered anxiety, and social deficit. , Moreover, the overexpression of TPH1 in neuroendocrine tumors in patients with carcinoid syndrome (CS), results in an increased secretion of serotonin into the bloodstream, causing severe side effects like skin flushing, diarrhea, shortness of breath, and rapid heart rate . In a proof of concept clinical study, Telotristat Etiprate (Xermelo) as new TPH1 inhibitor received fast track status ( 1.1 in Figure ) for the treatment of patients suffering from CS in 2017. , In addition, the companies Altavant Sciences GmbH and Actelion Pharmaceuticals, Ltd. described novel TPH inhibitors ( 2.1 and rac- 3 in Figure ) to treat diseases related to high levels of serotonin. , Currently, Enzyvant Therapeutics GmbH is conducting a clinical phase II study (ELEVATE 2, NCT04712669) with Rodatristat Ethyl 2.1 in patients suffering from PAH . The activated inhibitors 1.2 and 2.2 mainly cover the substrate-binding site of tryptophan, with the amino acid headgroup forming hydrogen bonds with Arg-257, whereas the inhibitor rac- 3 occupies both binding sites of the substrate and the pterin cosubstrate.…”