| Reference | 1. Clin Ther. 2016 Apr;38(4):759-68. doi: 10.1016/j.clinthera.2016.03.002. Epub 2016
Mar 31.
<br>
Patient-reported Symptom Experiences in Patients With Carcinoid Syndrome After
Participation in a Study of Telotristat Etiprate: A Qualitative Interview
Approach.
<br>
Gelhorn HL(1), Kulke MH(2), O’Dorisio T(3), Yang QM(4), Jackson J(4), Jackson
S(4), Boehm KA(4), Law L(4), Kostelec J(1), Auguste P(1), Lapuerta P(5).
<br>
Author information: <br>
(1)Evidera, Bethesda, Maryland.
(2)Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts.
(3)Department of Internal Medicine, University of Iowa Hospitals and Clinics,
Iowa City, Iowa.
(4)Lexicon Pharmaceuticals, Inc. The Woodlands, Texas.
(5)Lexicon Pharmaceuticals, Inc. The Woodlands, Texas. Electronic address:
[email protected].
<br>
PURPOSE: Telotristat etiprate, a tryptophan hydroxylase inhibitor, was previously
evaluated in a Phase II randomized, placebo-controlled clinical trial in patients
with carcinoid syndrome (CS) and diarrhea not adequately controlled by
octreotide. The objective of the current study was to characterize the symptom
experiences of patients participating in that trial.<br>
METHODS: Consenting patients participated in one-on-one, qualitative interviews
focused on eliciting symptoms they had experienced in association with their CS
diagnosis and recollection of symptom changes they experienced while
participating in the Phase II trial.<br>
FINDINGS: Among the 23 patients who participated in the previous 4-week
dose-escalation study, 16 were eligible for interviews and 11 participated in the
present study. The median time from study completion to the interview was 31
months; 4 of 11 patients were receiving telotristat etiprate in a follow-up,
open-label trial at the time of interview. All of the patients (100%) described
diarrhea as a symptom of CS, with effects on the emotional, social, and physical
aspects of their lives. Improvement in diarrhea during the study was described by
82% of participants, and was very impactful in several patients. Results led to
the design and implementation of a larger interview program in Phase III and
helped to establish a definition of clinically meaningful change for the clinical
development program.<br>
IMPLICATIONS: The diarrhea associated with CS can have a large impact on daily
lives, and patient interviews can characterize and capture clinically meaningful
improvements with treatment. ClinicalTrials.gov Identifier: NCT00853047.
<br><br>
2. Eur Endocrinol. 2016 Mar;12(1):44-46. doi: 10.17925/EE.2016.12.01.44. Epub 2016
Mar 15.
<br>
New Developments in the Treatment of Neuroendocrine Tumours – RADIANT-4, NETTER-1
and Telotristat Etiprate.
<br>
Sbardella E(1), Grossman A(1).
<br>
Author information: <br>
(1)Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and
Metabolism, Churchill Hospital, University of Oxford, Oxford, UK.
<br>
Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose
incidence has increased significantly in recent years, and whose optimal
management remains controversial. We report the latest innovations in their
management, in particular the results of three trials concerning the use of the
mammalian target of rapamycin (mTOR) inhibitor, everolimus, in non-functional
NETs of lung/ gastrointestinal (GI) origin, the first randomised trial of
radiolabelled 177Lu-DOTATATE in patients with mid-gut NETs, and the use of the
5-HT synthesis inhibitor, telotristat etiprate, in patients with the carcinoid
syndrome.
<br><br>
3. Am J Physiol Gastrointest Liver Physiol. 2015 Sep 15;309(6):G455-65. doi:
10.1152/ajpgi.00299.2014. Epub 2015 Jul 23.
<br>
Blocking peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606)
reduces severity of both chemical- and infection-induced intestinal inflammation.
<br>
Kim JJ(1), Wang H(1), Terc JD(1), Zambrowicz B(2), Yang QM(2), Khan WI(3).
<br>
Author information: <br>
(1)Department of Pathology and Molecular Medicine, Farncombe Family Digestive
Health Research Institute, Health Sciences Centre, McMaster University, Hamilton,
Ontario, Canada; and.
(2)Lexicon Pharmaceuticals Inc., The Woodlands, Texas.
(3)Department of Pathology and Molecular Medicine, Farncombe Family Digestive
Health Research Institute, Health Sciences Centre, McMaster University, Hamilton,
Ontario, Canada; and [email protected].
<br>
Mucosal inflammation is accompanied by an alteration in 5-HT. Intestinal 5-HT
synthesis is catalyzed by tryptophan hydroxylase 1 (Tph1) and we have shown that
mice deficient in this rate-limiting enzyme have reduced severity of intestinal
inflammation in models of chemical-induced experimental colitis. Here, we
investigated the effect of blocking peripheral 5-HT synthesis in generation of
intestinal inflammation by a using peripheral Tph inhibitor, telotristat etiprate
(LX1606), in models of intestinal inflammation. LX1606 was given orally either
prophylactically or therapeutically to mice with dextran sulfate sodium
(DSS)-induced colitis or with infection with Trichuris muris. Severity of
intestinal inflammation was measured by assessment of disease activity scores,
histological damage, and MPO and inflammatory cytokine levels. LX1606
significantly reduced intestinal 5-HT levels and delayed onset and severity of
DSS-induced acute and chronic colitis. This was associated with decreased MPO and
proinflammatory cytokine levels compared with vehicle-treated controls. In the
infection-induced inflammation model, treatment with LX1606 enhanced worm
expulsion as well as increased IL-10 production and goblet cell numbers.
LX1606-treated mice had significantly lower MPO and IL-1β levels compared with
controls postinfection. Our results demonstrate that peripheral 5-HT plays an
important role in intestinal inflammation and in the generation of immune
responses. Pharmacological reduction of peripheral 5-HT may serve as a potential
strategy for modulating various intestinal inflammatory disorders.
<br><br>
4. J Clin Endocrinol Metab. 2015 Apr;100(4):1511-9. doi: 10.1210/jc.2014-2247. Epub
2015 Jan 30.
<br>
Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.
<br>
Pavel M(1), Hörsch D, Caplin M, Ramage J, Seufferlein T, Valle J, Banks P,
Lapuerta P, Sands A, Zambrowicz B, Fleming D, Wiedenmann B.
<br>
Author information: <br>
(1)Charité – Universitätsmedizin (M.P., B.W.), Department of Gastroenterology and
Hepatology, 13353 Berlin Germany; Zentralklinik Bad Berka GmbH (D.H.), Department
of Gastroenterology and Endocrinology, 99437 Bad Berka, Germany; Royal Free
London National Health Service (NHS) Foundation Trust (M.C.), Department of
Gastroenterology and Hepatobiliary Medicine, London NW3 2QG, United Kingdom;
Basingstoke and North Hampshire NHS Foundation Trust (J.R.), Department of
Gastroenterology, Hampshire RG24 9NA, United Kingdom; Ulm University (T.S.),
Department of Internal Medicine I, 89070 Ulm, Germany; The University of
Manchester/The Christie NHS Foundation Trust (J.V.), Department of Medical
Oncology, Manchester M20 4BX, United Kingdom; and Lexicon Pharmaceuticals, Inc
(P.B., P.L., A.S., B.Z., D.F.), Department of Clinical Development, The
Woodlands, Texas 77381.
<br>
CONTEXT: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea,
flushing, and increased risk of valvular heart disease. Many patients respond to
somatostatin analogs initially, but response diminishes in most patients.
Additional options are needed.<br>
OBJECTIVE: To assess whether telotristat etiprate (TE) can reduce
gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid
(u5-HIAA; a biomarker of serotonin).<br>
DESIGN: A prospective, exploratory, dose-escalating 12-week, open-label,
multicenter study of TE with efficacy and safety analyses.
SETTING: A multicenter study.<br>
PATIENTS: Eligible patients had metastatic, well-differentiated, neuroendocrine
tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use
was allowed.<br>
INTERVENTIONS: TE, a novel oral inhibitor of peripheral serotonin synthesis.
MAIN OUTCOME MEASURES: Primary: safety. Secondary: daily BMs, stool form, and
u5-HIAA.<br>
RESULTS: Fifteen patients were enrolled, and 14 completed the treatment period.
All patients experienced reductions in BMs per day (mean decrease, 43.5%). A
74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed,
with generally greater reductions in patients with greater reductions in BMs per
day. Nine patients (75%) reported “adequate relief” of gastrointestinal symptoms
at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also
improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent
with underlying illness; three adverse events were serious (abdominal pain,
diarrhea, and gastroenteritis) but were judged unrelated.<br>
CONCLUSION: TE was generally safe and well tolerated. Patients experienced
substantial improvement in CS and reductions in u5-HIAA, consistent with the
mechanism of action of TE. These results support further evaluation in phase 3
studies.
<br><br>
5. Endocr Relat Cancer. 2014 Oct;21(5):705-14. doi: 10.1530/ERC-14-0173. Epub 2014
Jul 10.
<br>
Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with
carcinoid syndrome and diarrhea not adequately controlled by octreotide.
<br>
Kulke MH(1), O’Dorisio T(2), Phan A(2), Bergsland E(2), Law L(2), Banks P(2),
Freiman J(2), Frazier K(2), Jackson J(2), Yao JC(2), Kvols L(2), Lapuerta P(2),
Zambrowicz B(2), Fleming D(2), Sands A(2).
<br>
Author information: <br>
(1)Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline
Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and
ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer
CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan
Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH.
Lee Moffitt Cancer CenterTampa, Florida, USA [email protected].
(2)Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline
Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and
ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer
CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan
Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH.
Lee Moffitt Cancer CenterTampa, Florida, USA.
<br>
Serotonin produced by neuroendocrine tumors is believed to be a principal cause
of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of
telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with
diarrhea associated with carcinoid syndrome. In this prospective, randomized
study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day
despite stable-dose octreotide LAR depot therapy were enrolled in sequential,
escalating, cohorts of four patients per cohort. In each cohort, one patient was
randomly assigned to placebo and three patients to telotristat etiprate, at 150,
250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient
was assigned to placebo and six patients to telotristat etiprate 500 mg tid.
Patients were assessed for safety, BM frequency (daily diary), 24 h urinary
5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid
gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients
were treated: 18 received telotristat etiprate and five received placebo. Adverse
events were generally mild. Among evaluable telotristat etiprate-treated
patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks,
9/16 (56%) experienced biochemical response (≥50% reduction or normalization in
24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at
least 1 of the first 4 weeks of treatment. Similar activity was not observed in
placebo-treated patients. Telotristat etiprate was well tolerated. Our
observations suggest that telotristat etiprate has activity in controlling
diarrhea associated with carcinoid syndrome. Further studies confirming these
findings are warranted.
<br>
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