LX1032

Indications
IND application filed December 2007

Indications
Carcinoid Syndrome

Overview
Carcinoid syndrome is an array of symptoms experienced by patients with metastatic carcinoid tumors.  The majority of such tumors originate from enterochromaffin cells in the gastrointestinal tract and secrete large amounts of serotonin, leading to a variety of symptoms which often includes severe diarrhea.  LX1032 is an orally-delivered small molecule intended to provide a new therapeutic approach for treating the symptoms associated with carcinoid syndrome by inhibiting the enzyme tryptophan hydroxylase (TPH). 

Principal Target
The target for LX1032 is TPH, a key enzyme involved in serotonin biosynthesis.  From research conducted in the Genome5000 project, Lexicon scientists found that mice lacking the non-neuronal form of the TPH enzyme (TPH1) have virtually no peripheral serotonin, but do maintain normal levels of brain serotonin.  In previous studies, TPH inhibitors have controlled diarrhea in carcinoid patients, but also depleted brain serotonin and caused depression.  LX1032 has the potential to avoid these negative side effects by not affecting brain serotonin production.

Metastatic carcinoid tumors release excessive serotonin and other bioactive molecules into the blood stream resulting in symptoms such as severe diarrhea, bronchial restriction, facial flushing, and rapid heartbeat.

LX1032 reduces peripheral serotonin production by inhibiting the enzyme TPH.

Preclinical Data
In preclinical studies, animals treated with LX1032 had reduced amounts of peripheral serotonin; brain levels of serotonin were unaffected.

Clinical Status
Lexicon filed an Investigational New Drug (IND) application for LX1032 at the end of 2007.  Following FDA review, Lexicon plans to initiate Phase 1 clinical trials to evaluate the safety, tolerability, and pharmacokinetics of single oral doses of LX1032 in healthy volunteers.  Additionally, a multiple dose study will be conducted in patients with metastatic carcinoid tumor, experiencing GI symptoms.

Related Publications
K. Engelman, M.D., W. Lovenberg, Ph.D., and A. Sjoerdsma, M.D., Ph.D.
Inhibition of Serotonin Synthesis by Para-chlorophenylalanine in Patients with the Carcinoid Syndrome, New England Journal of Medicine, November 23, 1967
Volume 277, Number 21

A TPH inhibitor was found to be equally effective to Zofran in controlling nausea and vomiting.
Treatment with Para-chlorophenylalanine Antagonises the Emetic Response and the Serotonin-releasing Actions of Cisplatin in Cancer Patients, British Journal of Cancer  (1995) 71, 629-632

Zuetenhorst JM, Taal BG.  Metastatic carcinoid tumors: a clinical review. Oncologist. 2005 Feb;10(2):123-31.

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