Indication
Carcinoid Syndrome (Fast Track status in U.S.; Orphan designation in EU)

Stage of Development
Phase 2



Clinical Trial Enrollment
For enrollment information for the Phase 2 clinical trial, please visit http://www.clinicaltrials.gov/ and reference LX1032 or click here. 

Clinical Status
Lexicon has successfully completed Phase 1 clinical trials of LX1032.  In all trials completed to date, LX1032 was well tolerated at all dose levels.  Adverse events were generally mild and evenly distributed across all treatment groups.  A dose-dependent reduction in blood serotonin and urinary 5-HIAA levels was observed.  For additional information about the Phase 1 clinical results, please view our video presentation .  Lexicon initiated a Phase 2 study in patients with carcinoid syndrome in July 2009.  The clinical trial is planned as a four-week, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effects of LX1032 on symptoms associated with carcinoid syndrome.

Overview
LX1032 is an orally-delivered small molecule under development as a potential treatment for the symptoms associated with carcinoid syndrome.  LX1032 acts by inhibiting the enzyme tryptophan hydroxylase (TPH).  Unlike LX1031, LX1032 was specifically designed to be better absorbed into the blood stream and, therefore, capable of reducing serotonin production both inside and outside the GI tract without affecting brain serotonin levels.

Key Target
The target for LX1032 is TPH, the rate-limiting enzyme involved in serotonin biosynthesis and present in metastatic carcinoid tumor cells.  From research conducted in the Genome5000^TM program, 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.

Metastatic carcinoid tumors release excessive serotonin and other substances 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, LX1032 was able to reduce peripheral serotonin levels in several different species without affecting serotonin levels in the brain.

About Fast Track Status
FDA’s Fast Track program facilitates the development of potential new drugs and expedites the review of new drugs intended to serve unmet medical needs in serious or life-threatening conditions.  Fast Track status also provides formal mechanisms for sponsors to communicate with the FDA on product development issues, including clinical trial design.  Fast Track benefits include eligibility for an early review process that may significantly shorten FDA approval times by allowing for the possibility of a “rolling submission” for marketing authorization.  Carcinoid syndrome is the first therapeutic indication for which Lexicon has obtained Fast Track status. 
 
About Orphan Designation
The goal of EMEA’s orphan drug program is to promote the development of drugs intended for the prevention or treatment of life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the EU.  Incentives for developing new drugs under orphan drug designation in the EU include 10 years of marketing exclusivity, regulatory assistance, reduced regulatory fees associated with applying for marketing approval, and assistance with clinical trial design.  LX1032 is the first drug candidate for which Lexicon has obtained orphan drug status.

Related Publications
Philip Brown, M.D., J.D., K.S. Frazier, S. Jackson, A. Turnage, W.E. Heydorn, Q. Yang, P. Yalamanchili, Q. Liu (2009) LX1032: A Novel Agent to Reduce Peripheral Serotonin as a Potential Treatment for Carcinoid Syndrome. 2009 Digestive Disease Week (DDW)  Poster 

Philip M. Brown, M.D., J.D. (2009). Trytophan Hydroxylase (TPH) Inhibition: Potential New Therapy For Chronic Diarrhea in Carcinoid Syndrome. 2009 Digestive Diease Week (DDW)  Presentation (166 KB)

Philip M. Brown, M.D., J.D. (2009).  LX1032:  A Novel Approach for Managing Gastrointestinal Symptoms in Carcinoid Syndrome.  2009 European Neuroendocrine Tumor Society (ENETS)  Presentation (107 KB)

J.M. Zuetenhorst, B.G. Taal (2005).  Metastatic carcinoid tumors: a clinical review. Oncologist 10(2):123-131.

A.B. Alfieri, L.X. Cubeddu (1995). Treatment with Para-chlorophenylalanine Antagonises the Emetic Response and the Serotonin-releasing Actions of Cisplatin in Cancer Patients. British Journal of Cancer 71(3):629-632

K. Engelman, M.D., W. Lovenberg, Ph.D., and A. Sjoerdsma, M.D., Ph.D. (1967). Inhibition of Serotonin Synthesis by Para-chlorophenylalanine in Patients with the Carcinoid Syndrome. New England Journal of Medicine 277(21):1103-1108.