Indications
Carcinoid Syndrome (Fast Track status)
Stage of Development
Completed Phase 1
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. Based on the Phase 1 results, Lexicon plans to initiate a Phase 2 study in patients with carcinoid syndrome. The clinical trial is planned as a randomized, double-blind, placebo-controlled study in patients with symptomatic carcinoid syndrome who are refractory to current therapy. The study is designed to evaluate the safety, tolerability, and effects of LX1032 on symptoms associated with carcinoid syndrome. For additional information about the Phase 1 clinical results, please view our video presentation  .
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.
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 Genome5000TM 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.
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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. |
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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.
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
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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