Lexicon Pharmaceuticals
Encyclopedia
Lexicon Pharmaceuticals, Inc. (Nasdaq LXRX) is a biopharmaceutical
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 company engaged in discovering and developing breakthrough treatments for human disease. The company was founded in 1995 in The Woodlands, Texas
The Woodlands, Texas
The Woodlands is a master-planned community and a Census-designated place in the U.S. state of Texas within the metropolitan area. The population of the CDP was 55,649 at the 2000 census—a 90 percent increase over its 1990 population. According to the 2010 census, The Woodlands' population rose...

 under the name Lexicon Genetics, Incorporated. The company has used its patented mouse gene knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...

 technology and extensive in vivo screening capabilities to study nearly 5,000 genes in its Genome5000TM program and has identified over 100 potential therapeutic targets
Biological target
A biological target is a biopolymer such as a protein or nucleic acid whose activity can be modified by an external stimulus. The definition is context-dependent and can refer to the biological target of a pharmacologically active drug compound, or the receptor target of a hormone . The...

. Lexicon has advanced multiple drug candidates into human clinical trials and has a broad and diverse pipeline of drug targets behind its clinical programs. Lexicon is pursuing drug targets in five therapeutic areas including oncology
Oncology
Oncology is a branch of medicine that deals with cancer...

, gastroenterology
Gastroenterology
Gastroenterology is the branch of medicine whereby the digestive system and its disorders are studied. The name is a combination of three Ancient Greek words gaster , enteron , and logos...

, immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

, and ophthalmology
Ophthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...

.

The company's clinical drug candidates include LX4211 for the treatment of type 2 diabetes; LX1031 for the treatment of irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...

 and other gastrointestinal disorders; LX1032 for the treatment of the symptoms associated with carcinoid syndrome
Carcinoid syndrome
Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction...

; and LX2931 for the treatment of autoimmune diseases, such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

.

Company history

Lexicon Pharmaceuticals was founded in September 1995 as a biotech venture of Baylor College of Medicine
Baylor College of Medicine
Baylor College of Medicine, located in the Texas Medical Center in Houston, Texas, USA, is a highly regarded medical school and leading center for biomedical research and clinical care...

. The company went public in April 2000 with one of the largest initial public offerings in biotech history ($220 million). In June, 2001 Lexicon purchased a privately owned small chemical library synthesis company, Coelacanth Corporation in Princeton, New Jersey
Princeton, New Jersey
Princeton is a community located in Mercer County, New Jersey, United States. It is best known as the location of Princeton University, which has been sited in the community since 1756...

, which became the site for the company's small molecule and medicinal chemistry efforts. The company's original name was Lexicon Genetics Incorporated, but in 2007, the name changed to Lexicon Pharmaceuticals, Inc. to reflect a renewed focus on drug development.

The company initially focused on using gene knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...

 technology to define the function of genes. This effort complemented and benefited from the international effort to sequence the human and mouse genomes (see Human Genome Project
Human Genome Project
The Human Genome Project is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional...

). Using its proprietary gene trapping
Gene trapping
Gene trapping is a high-throughput approach that is used to introduce insertional mutations across the mammalian genome. It is performed with gene trap vectors whose principal element is a gene trapping cassette consisting of a promoterless reporter gene and/or selectable genetic marker flanked by...

 and gene targeting
Gene targeting
Gene targeting is a genetic technique that uses homologous recombination to change an endogenous gene. The method can be used to delete a gene, remove exons, add a gene, and introduce point mutations. Gene targeting can be permanent or conditional...

 technologies, the company created the world’s largest repository of genetically modified mouse embryonic stem cells, known as OmniBankR, and established a large-scale mammalian knockout program to discover the physiological and behavioral functions of the most druggable mammalian genes. The information collected from this program is stored in the company’s LexVisionTM database, which contains almost 5,000 gene knockouts studied. Over the years, Lexicon evolved from a genomics company into a drug discovery and development company focused on discovering and developing breakthrough treatments for human disease. The company currently has multiple drug candidates in various stages of clinical trials.

Technology

Lexicon uses patented gene trapping
Gene trapping
Gene trapping is a high-throughput approach that is used to introduce insertional mutations across the mammalian genome. It is performed with gene trap vectors whose principal element is a gene trapping cassette consisting of a promoterless reporter gene and/or selectable genetic marker flanked by...

 and gene targeting
Gene targeting
Gene targeting is a genetic technique that uses homologous recombination to change an endogenous gene. The method can be used to delete a gene, remove exons, add a gene, and introduce point mutations. Gene targeting can be permanent or conditional...

 technologies to generate and study knockout mice to discover the physiological and behavioral effects that result from the disruption of a single gene knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...

. Because there is a close similarity in gene function and physiology between mice and humans, with a large majority of human genes having a counterpart in the mouse genome, knockout mouse technology has become a powerful tool in the discovery of new medicines.

The value of Lexicon’s technology in drug discovery has been described in a retrospective analysis by the scientific journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...

. The conclusion of this analysis was that, in most cases, there was a direct correlation when comparing the physiological characteristics, or phenotypes, of knockout mice to the therapeutic effect of the 100 best-selling drugs of 2001. The tremendous utility of knockout mouse technology was recognized in 2007 with the Nobel Prize in Physiology or Medicine to Drs. Mario Capecchi
Mario Capecchi
Mario Renato Capecchi is an Italian-born American molecular geneticist and a co-winner of the 2007 Nobel Prize in Physiology or Medicine for discovering a method for introducing homologous recombination in mice employing embryonic stem cells, with Martin Evans and Oliver Smithies...

, Martin Evans
Martin Evans
Sir Martin John Evans FRS is a British scientist who, with Matthew Kaufman, was the first to culture mice embryonic stem cells and cultivate them in a laboratory in 1981...

, and Oliver Smithies
Oliver Smithies
Oliver Smithies is a British-born American geneticist and Nobel laureate, credited with the invention of gel electrophoresis in 1955, and the simultaneous discovery, with Mario Capecchi and Martin Evans, of the technique of homologous recombination of transgenic DNA with genomic DNA, a much more...

.

In developing small molecule drugs for its validated targets, Lexicon uses sophisticated medicinal chemistry known as “click chemistry
Click chemistry
Click chemistry is a chemical philosophy introduced by K. Barry Sharpless of The Scripps Research Institute, in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together...

.” Dr. K. Barry Sharpless
K. Barry Sharpless
Karl Barry Sharpless is an American chemist known for his work on stereoselective reactions.-Early years:Sharpless was born in Philadelphia. He graduated from Friends' Central School in 1959. He continued his studies at Dartmouth College and earned his Ph.D from Stanford University in 1968...

, who was awarded the 2001 Nobel Prize in Chemistry, pioneered this set of powerful and reliable tools for the rapid synthesis of novel compounds. Lexicon uses solution-phase chemistry to generate diverse libraries of optically pure compounds that are built using highly robust and scalable organic reactions that allow the company to generate compound collections of great diversity and to specially tailor the compound collections to address various therapeutic target families. Lexicon’s medicinal chemists design these libraries by analyzing the chemical structures of drugs that have been proven safe and effective against human disease and using that knowledge in the design of scaffolds and chemical building blocks for the generation of large numbers of new drug-like compounds.

LX4211 for Diabetes

LX4211 is an orally-delivered small molecule under development for the potential treatment of type 2 diabetes mellitus. Data from a Phase 2 clinical trial evaluating the safety and tolerability of LX4211and its effects on biomarkers associated with type 2 diabetes showed that treatment with 150 mg and 300 mg of LX4211 was well tolerated and provided improvements in glycemic control. The study also demonstrated statistically significant benefits in the primary and multiple secondary efficacy endpoints. Lexicon previously completed a combined Phase 1 single ascending-dose and multiple ascending-dose study of LX4211, in which LX4211 was well tolerated at all dose levels and produced a dose-dependent increase in urinary glucose excretion. LX4211 is a dual inhibitor of both the sodium-glucose cotransporter type 2
Sodium-glucose transport proteins
Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa of the small intestine and the proximal tubule of the nephron . They contribute to renal glucose reabsorption...

 (SGLT2), a transporter responsible for most of the glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 reabsorption performed by the kidney, and the sodium-glucose cotransporter type 1
Sodium-glucose transport proteins
Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa of the small intestine and the proximal tubule of the nephron . They contribute to renal glucose reabsorption...

 (SGLT1), a transporter responsible for glucose and galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....

 absorption in the gastrointestinal tract, and, to a lesser extent than SGLT2, glucose reabsorption in the kidney.

LX1031 for Irritable Bowel Syndrome (IBS)

LX1031 is an orally-delivered small molecule under development for the potential treatment of irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...

 (IBS) and other gastrointestinal disorders. Data from a Phase 2 clinical trial evaluating the safety and tolerability of LX1031 and its effects on symptoms associated with IBS showed that treatment with 1,000 mg of LX1031 four times daily was well tolerated and produced a statistically significant improvement in the global assessment of relief of IBS pain and discomfort over the four-week treatment period compared to placebo. Improvements in the global assessment of adequate relief corresponded with statistically significant improvements in stool consistency in the same dose group. Increased clinical response correlated with a greater reduction in serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 synthesis as reflected by measures of urinary 5-HIAA, the primary metabolite of serotonin and a biomarker for serotonin production. In Phase 1 clinical trials, all dose levels were well tolerated, no dose-limiting toxicities were observed, and LX1031 was shown to reduce levels of urinary 5-HIAA. LX1031 was designed to inhibit tryptophan hydroxylase
Tryptophan hydroxylase
Tryptophan hydroxylase is an enzyme involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reactionIt employs one cofactor, iron.- Function :...

, or TPH, the rate-limiting enzyme for serotonin production found primarily in enterochromaffin
Enterochromaffin
Enterochromaffin cells are a type of enteroendocrine cell occurring in the epithelia lining the lumen of the digestive tract and the respiratory tract.-Function:They contain about 90% of the body's store of serotonin ....

, or EC, cells of the gastrointestinal tract.

LX1032 for Carcinoid Syndrome

LX1032 is an orally-delivered small molecule under development for the potential treatment of symptoms associated with carcinoid syndrome
Carcinoid syndrome
Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction...

. Lexicon initiated a Phase 2 clinical trial to evaluate the safety and tolerability of LX1032 and its effects on symptoms associated with carcinoid syndrome. The Phase 2 trial is expected to enroll up to 28 patients with symptomatic carcinoid syndrome refractory to octreotide therapy. Lexicon has also initiated a complementary open-label clinical trial of LX1032, which is expected to enroll up to 16 additional patients. LX1032 was well tolerated in the Phase 1 clinical trials, and results demonstrated a potent dose-dependent reduction in both blood serotonin levels and urinary 5-HIAA which was consistent with the reductions observed in preclinical animal models. LX1032 was designed to inhibit TPH, the same target as LX1031, but LX1032 is chemically distinct and, unlike LX1031, was specifically designed to achieve enhanced systemic exposure. LX1032 has received Fast Track status
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...

 from the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 and Orphan Drug Status
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...

 from the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

.

LX2931 for Rheumatoid Arthritis

LX2931 is an orally-delivered small molecule under development for the potential treatment of autoimmune diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

. Lexicon initiated a Phase 2 clinical trial to evaluate the safety and tolerability of LX2931 and its effects on symptoms and signs associated with rheumatoid arthritis. The Phase 2 trial is expected to enroll up to 200 patients with rheumatoid arthritis who are also taking methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

, a standard therapy. In Phase 1 clinical trials, LX2931 was well tolerated and demonstrated a dose-dependent reduction in circulating lymphocytes similar to those associated with a beneficial response observed with LX2931 treatment in animal arthritis models. LX2931 was designed to target sphingosine-1-phosphate lyase, or S1P lyase, an enzyme in the sphingosine-1-phosphate
Sphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...

 (S1P) pathway associated with the activity of lymphocytes.

Locations

Lexicon operates from two locations found in Texas
Texas
Texas is the second largest U.S. state by both area and population, and the largest state by area in the contiguous United States.The name, based on the Caddo word "Tejas" meaning "friends" or "allies", was applied by the Spanish to the Caddo themselves and to the region of their settlement in...

 and New Jersey
New Jersey
New Jersey is a state in the Northeastern and Middle Atlantic regions of the United States. , its population was 8,791,894. It is bordered on the north and east by the state of New York, on the southeast and south by the Atlantic Ocean, on the west by Pennsylvania and on the southwest by Delaware...

. The corporate headquarters are in The Woodlands, Texas
The Woodlands, Texas
The Woodlands is a master-planned community and a Census-designated place in the U.S. state of Texas within the metropolitan area. The population of the CDP was 55,649 at the 2000 census—a 90 percent increase over its 1990 population. According to the 2010 census, The Woodlands' population rose...

 just north of Houston. This location serves as Lexicon’s primary research facility to discover and validate the company's drug targets and test drug candidates in preclinical research. The company’s clinical development and regulatory team is also based at the corporate headquarters.

Lexicon's campus in Princeton, New Jersey
Princeton, New Jersey
Princeton is a community located in Mercer County, New Jersey, United States. It is best known as the location of Princeton University, which has been sited in the community since 1756...

is the home of Lexicon's small molecule medicinal chemistry and preclinical development efforts. This site serves as Lexicon's primary medicinal chemistry site to create new chemical entities for therapeutic development.
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