Lexicon Pharmaceuticals

Lexicon Pharmaceuticals

Type	Public
Traded as	NASDAQ: LXRX
Industry	Pharmaceutical
Founded	The Woodlands, TX, 1995
Headquarters	The Woodlands, United States
Key people	Lonnel Coats, President and Chief Executive Officer Brian P. Zambrowicz, EVP & Chief Scientific Officer Jeffrey L. Wade, EVP of Corporate Development & Chief Scientific Officer Alan J. Main, EVP of Pharmaceutical Research Pablo Lapuerta, EVP of Clinical Development & Chief Medical Officer James F. Tessmer, VP of Finance and Accounting
Number of employees	225 (2011)
Website	www.lexpharma.com

Lexicon Pharmaceuticals, Inc. is a biopharmaceutical company engaged in discovering and developing breakthrough treatments for human disease. The company was founded in 1995 in The Woodlands, Texas under the name Lexicon Genetics, Incorporated by co-founders Arthur T Sands, Ray B Webb and.^[1] The company has used its patented mouse gene knockout technology and extensive in vivo screening capabilities to study nearly 5,000 genes in its Genome5000 program and has identified over 100 potential therapeutic targets. 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, gastroenterology, immunology, metabolism, and ophthalmology.

The company's clinical drug candidates include LX4211 for the treatment of type 2 diabetes; LX1033 for the treatment of irritable bowel syndrome and other gastrointestinal disorders; LX1032 for the treatment of the symptoms associated with carcinoid syndrome; and LX2931 for the treatment of autoimmune diseases, such as rheumatoid arthritis.

Company history

A Lexicon Genetics knockout mouse (left) that is a model of obesity, compared with a normal mouse.

Lexicon Pharmaceuticals was founded in September 1995 as a biotech venture of Baylor College of Medicine. The company went public in April 2000 with one of the largest initial public offerings in biotech history ($220 million).^[2] In June, 2001 Lexicon purchased a privately owned small chemical library synthesis company, Coelacanth Corporation in Princeton, New Jersey,^[3] 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 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). Using its proprietary gene trapping and gene targeting technologies, the company created the world’s largest repository of genetically modified mouse embryonic stem cells, known as OmniBank, and established a large-scale mammalian knockout program to discover the physiological and behavioral functions of the most druggable mammalian genes.^[4] The information collected from this program is stored in the company’s LexVision 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 and gene targeting technologies to generate and study knockout mice to discover the physiological and behavioral effects that result from the disruption of a single gene knockout.^[5] 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,^[6] 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. 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.^[7] The tremendous utility of knockout mouse technology was recognized in 2007 with the Nobel Prize in Physiology or Medicine to Drs. Mario Capecchi, Martin Evans, and Oliver Smithies.^[8]

In developing small molecule drugs for its validated targets, Lexicon uses sophisticated medicinal chemistry known as "click chemistry." Dr. K. Barry Sharpless, who was awarded the 2001 Nobel Prize in Chemistry,^[9] 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.^[10]

Clinical pipeline

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.^[11][12] 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 (SGLT2), a transporter responsible for most of the glucose reabsorption performed by the kidney, and the sodium-glucose cotransporter type 1 (SGLT1), a transporter responsible for glucose and galactose absorption in the gastrointestinal tract, and, to a lesser extent than SGLT2, glucose reabsorption in the kidney.^[13]

LX1031 for irritable bowel syndrome

LX1031 is an orally-delivered small molecule under development for the potential treatment of irritable bowel syndrome (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.^[14] Increased clinical response correlated with a greater reduction in serotonin 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, or TPH, the rate-limiting enzyme for serotonin production found primarily in enterochromaffin, or EC, cells of the gastrointestinal tract.^[15]

Telotristat etiprate (LX1032/LX1606) for carcinoid syndrome

LX1032 is an orally-delivered small molecule under development for the potential treatment of symptoms associated with carcinoid syndrome. 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.^[16] LX1032 has received Fast Track status from the United States Food and Drug Administration and Orphan Drug Status from the European Medicines Agency.^[17][18]

LX2931 for rheumatoid arthritis

LX2931 is an orally-delivered small molecule under development for the potential treatment of autoimmune diseases such as rheumatoid arthritis. 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, 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 (S1P) pathway associated with the activity of lymphocytes.^[19][20]

Locations

Lexicon operates from two locations found in Texas and New Jersey. The corporate headquarters are in The Woodlands, Texas 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.^[21]

Lexicon's campus in Princeton, New Jersey 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.^[21]

References

1. http://www.nasdaq.com/markets/ipos/filing.ashx?filingid=1129388
2. http://moneycentral.hoovers.com/global/msn/factsheet.xhtml?COID=99953 MSN Fact Sheet – IPO center
3. United States Securities and Exchange Commission
4. Raymond CS, Soriano P (September 2006). "Engineering mutations: deconstructing the mouse gene by gene". Dev. Dyn. 235 (9): 2424–36. doi:10.1002/dvdy.20845. PMID 16724325.
5. Lexicon Pharmaceutical’s Technology page
6. Church DM, Goodstadt L, Hillier LW, et al. (May 2009). Roberts RJ, ed. "Lineage-specific biology revealed by a finished genome assembly of the mouse". PLoS Biol. 7 (5): e1000112. doi:10.1371/journal.pbio.1000112. PMC 2680341. PMID 19468303.
7. Zambrowicz BP, Sands AT (January 2003). "Knockouts model the 100 best-selling drugs--will they model the next 100?". Nat Rev Drug Discov. 2 (1): 38–51. doi:10.1038/nrd987. PMID 12509758.
8. 2007 Nobel Prize Laureate – Medicine
9. 2001 Nobel Prize Laureate – Chemistry
10. Kolb HC, Sharpless KB (December 2003). "The growing impact of click chemistry on drug discovery". Drug Discov. Today. 8 (24): 1128–37. doi:10.1016/S1359-6446(03)02933-7. PMID 14678739.
11. Lexicon Presents Phase 2 Results for Diabetes Drug Candidate (LX4211) at ADA Conference
12. Lexicon Presents Phase 2 Results for Diabetes Drug Candidate (LX4211) at ENDO 2010 Conference
13. Goodwin NC, Mabon R, Harrison BA, et al. (October 2009). "Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes". J. Med. Chem. 52 (20): 6201–4. doi:10.1021/jm900951n. PMID 19785435.
14. Lexicon Presents Phase 2 Results for IBS Drug Candidate, LX1031, at Digestive Disease Week (DDW)
15. Jin H, Cianchetta G, Devasagayaraj A, et al. (September 2009). "Substituted 3-(4-(1,3,5-triazin-2-yl)-phenyl)-2-aminopropanoic acids as novel tryptophan hydroxylase inhibitors". Bioorg. Med. Chem. Lett. 19 (17): 5229–32. doi:10.1016/j.bmcl.2009.07.005. PMID 19631532.
16. Liu Q, Yang Q, Sun W, et al. (April 2008). "Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract". J. Pharmacol. Exp. Ther. 325 (1): 47–55. doi:10.1124/jpet.107.132670. PMID 18192499.
17. LX1032 Granted Fast-track Status for Carcinoid Syndrome
18. Lexicon's Drug Candidate LX1032 For Carcinoid Syndrome Receives Orphan Drug Designation From EMEA
19. Yu XQ, Kramer J, Moran L, et al. (May 2010). "Pharmacokinetic/pharmacodynamic modelling of 2-acetyl-4(5)-tetrahydroxybutyl imidazole-induced peripheral lymphocyte sequestration through increasing lymphoid sphingosine 1-phosphate". Xenobiotica. 40 (5): 350–6. doi:10.3109/00498251003611376. PMID 20175664.
20. Serra M, Saba JD (2010). "Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function". Adv. Enzyme Regul. 50 (1): 349–62. doi:10.1016/j.advenzreg.2009.10.024. PMC 2862839. PMID 19914275.
21. Lexicon Pharmaceutical’s locations