Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

TPS168 Background: Carcinoid tumors are associated with serotonin (5-HT) secretion. High levels of serotonin are thought to contribute to the flushing, diarrhea, and abdominal discomfort observed in patients with carcinoid syndrome (CS). LX1606 (aka LX1032), an oral peripheral tryptophan hydroxylase (TPH) inhibitor that blocks serotonin synthesis, offers a potential novel therapeutic approach to CS. LX1606 has been granted “Fast Track” designation by the FDA. Methods: This study is evaluating the safety, tolerability, and preliminary efficacy of LX1606 in patients with CS. Endpoints include: reduction in daily bowel movements (BM), cutaneous flushing episodes, abdominal discomfort, and use of rescue short-acting octreotide or other rescue medication. Pharmacokinetics and pharmacodynamics (including whole blood 5-HT and urinary 5-HIAA) will also be assessed. Treatment: Patients with octreotide-refractory CS will be sequentially assigned to receive 4-weeks of LX1606 or placebo, in a 3:1 ratio. Oral LX1606 or placebo are administered 3 times daily; dose cohorts are 150 mg, 250 mg, 350 mg, 500 mg. All patients will continue stable-dose octreotide LAR for the duration of the study. After completing the 4-week blinded portion of the study, patients may receive open-label drug at their previously assigned dose level for 32 additional weeks. After completion of the dose escalation phase, 8 additional patients will receive treatment at the identified optimal dose level. Key eligibility: Patients with octreotide-refractory carcinoid syndrome, (defined as >4 BM/day).Current enrollment: 16 patients have been treated in the dose escalation phase. LX1606 500 mg TID has been identified as the optimal dose. As of 2/2011, enrollment is ongoing in the expansion phase. ClinicalTrials.gov registry: NCT00853047.

e13543 Background: Carcinoid syndrome (CS) occurs when metastatic carcinoid tumors secrete large amounts of serotonin (5-HT) and other bioactive substances into systemic circulation causing a variety of symptoms, including GI symptoms such as profound diarrhea. Reduction in 5-HT production by the tumor would be expected to improve symptoms in patients with CS. We therefore have examined the utility of inhibiting tryptophan hydroxylase (TPH), the enzyme that catalyzes the rate-limiting step in the synthesis of 5-HT, as a strategy to reduce 5-HT production in vivo with the goal of developing a new therapeutic approach to CS. The ability of LX1031 and LX1032, two novel TPH inhibitors to reduce 5-HT production was determined in clinical trials. Methods: Single and multiple ascending dose studies with LX1031 and LX1032 were conducted in normal volunteers. In addition, a 28-day study was conducted with the locally acting TPH inhibitor LX1031 in patients with non-constipating IBS. In the IBS study, multiple measures of GI symptoms were recorded daily along with a weekly global assessment. In all studies, blood and urine was collected for measurement of 5-HT and 5-HIAA, biomarkers of 5-HT production. Results: In normal volunteers LX1032 significantly reduced 5-HT production in a dose-dependent manner. Both LX1031 and LX1032 gave a 50-60% decrease in 24-hour urinary 5-HIAA after 14 days of 1000 mg QID and 500 mg TID, respectively, compared to placebo. In IBS patients, LX1031 produced a similar dose-dependent reduction in 5-HT production, and in the high dose arm demonstrated statistically significant improvements in parameters of global relief and stool consistency that correlated with the decrease in 5-HT production. Conclusions: These results demonstrate that TPH inhibitors, such as LX1032 and the locally acting LX1031, can significantly reduce 5-HT production in normal subjects at well-tolerated dose levels. In patients with IBS, administration of LX1031 was shown to lower 5-HT production and improve clinical GI symptoms. These results indicate that inhibiting serotonin synthesis via TPH inhibition is a viable new strategy for the symptomatic treatment of patients with carcinoid syndrome. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lexicon Pharmaceuticals, Inc. Lexicon Pharmaceuticals, Inc. No significant financial relationships to disclose.

Sarcoidosis is a systemic granulomatous disease that is triggered by an autoimmune process, and is now a well recognized but uncommon complication of antiviral therapy for Hepatitis C virus (HCV) infection, likely related to its immunomodulatory effects. The clinical presentation of HCV related sarcoidosis is as varied as systemic sarcoidosis, but ocular presentation alone has not been reported previously. We present a 23 year-old female who developed visual disturbances due to ocular sarcoidosis during the course of antiviral therapy for chronic HCV infection. Our case presentation is then followed by a review of the literature on the topic. We aim to stress the importance of screening for eye problems in following HCV patients undergoing antiviral therapy, and raise clinicians' awareness of sarcoidosis as a possible cause for eye problems even in the absence of respiratory complaints.