The purposes of the Phase 2 inTandem4 study were to confirm the appropriateness of the doses selected for Lexicon's ongoing Phase 3 program in type 1 diabetes and to evaluate secondary endpoints relating to sotagliflozin's dual mechanism of action involving inhibition of SGLT1 in the gastrointestinal (GI) tract and SGLT2 in the kidney. Both Phase 3 doses of sotagliflozin, 200 mg and 400 mg once-daily, demonstrated statistically significant (p<0.001 and p=0.006, respectively) and clinically meaningful reductions in A1C relative to placebo. Patients treated with sotagliflozin had mean A1C reductions from baseline of 0.60%, 0.84%, and 0.73% on the 75 mg, 200 mg and 400 mg doses, respectively, after 12 weeks of treatment, as compared to a reduction of 0.35% on placebo. In addition, sotagliflozin demonstrated results on several measures consistent with its dual mechanism of action:
- Post-Prandial Glucose. Consistent with the expected effects of inhibiting SGLT1 in the GI tract, patients treated with sotagliflozin achieved dose-related reductions in post-prandial glucose (PPG) following a standardized meal. Patients treated with sotagliflozin had mean two-hour PPG reductions from baseline to week 12 of the study of 20.51 mg/dL, 27.60 mg/dL and 49.67 mg/dL on the 75 mg, 200 mg and 400 mg doses, respectively, as compared to a reduction of 0.21 mg/dL on placebo.
- Urinary Glucose Excretion. Consistent with the expected effects of inhibiting SGLT2 in the kidney moderated by the impact of GI tract inhibition of SGLT1 on post-prandial blood glucose levels, sotagliflozin produced relatively modest, dose-dependent 24-hour urinary glucose excretion (UGE). Patients treated with sotagliflozin had mean 24-hour UGE increases from baseline to week 12 of the study of 42.02 g, 57.99 g and 70.71 g on the 75 mg, 200 mg and 400 mg doses, respectively, as compared to an increase of 0.26 mg on placebo.
- Body Weight. Mean baseline body weight for patients at the time of randomization ranged from 79.97 kg to 91.92 kg across the four arms of the study. Patients treated with sotagliflozin achieved dose dependent reductions in body weight after 12 weeks of treatment, while patients on placebo gained weight. Patients in the 75 mg, 200 mg and 400 mg dose arms achieved mean weight loss of 0.16 kg, 1.24 kg and 1.48 kg, respectively, as compared to a mean gain of 1.13 kg for patients in the placebo arm.
- Blood Pressure. Overall, patients treated with sotagliflozin achieved dose-dependent reductions from baseline to week 12 in systolic blood pressure ranging from 1.5 mmHg for the 75 mg dose to 4.4 mmHg in the 400 mg dose. Notably, in the subset of patients with hypertension at baseline (baseline systolic blood pressure equal to or greater than 130 mmHg), patients in the 400 mg dose arm experienced a placebo-adjusted reduction of 14.3 mmHg in systolic blood pressure. This result was consistent with results seen in a post-hoc analysis of data from Lexicon's Phase 2b study of sotagliflozin in type 2 diabetes, and supports further exploration of the potential effects on blood pressure of inhibition of SGLT1 in the GI tract.
Sotagliflozin was generally well tolerated in the study. Across all four dose arms (placebo, 75 mg, 200 mg, 400 mg), the proportions of patients with treatment-emergent adverse events (AEs) during the 12-week treatment period were 50.0%, 48.6%, 28.6% and 34.3%, respectively; the incidence of serious AEs (SAEs) were 2.8%, 2.9%, 2.9% and 2.9%, respectively; and discontinuation due to AEs were 2.8%, 2.9%, 0.0% and 0.0%, respectively. There were no reported deaths in the study. There were three events of severe hypoglycemia during the 12-week treatment period (one each in the 75 mg, 200 mg and 400 mg dose arms), and one event of diabetic ketoacidosis (DKA) during the 12-week treatment period (for a patient on the 400 mg dose) compared to two separate events of DKA in one patient during the pre-randomization, placebo run-in period of the study.
The double-blind, placebo controlled, Phase 2 dose-ranging study known as inTandem4 randomized 141 patients in the United States with type 1 diabetes on insulin pump or multiple daily injection therapy who had an A1C level entering the study between 7.0% and 10.0%. The four-arm study evaluated three doses of sotagliflozin, 75 mg, 200 mg and 400 mg, each taken once daily before the first meal of the day, against placebo. Prior to randomization, there was a two-week run-in period in which patients received placebo in addition to insulin. After completion of the run-in period, patients were randomized to one of three doses of sotagliflozin or placebo. Following randomization, adjustments in insulin doses could be made when needed. The mean baseline A1C level at the time of randomization ranged from 7.95% to 8.07% across the four arms of the study.
Discovered using Lexicon's unique approach to gene science, sotagliflozin is a first-in-class, oral dual inhibitor of two proteins responsible for glucose regulation known as sodium-glucose co-transporter types 1 and 2 (SGLT1 and SGLT2). SGLT1 is responsible for glucose absorption in the gastrointestinal tract, and SGLT2 is responsible for glucose reabsorption by the kidney.
Lexicon entered into a collaboration and license agreement with Sanofi in November 2015 under which Lexicon granted Sanofi an exclusive, worldwide, royalty-bearing right and license to develop, manufacture and commercialize sotagliflozin. Lexicon is responsible for all clinical development activities relating to type 1 diabetes and retains an exclusive option to co-promote and have a significant role, in collaboration with Sanofi, in the commercialization of sotagliflozin for the treatment of type 1 diabetes in the United States. Sanofi is responsible for all clinical development and commercialization of sotagliflozin for the treatment of type 2 diabetes worldwide and is solely responsible for the commercialization of sotagliflozin for the treatment of type 1 diabetes outside the United States.
Lexicon announced positive top-line results of its first pivotal Phase 3 clinical trial of sotagliflozin in patients with type 1 diabetes, on a background of optimized insulin (inTandem1), on September 9, 2016. Lexicon is conducting a second pivotal Phase 3 clinical trial (inTandem2) from which top-line results are expected in December 2016. Lexicon is also completing a Phase 2 clinical trial in collaboration with JDRF in young adults with type 1 diabetes, from which results are expected prior to the end of the year. A third type 1 diabetes Phase 3 clinical trial, inTandem3, is underway globally and is studying approximately 1,400 patients treated with sotagliflozin 400 mg once daily or placebo on a background of any insulin therapy, but without insulin optimization prior to randomization. Sanofi is expected to commence Phase 3 clinical trials for sotagliflozin in patients with type 2 diabetes this year.
Lexicon is a fully integrated biopharmaceutical company that is applying a unique approach to gene science based on Nobel Prize-winning technology to discover and develop precise medicines for patients with serious, chronic conditions. Through its Genome5000™ program, Lexicon scientists have studied the role and function of nearly 5,000 genes over the last 20 years and have identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to safely and effectively treat disease. Lexicon has a pipeline of promising drug candidates in clinical and pre-clinical development in oncology, diabetes and metabolism. For additional information please visit www.lexpharma.com.
Safe Harbor Statement
This press release contains "forward-looking statements," including statements relating to Lexicon's and its licensees' clinical development of and regulatory filings for sotagliflozin (LX4211) and the results and projected timing of clinical trials and the potential therapeutic and commercial potential of sotagliflozin. In addition, this press release also contains forward-looking statements relating to Lexicon's growth and future operating results, discovery and development of products, strategic alliances and intellectual property, as well as other matters that are not historical facts or information. All forward-looking statements are based on management's current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including the risk that clinical studies of sotagliflozin may be halted, delayed or otherwise not demonstrate safety or efficacy, the risk that the FDA and other regulatory authorities may not grant regulatory approval of sotagliflozin in accordance with Lexicon's currently anticipated timelines or at all, and the risk that such regulatory approvals, if granted, may have significant limitations on the approved use of sotagliflozin. As a result, sotagliflozin may never be successfully commercialized. Other risks include Lexicon's ability to meet its capital requirements, successfully conduct preclinical and clinical development and obtain necessary regulatory approvals of its other potential drug candidates, achieve its operational objectives, obtain patent protection for its discoveries and establish strategic alliances, as well as additional factors relating to manufacturing, intellectual property rights, and the therapeutic or commercial value of its drug candidates. Any of these risks, uncertainties and other factors may cause Lexicon's actual results to be materially different from any future results expressed or implied by such forward-looking statements. Information identifying such important factors is contained under "Risk Factors" in Lexicon's annual report on Form 10-K for the year ended December 31, 2015, as filed with the Securities and Exchange Commission. Lexicon undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.
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SOURCE Lexicon Pharmaceuticals, Inc.