Lexicon Pharmaceuticals, Inc. · NASDAQ:LXRX
Lexicon Pharmaceuticals — Investor Day (April 2018)
131 slides from Lexicon Pharmaceuticals's investor day presentation, Apr 10, 2018
Slide 1: Welcome and Introduction
April 10, 2018 Welcome and Introduction Kimberly Lee, D.O. Head of Investor Relations and Corporate Strategy Precision Science. Pioneering Medicine. Patient Driven. 0 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 2: Forward-looking Statements
Forward-looking Statements This presentation, including any oral presentation accompanying it, contains “forward- looking statements,” including statements about Lexicon’s strategy and operating performance and events or developments that we expect or anticipate will occur in the future, such as pro
Slide 3: Opening Remarks
April 10, 2018 Opening Remarks Lonnel Coats President and Chief Executive Officer Precision Science. Pioneering Medicine. Patient Driven. 2 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 4: R&D Day Agenda and Speakers
R&D Day Agenda and Speakers Time Topic Speaker 8:30 – 8:35 Introduction Lonnel Coats 8:35 - 8:40 XERMELO market opportunity Alex Santini 8:40 – 8:50 XERMELO life cycle management introduction Praveen Tyle, Ph.D. 8:50 – 9:15 Preclinical evidence for and clinical development of XERMELO in cancer Ranuk
Slide 5: Speaker Biographies
Speaker Biographies Lonnel Coats, President and Chief Executive Officer and Director Mr. Coats has been our president and chief executive officer and a director since July 2014. From 1996 through June 2014, Mr. Coats served in a series of leadership positions at Eisai Inc. and Eisai Corporation of N
Slide 6: Speaker Biographies
Speaker Biographies Praveen Tyle, Ph.D., Executive Vice President of Research and Development Dr. Tyle has been our executive vice president of research and development since May 2016. Dr. Tyle was previously a member of the executive management team at Osmotic Pharmaceutical Corp., serving as presi
Slide 7: Speaker Biographies
Speaker Biographies Pablo Lapuerta, M.D., Executive Vice President and Chief Medical Officer Dr. Lapuerta is our executive vice president and chief medical officer and previously served in a number of other roles since joining Lexicon in 2011, including executive vice president, safety, pharmacovigi
Slide 8: Speaker Biographies
Speaker Biographies Jake Kushner, M.D., McNair Medical Institute Scholar and Associate Professor at the Baylor College of Medicine Dr. Jake Kushner is a McNair Medical Institute Scholar and an Associate Professor at the Baylor College of Medicine. For 6 years he served as Chief of Pediatric Diabetes
Slide 9: XERMELO Market Opportunity
April 10, 2018 XERMELO Market Opportunity Alex Santini Executive Vice President and Chief Commercial Officer Precision Science. Pioneering Medicine. Patient Driven. 8 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 10: XERMELO First and Only Oral Treatment Approved for Carcinoid Syndrome Diarrhea
XERMELO® (telotristat ethyl) - First and Only Oral Treatment Approved for Carcinoid Syndrome Diarrhea • Reduces serotonin production • Reduces frequency of carcinoid Novel, oral tryptophan syndrome diarrhea hydroxylase (TPH) inhibitor • U.S. approval February 28, 2017 • U.S. launch March 1, 2017 • E
Slide 11: Carcinoid Syndrome Diarrhea – Meaningful Market Opportunity
Carcinoid Syndrome Diarrhea – Meaningful Market Opportunity DESCRIPTION PATIENT POPULATION* Carcinoid syndrome results from metastatic neuroendocrine tumors (mNETs) that produce large amounts of serotonin, a key mediator of gastrointestinal motility, pain and inflammation ~14,000 Patients in U.S. DI
Slide 12: Perception Study – Physicians' vs. Patients' View of Symptom Control
Perception Study – Physicians’ vs. Patients’ View of Symptom Control Physicians’ View Patients’ View 20% Controlled 45% 55% Uncontrolled Controlled 80% Uncontrolled 80% There remains a significant difference between patients’ and physicians’ attitudes toward how well controlled the disease is Source
Slide 13: XERMELO Life Cycle Management – Introduction
April 10, 2018 XERMELO Life Cycle Management – Introduction Praveen Tyle, Ph.D. Executive Vice President, Research & Development Precision Science. Pioneering Medicine. Patient Driven. 12 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 14: XERMELO Life Cycle Management
XERMELO® (telotristat ethyl) Life Cycle Management Compound Indication Preclinical Phase 1 Phase 2 Phase 3 Registration Marketed Carcinoid syndrome diarrhea FDA approval Feb 28, 2017; US launch Mar 01, 2017 Carcinoid syndrome diarrhea EMA approval Sept 19, 2017; EU launch ongoing Neuro-endocrine Tel
Slide 15: XERMELO and SSAs Have Different and Complementary Mechanisms of Action
XERMELO (telotristat ethyl) and Somatostatin Analogs (SSAs) Have Different and Complementary Mechanisms of Action Neuroendocrine tumor (NET) cell Inside the Cell Tryptophan • Telotristat ethyl Telotristat inhibits TPH 1,3 Tryptophan ethyl • Telotristat ethyl hydroxylase (TPH) decreases serotonin 5-h
Slide 16: Anti-tumor Activity Driven by Mechanism of Action
XERMELO (telotristat ethyl) Life Cycle Management – Anti-tumor Activity Driven by Mechanism of Action ➢ Clinical studies have established anti-tumor activity of SSAs in patients with NETs ▪ Multiple pathways are involved, one of which relates to inhibition of serotonin release ➢ Preclinical data sho
Slide 17: Preclinical evidence for and clinical development of XERMELO in cancer
Preclinical evidence for and clinical development of XERMELO in cancer Renuka Iyer, M.D., Roswell Park Comprehensive Cancer Center
Slide 18: Relevant Disclosure and Resolution
Relevant Disclosure and Resolution Under Accreditation Council for Continuing Medical Education, guidelines disclosure must be made regarding relevant financial relationships with commercial interests within the last 12 months. Name/ Topic Company Role Novartis; Consulting / Speaking / Teaching Ipse
Slide 19: Overview
Overview • Role of serotonin in solid tumors • 5HT blockade slows tumor growth • Neuroendocrine Tumor (NET) Overview- NET Space • Where Xermelo may fit (Rationale: 5HT+ mTOR/ 5HIAA) • Biliary Tract Cancer (BTC) Overview - BTC Space • Preclinical studies in BTC models • Chronic inflammation and Immun
Slide 20: Serotonin in Solid Tumors
Serotonin in Solid Tumors • Serotonin is a mitotic factor • Serotonin growth stimulatory effect also seen on several types of carcinoma and carcinoid cell lines • Inhibition of cancer cell growth occurs in some cases through serotonin receptor antagonists • Current evidence suggests / NETs inhibitin
Slide 21: Anti-5HT inhibits tumor growth - Synergy with mTOR
Anti-5HT inhibits tumor growth - Synergy with mTOR Rapa Rapa SB 204 SB 204 SB 204 + rapa SB 204 + rapa Growth with rapamycin + SB 204 (antagonist of • Anti-5HT therapy showed slower growth rate (A, 5HT)1 B) (CHEMOPREVENTIVE EFFECT) In presence of fetal calf serum (control) rapa • 4/12 mice developed
Slide 22: Neuroendocrine Tumors – Overview
Neuroendocrine Tumors – Overview • Neuroendocrine tumors (NETs), a relatively rare and heterogeneous tumor type, affect approximately 171,321 people in the United States1 • Cause debilitating symptoms and potentially life-threatening issues2, many from dense fibrosis • Classified by embryonic origin
Slide 23: NET Space: New Antitumor Agents Needed
NET Space: New Antitumor Agents Needed • SSA: Anti-proliferative effects (PROMID 13 months, CLARINET 29 months NR) control arm placebo First line untreated, GEPNETs. Not lung. • Everolimus: RR ~7-9%, PFS 11 months RADIANT 4 control arm placebo 3.9 months. After SSA, progressed within last 6 months.
Slide 24: Correlation Between u5-HIAA Levels and Outcome in NETs
Correlation Between u5-HIAA Levels and Outcome in NETs Re-analysis of RADIANT 2: Everolimus + Octreotide vs Octreotide Median PFS was significantly longer for pts with baseline 5-HIAA <median vs >median at baseline. 5-HIAA< median 17months vs 11 months > median; p<.001) High 5HIAA correlated Telotri
Slide 25: NET Proof-of-Concept (POC) Study Design
NET Proof-of-Concept (POC) Study Design • Efficacy and safety of everolimus plus Xermelo will be studied in patients with well differentiated NETs of midgut origin • Single arm, open label study • Primary endpoint will be the rate of progression-free survival at 12 months – Historical control 12-mon
Slide 26: Biliary Tract Cancers – Overview
Biliary Tract Cancers – Overview • Approximately 10,000 cases per year were diagnosed as aggressive malignancies with poor prognosis1, but intrahepatic cholangiocarcinoma is increasing2 • Multiple molecular signatures identified in different biliary tract cancer types3 • Palliative first-line chemot
Slide 27: Only One Approved Therapy - Urgent Need in Biliary Cancer
Only One Approved Therapy - Urgent Need in Biliary Cancer • GEM CIS (approved): versus gem alone, 12 weeks (stop or continue). 11.7 mo OS vs 8.1 with gem and PFS 8.0 vs 5.0 with gem alone. RR 20%.1 ABC-02 - Phase 3 study of advanced biliary cancer accrued 410 pts in 28 months. • FOLFOX (off-label)
Slide 28: Evidence Supporting Serotonin's Role in BTC Preclinical Models
Evidence Supporting Serotonin’s Role in BTC Preclinical Models • Dysregulation of serotonin may pCPA: p-chlorophenylalanine be associated with progression of BTC1 Vehicle • TPH1 is upregulated1 and monoamine oxidase-A is TPH markedly decreased in BTC2 inhibitor • Increased serotonin secretion in BTC
Slide 29: Chronic Inflammation and Immune Dysfunction are Drivers in BTC Progression
Chronic Inflammation and Immune Dysfunction are Drivers in BTC Progression - Tryptophan Plays a Role in Regulation of Both Tryptophan is a key factor BTC is caused by inflammation3 in chronic inflammation • Bile duct stones and cancer1 • Liver fluke infections • Chronic HBV and HCV infection Tumor i
Slide 30: BTC POC Study Design
BTC POC Study Design • Efficacy and safety of Xermelo in combination with standard 1st-line chemotherapy (gemcitabine plus cisplatin) will be studied in patients with advanced BTC • Single arm, open label study • Primary endpoint will be the rate of progression-free survival at 6 months – Historical
Slide 31: Takeaways
Takeaways • Serotonin is overproduced in many cancers and has a role in cancer progression • Significant need exists in NETs and BTC, orphan diseases, but rising in incidence • In NETs, in combination with everolimus, especially in elevated 5HIAA where everolimus doesn’t work as well, Xermelo lowers
Slide 32: THANK YOU!
THANK YOU!
Slide 33: XERMELO Life Cycle Management – Opportunities for XERMELO
April 10, 2018 XERMELO Life Cycle Management – Opportunities for XERMELO Praveen Tyle, Ph.D. Executive Vice President, Research & Development Precision Science. Pioneering Medicine. Patient Driven. Precision Science. Pioneering Medicine. Patient Driven.
Slide 34: Estimated Number of U.S. Patients Eligible for XERMELO by Indication
Estimated Number of U.S. Patients Eligible for XERMELO by Indication, if Approved, By 2025 20,000 18,000 Progressing 10,000 Mid-Gut NETs Carcinoid Syndrome Diarrhea + Biliary Tract Cancers US prevalence for NETs based on Dasari 2017. US growth rate to 2025 assumes the last 5-year (2007-2011) growth
Slide 35: Q&A Session #1
April 10, 2018 Q&A Session #1 Precision Science. Pioneering Medicine. Patient Driven. Precision Science. Pioneering Medicine. Patient Driven.
Slide 36: Sotagliflozin Discovery and Differentiation
April 10, 2018 Sotagliflozin Discovery and Differentiation Pablo Lapuerta, M.D. Executive Vice President and Chief Medical Officer 35 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 37: Sotagliflozin Development and Differentiation
Sotagliflozin Development and Differentiation • Genetic technology guided a discovery biology program that differentiated sotagliflozin - First company to develop a dual SGLT1/2 inhibitor • A profile with robust efficacy and potential opportunities in safety has guided sotagliflozin clinical researc
Slide 38: Mechanism of Action of Sotagliflozin
April 10, 2018 Mechanism of Action of Sotagliflozin David Powell, M.D. Senior Vice President, Metabolism Precision Science. Pioneering Medicine. Patient Driven. 37 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 39: Sotagliflozin - First-in-Class Dual SGLT1/SGLT2 Inhibitor for Diabetes
Sotagliflozin - First-in-Class Dual SGLT1/SGLT2 Inhibitor for Diabetes SGLT2 SGLT2 reabsorbs 90% of filtered glucose in the kidney Inhibiting SGLT2 in the kidney increases glucose excretion in the urine Results in reduced glucose reabsorbed into the body Mechanism is independent of insulin Effect di
Slide 40: Sotagliflozin - First-in-Class Dual SGLT1/SGLT2 Inhibitor for Diabetes
Sotagliflozin - First-in-Class Dual SGLT1/SGLT2 Inhibitor for Diabetes SGLT2 SGLT1 SGLT2 is the reabsorbs primary transporter 90% of for glucose/galactose filtered glucose in the in the kidney GI tract SGLT1 Inhibiting Inhibiting SGLT1 SGLT2 in in the the GI kidney tract reduces increases glucose gl
Slide 41: Mechanism of Action (MOA): Preclinical Data
Mechanism of Action (MOA): Preclinical Data 40 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 42: SGLT2 KO Mice: Increased Urinary Glucose Excretion
SGLT2 Knockout (KO) Mice: Increased Urinary Glucose Excretion (MOA) Improved Glucose Tolerance Initial Screen: SGLT2 KO Mouse Data Oral Glucose Tolerance Test Oral Glucose Tolerance Test WT 4 KO 4 WT 4 KO 4 Recent pooled WT Recent pooled WT Glucose Area Under the Curve t0 t30 t60 t90 WT KO Time in M
Slide 43: SGLT1 KO Mice: Reduced Glucose Absorption
SGLT1 KO Mice: Reduced Glucose Absorption (MOA) Profoundly Improved Glucose Tolerance Initial Screen: SGLT1 KO Mouse Data Oral Glucose Tolerance Test Oral Glucose Tolerance Test WT 4 KO 6 WT 4 KO 6 Recent pooled WT Recent pooled WT Glucose Area Under the Curve t0 t30 t60 WT KO Time in Minutes Source
Slide 44: Lexicon Screen of Gene Knockouts Identified SGLT1 and SGLT2 as Top Targets
Lexicon Screen of Gene Knockouts Identified SGLT1 and SGLT2 as Top Anti-Diabetic Targets Glucose Tolerance: Improved Normal Impaired 500 400 Number of KO Lines 300 SGLT2 200 DPP4 100 SGLT1 0 0.4 0.6 0.8 1.0 1.2 1.4 1.6 KO / WT Glucose Excursion AUC Source: Powell DR et al 2013 Am J Physiol Endocrino
Slide 45: Plasma GLP-1 Levels Increase in SGLT1 KO Mice after a Glucose Challenge
Plasma GLP-1 Levels Increase in SGLT1 KO Mice after a Glucose Challenge Cecal Glucose Cecal pH Plasma Total GLP-1 Meal challenge provided at hr 0 N = 4-5 mice for each data point Source: Powell DR et al 2013 J Pharmacol Exp Ther 44 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 46: Plasma GLP-1 Levels Do Not Increase in SGLT2 KO Mice
Plasma GLP-1 Levels Do Not Increase in SGLT2 KO Mice after a Glucose Challenge Cecal Glucose Cecal pH Plasma Total GLP-1 Meal challenge provided at hr 0 N = 4-5 mice for each data point Source: Powell DR et al 2013 J Pharmacol Exp Ther 45 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 47: Sotagliflozin Improved Glycemic Control and Increased GLP-1 in Type 2 Model
Sotagliflozin Improved Glycemic Control and Increased GLP-1 in a Preclinical Model of Type 2 Diabetes Improved Glucose Tolerance Lower A1C Increased GLP-1 • Data from KKAy mouse model of T2D (n = 15 mice/group) • Favorable preclinical safety profile; no evidence of gastrointestinal side effects Sour
Slide 48: Sotagliflozin and Sitagliptin Synergistically Increased Active GLP-1 Levels
Combination of Sotagliflozin and Sitagliptin Synergistically Increased Active GLP-1 Levels Meal challenge provided at hr 0 N = 5 mice for each data point Measures taken after 14 days of combination dosing in mice Source: Zambrowicz et al 2013 Clin Ther 47 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 49: Sotagliflozin Lowered Blood Glucose While Avoiding Hypoglycemia in Type 1 Model
Sotagliflozin Lowered Blood Glucose While Avoiding Hypoglycemia in Preclinical Model of Type 1 Diabetes Study performed in NOD Mouse model of T1D (n = 9-10 mice/group) * * * * * * * * * *Different from other groups, p < 0.05 Frequency of hypoglycemia (Number of samples): < 70 mg/dL <50 mg/dL 0.05U i
Slide 50: Mechanism of Action: Clinical Data
Mechanism of Action: Clinical Data 49 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 51: Postprandial Glucose Reduction is Characteristic of SGLT1 Inhibition in T2D
Postprandial Glucose Reduction is Characteristic of SGLT1 Inhibition in Subjects with T2D Blood Glucose Above Fasting Level (from Randomized, Placebo- controlled Phase 2a Study of Sotagliflozin; n=12/group) p < 0.001, placebo AUC vs AUC of 150 mg or 300 mg Source: Zambrowicz et al 2012 Clin Pharmaco
Slide 52: Glucose Absorption and Reabsorption in Individuals with T2D
Glucose Absorption and Reabsorption in Individuals with Type 2 Diabetes (T2D) Meal Tissues SGLT1 Glucose Glucose Absorption Filtration Blood Glucose SGLT2 Glucose Reabsorption No Urinary Glucose Post-meal Glucose Levels, T2D Source: Zambrowicz et al 2012 Clin Pharmacol Ther 51 © 2018 Lexicon Pharmac
Slide 53: Glucose Absorption and Reabsorption in Patients on an SGLT2 Inhibitor
Glucose Absorption and Reabsorption in Patients with T2D on an SGLT2 Inhibitor Meal Tissues SGLT1 Glucose Glucose Absorption Filtration Blood Glucose X SGLT2 Glucose Reabsorption Post-meal Increased Glucose Levels, T2D Urinary Glucose Excretion Sources: Zambrowicz et al 2012 Clin Pharmacol Ther 52 ©
Slide 54: Glucose Absorption and Reabsorption on a Dual SGLT1/SGLT2 Inhibitor
Glucose Absorption and Reabsorption in Patients with T2D on a Dual SGLT1/SGLT2 Inhibitor Meal Tissues X SGLT1 Glucose Glucose Absorption Filtration Blood Glucose X SGLT2 Glucose Reabsorption Post-meal Moderately Glucose Levels, T2D Increased Urinary Glucose Excretion Sources: Zambrowicz et al 2012 C
Slide 55: Single Dose of Sotagliflozin Elevates GLP-1 Over the Course of the Day
Single Dose of Sotagliflozin Elevates GLP-1 Over the Course of the Day in Subjects with Type 2 Diabetes Baseline 2x150 mg Tablet 300 mg Liquid Randomized, cross-over study of subjects with T2D (n = 12) treated with single oral doses of different sotagliflozin formulations. A 5-day washout period sep
Slide 56: Combining Sotagliflozin & Sitagliptin Increases Active GLP-1
Combining Sotagliflozin & Sitagliptin in Subjects with T2D Increases Active GLP-1 Compared to Either Agent Alone * * p < 0.001 * vs combination Randomized, cross-over study of subjects with T2D (n = 18) treated with single oral doses of sotagliflozin, sitagliptin or the sotagliflozin/sitagliptin com
Slide 57: Sotagliflozin Clinical Differentiation
April 10, 2018 Sotagliflozin Clinical Differentiation Pablo Lapuerta, M.D. Executive Vice President and Chief Medical Officer Precision Science. Pioneering Medicine. Patient Driven. 56 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 58: Sotagliflozin Differentiation - Dual Inhibition of SGLT1 and SGLT2
Sotagliflozin Differentiation - Dual Inhibition of SGLT1 and SGLT2 • Potential for more robust efficacy than SGLT2 inhibition alone - Greater post-prandial glucose reduction - GLP-1 elevation after meals - Consistent A1C reduction - Efficacy in the setting of renal impairment • Potential for differe
Slide 59: Sotagliflozin - Modest Urinary Glucose Excretion (UGE)
Sotagliflozin - Modest Urinary Glucose Excretion (UGE) 24 hour Sotagliflozin Canagliflozin Empagliflozin Dapagliflozin Ertugliflozin UGE (g) 400 mg 300 mg 25 mg 10 mg 15 mg Healthy Volunteers 24 hour UGE (g)1 36-44 70 56 40 58 Type 2 Diabetes 24 hour UGE (g)2 54 >100 80 68 >69-80 Type 1 Diabetes 24
Slide 60: Urinary Glucose Excretion from SGLT2 Inhibition - Function of Plasma Glucose
Urinary Glucose Excretion from SGLT2 Inhibition - Function of Plasma Glucose Reductions in post-prandial glucose from gastrointestinal SGLT1 inhibition may limit UGE Example - Canagliflozin urinary glucose excretion after a meal is elevated for about 3 hours while glucose levels are high – Canaglifl
Slide 61: Sotagliflozin Phase 2 Results in Type 2 Diabetes
Sotagliflozin Phase 2 Results in Type 2 Diabetes - Large Reductions in Postprandial Glucose Green: Placebo, Blue: Sota 150 mg, Red: Sota 300 mg Source: Lapuerta, P et al. Diabetes & Vascular Disease Research 2015, Vol. 12(2) 101–110 60 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 62: Sotagliflozin Differentiation - Long Half-life Supports GI SGLT1 Inhibition
Sotagliflozin Differentiation - Long Half-life Supports Gastrointestinal SGLT1 Inhibition Sotagliflozin Canagliflozin Empagliflozin Dapagliflozin Ertugliflozin 400 mg 300 mg 25 mg 10 mg 15 mg Half-life 29 13.1 12 3* 15.3 (hours)1 Reductions in post-prandial glucose have been shown with sotagliflozin
Slide 63: Sotagliflozin in Renal Impairment- Reduction in Postprandial Glucose
Sotagliflozin in Renal Impairment- Reduction in Postprandial Glucose Sotagliflozin Placebo n=16 n=15 240 240 220 220 Glucose (mg/dl) Glucose (mg/dl) 200 200 180 180 160 160 140 140 120 120 100 100 -1 0 1 2 3 4 -1 0 1 2 3 4 Day -1 Day 7 Hours Hours Day -1 Day 7 Mean 24-hour Urinary Glucose Excretion:
Slide 64: Sotagliflozin in Renal Impairment - Elevation in Total GLP-1
Sotagliflozin in Renal Impairment - Elevation in Total GLP-1 Sotagliflozin Placebo n=16 n=15 20 20 Total GLP-1, pmol/L Total GLP-1, pmol/L 15 15 10 10 5 5 -1 0 1 2 3 4 -1 0 1 2 3 4 Day -1 Day 7 Hours Day -1 Day 7 Hours Source: Zambrowicz et al. Clin Ther. 2015 Jan 1;37(1):71-82 63 © 2018 Lexicon Pha
Slide 65: Advancing Sotagliflozin into Type 1 Diabetes - Reducing Glycemic Variability
Advancing Sotagliflozin into Type 1 Diabetes - Reducing Glycemic Variability Baseline (Day -1) Day 1 Insulin without Sotagliflozin Figure 1: Continuous Glucose Monitoring (CGM) Data by Study day and Time No insulin at breakfast Figure 1: Continuous Glucose Monitoring (CGM) Data by Study day and Time
Slide 66: Type 1 Diabetes- Key Development Choices
Type 1 Diabetes- Key Development Choices Sotagliflozin Dapagliflozin Optimizing insulin as robustly as possible ✓ Enrolling patients with A1C < 7.0% ✓ Enrolling patients with A1C >10.5% ✓ Enrolling patients with eGFR < 60 mg/dL ✓ Including a study in patients at risk for DKA ✓ Including a
Slide 67: Largest Phase 3 Program for an Oral Anti-Diabetic Agent in T1DM
Sotagliflozin – Largest Phase 3 Program for an Oral Anti-Diabetic Agent in Broad Range of T1DM Patients Phase 3 Studies Primary Top-Line Study in T1DM Patient Size/Dose Endpoint Results Completion • 750 patients Met primary Completed Reduction of A1C vs. endpoint of inTandem1 • Placebo, 200mg, place
Slide 68: Significant A1C Reductions on Top of Optimized Insulin in T1DM
Sotagliflozin – Significant A1C Reductions on Top of Optimized Insulin in Patients with T1DM inTandem1 (n=793) inTandem2 (n=782) A1C reduction (%) after A1C reduction (%) after 24 weeks 24 weeks 400mg dose 200mg dose Placebo 400mg dose 200mg dose Placebo -0.03% -0.08% -0.43% -0.49% -0.37% -0.39% 67
Slide 69: inTandem3 NEJM Publication in Sept 2017
inTandem3 Phase 3 Clinical Trial – NEJM Publication in Sept 2017 Validates Need for New T1DM Therapy 68 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 70: inTandem3 Data from the NEJM
inTandem3 Data from the NEJM – Primary Endpoint and All Secondary Endpoints Achieved inTandem3 (n=1,405) Sotagliflozin Placebo 400 mg P-Value Net benefit 15.2% 28.6% p<0.001 A1C (%) -0.33 -0.79 p<0.001 Body weight (kg) +0.8 -2.2 p<0.001 Blood pressure (mmHg)* -5.7 -9.2 p=0.002 Bolus insulin -1.1 IU/
Slide 71: Sotagliflozin Improved Time in Range by Up to 3 Hours/day
Continuous Glucose Monitoring Data - Sotagliflozin Improved Time in Range by Up to 3 Hours/day • Positive pooled continuous glucose monitoring (CGM) data from the pivotal inTandem1 and inTandem2 studies announced recently - Sotagliflozin significantly increased the time in target glucose range of 70
Slide 72: inTandem3 Weight Data – Body Weight Significantly Reduced
inTandem3 Weight Data – Body Weight Significantly Reduced 71 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 73: Safety – Largest and Most Comprehensive Safety Database
Safety – Largest and Most Comprehensive Safety Database, Lower Hypoglycemia and Manageable DKA in High-Risk Patients Severe Hypoglycemia DKA 24 week data Overall Rate Discontinuation Rate Overall Rate Discontinuation Rate inTandem1 (n=793) • Placebo 6.7% 0.4% 0.0% 0.0% • Sotagliflozin 200 mg 4.2% 0.
Slide 74: Incremental DKA Risk that Can Be Managed with Proper Care
Sotagliflozin and SGLT Inhibition – Incremental DKA Risk that Can Be Managed with Proper Care Instructions • Background rate of DKA in people with type 1 diabetes ranges between 5-8% annually1 • Sotagliflozin’s inTandem program and dapagliflozin DEPICT-1 have demonstrated manageable incremental DKA
Slide 75: Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity
Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity • 1.55 million adults are estimated to be living with type 1 diabetes in the United States in 2018 and has grown at 3.5%/year over the last 5 years • 75% of adults living with type 1 have an A1C > 7.0% 1.55 Million Adults Living With T1D in
Slide 76: Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity
Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity • 1.55 million adults are estimated to be living with type 1 diabetes in the United States in 2018 and has grown at 3.5%/year over the last 5 years • 75% of adults living with type 1 have an A1C > 7.0% DEPICT-1 excluded about 43% of the popu
Slide 77: Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity
Type 1 Diabetes Mellitus (T1DM) – Large Market Opportunity • 1.55 million adults are estimated to be living with type 1 diabetes in the United States in 2018 and has grown at 3.5%/year over the last 5 years • 75% of adults living with type 1 have an A1C > 7.0% Dapagliflozin Sotagliflozin is thewas r
Slide 78: Unmet needs in type 1 diabetes
Unmet needs in type 1 diabetes Jake A. Kushner, M.D. jake.kushner@mac.com @JakeKushnerMD
Slide 79: Disclosure: consultant for Lexicon, Virta Health, KNOW foods, and Sanofi
Disclosure: consultant for Lexicon, Virta Health, KNOW foods, and Sanofi
Slide 80: Michael Bliss, The Discovery of Insulin
Michael Bliss, The Discovery of Insulin, University of Chicago Press, 1982, 2007
Slide 81: Was insulin a "cure" for type 1 diabetes?
Was insulin a “cure” for type 1 diabetes?
Slide 82: Insulin-treated T1D patients began to suffer from unforeseen complications
Insulin-treated T1D patients began to suffer from unforeseen complications The Cumulative Incidence of Long- Term Sequelae of Juvenile Diabetes, by Duration of Diabetes, Joslin Clinic, 1898-1956.
Slide 83: Insulin-treated T1D patients had high rates of mortality
Insulin-treated T1D patients had high rates of mortality, even into the 1990s
Slide 84: Does improved glycemic control reduce complications? DCCT
Does improved glycemic control reduce complications? Diabetes Control Complication Trial (DCCT): 1441 T1D patients, 1-5 years duration, ages 13-39 “intensive therapy” vs. “conventional therapy”
Slide 85: Improved glucose control for ~6.5 years in DCCT
Improvedglucose Intensive glucosecontrol controlfor ~6.5 years in DCCT
Slide 86: Decreased retinopathy with intensive T1D treatment!
Decreased retinopathy with intensive T1D treatment!
Slide 87: Intensive glucose control for only ~10 years in DCCT
for~10 Intensive glucose control for only 10 years years in DCCT
Slide 88: Decreased cardiovascular disease with intensive T1D treatment!
Decreased cardiovascular disease with intensive T1D treatment!
Slide 89: Decreased mortality with intensive T1D treatment!
Decreased mortality with intensive T1D treatment!
Slide 90: Millions of people have type 1 diabetes
Millions of people have type 1 diabetes • Injected insulin is the only available therapy • High burden of illness: Very challenging to keep blood sugars in normal range • Risk of weight gain & hypoglycemia with increased insulin • Frequent hypoglycemia (typically 1-2 episodes per week) • Severe hypo
Slide 91: Most with T1D fail to achieve A1c target
Most with T1D fail to achieve A1c target
Slide 92: Most with T1D fail to achieve A1c target
Most with T1D fail to achieve A1c target A1c target: <7 in adults
Slide 93: 18 y old, T1D for >10 yrs (High carb diet)
18 y old, T1D for >10 yrs (High carb diet)
Slide 94: Adverse consequences in typically treated T1D?
Adverse consequences in typically treated T1D?
Slide 95: Typically treated T1D results in excess risk of cardiovascular death
Typically treated T1D results in excess risk of cardiovascular death
Slide 96: Weight gain is associated with cardiovascular disease in intensive T1D treatment
Weight gain is associated with cardiovascular disease in intensive T1D treatment
Slide 97: Sotagliflozin Results inTandem3
Sotagliflozin Results inTandem3 inTandem3 Sotagliflozin Placebo 400 mg P-Value Net benefit (A1c<7.0% without 15.2% 28.6% p<0.001 severe hypo or DKA) A1C (%) change at 24 weeks -0.33 -0.79 p<0.001 Body weight (kg) +0.8 -2.2 p<0.001 Blood pressure (mmHg)* -5.7 -9.2 p=0.002 Bolus insulin -1.1 IU/day -3
Slide 98: Sotagliflozin Clinical Trial Safety Experience
Sotagliflozin Clinical Trial CORRESPONDENCE Safety Experience Effects of Sotagliflozin Added to Insulin in Type 1 CORRESPONDENCE Diabetes • DKA education by healthcare providers Effects of Sotagliflozin Added t March 8, 2018 • Ketone monitoring recommended N Engl J Med 2018; 378:966-968 DOI: 10.1056
Slide 99: Patient Education and Monitoring for DKA
Patient Education and Monitoring for DKA • Recognize potential symptoms of ketosis or DKA, even when glucose is normal or only mildly elevated - Nausea, vomiting, or stomach pain - Constantly feeling tired, general malaise - Thirst, frequent urination, or very dry mouth • Check ketones If these symp
Slide 100: Sotagliflozin: Patient Perspective
Sotagliflozin: Patient Perspective Potential Benefits Patient commitment • Short-term • Recognize the potential for DKA – A1c reduction – Potentially 2% to 4% – Greater time in range incidence at 1 year • Less hyperglycemia and hypoglycemia • Monitor ketones to mitigate risk of – Weight loss DKA, wi
Slide 101: Sotagliflozin Program Summary
April 10, 2018 Sotagliflozin Program Summary Pablo Lapuerta, M.D. Executive Vice President and Chief Medical Officer Precision Science. Pioneering Medicine. Patient Driven. 100 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 102: Phase 3 Program in T1DM – Summary
Phase 3 Program in T1DM – Summary • inTandem program has the largest efficacy and safety database of an oral anti-diabetic agent for T1DM • Sotagliflozin profile - Robust A1C efficacy on top of insulin - Improved glucose time in range - Robust weight reduction - Lower rate of hypoglycemic episodes w
Slide 103: T2DM Phase 3 Program – Ten Ongoing Studies
T2DM Phase 3 Program – Ten Ongoing Studies Targeting Over 15,000 Patients with More to Come This Year Monotherapy Metformin Combination CV and Renal Glimepiride Study Study Study with Events (SOTA-GLIM) sulfonylurea (SCORED) Study or metformin Study 400 500 patients patients 500 10,500 930 patients
Slide 104: Sotagliflozin Program – Summary
Sotagliflozin Program – Summary • Type 1 diabetes - NDA and MAA filings submitted in 1Q 2018 • Type 2 diabetes - Data for majority of the Phase 3 studies expected in 2019 - MAA filing planned for 2H19 - NDA filing planned for early 2020 103 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 105: Pipeline Progress – LX2761 and LX9211
April 10, 2018 Pipeline Progress – LX2761 (diabetes) and LX9211 (neuropathic pain) Praveen Tyle, Ph.D. Executive Vice President, Research & Development Precision Science. Pioneering Medicine. Patient Driven. 104 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals,
Slide 106: Lexicon's Scientific Platform Has Produced a Commercial Product and Pipeline
Lexicon’s Scientific Platform Has Produced a Commercial Product and a Pipeline of Innovative Drug Candidates Compound Partner Target Indication Preclinical Phase 1 Phase 2 Phase 3 Registration Marketed Wholly Carcinoid owned (U.S./ TPH1 syndrome FDA approval Feb 28, 2017; US launch Mar 01, 2017 Japa
Slide 107: LX2761 - Diabetes
LX2761 - Diabetes Precision Science. Pioneering Medicine. Patient Driven. 106 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 108: LX2761 – Locally-acting SGLT1 Inhibitor for Diabetes
LX2761 – Locally-acting SGLT1 Inhibitor for Diabetes SGLT2 SGLT1 SGLT2 is the reabsorbs primary transporter 90% of for glucose/galactose filtered glucose in the in the kidney GI tract SGLT1 Inhibiting Inhibiting SGLT1SGLT2 in theinGI the tract kidney delays & reduces increasesglucose glucose absorpt
Slide 109: LX2761 - Drug Candidate for Diabetes Focused on SGLT1 in GI Tract
LX2761 - Drug Candidate for Diabetes Focused on SGLT1 in GI Tract ➢ Potent, orally-delivered small molecule strategically designed to maximize SGLT1 inhibition locally in the gastrointestinal tract with no urinary glucose excretion ➢ Ability to minimize PPG excursions ➢ Ability to maximize GLP-1 rel
Slide 110: LX2761 - Designed to Remain in the Intestine
LX2761 - Designed to Remain in the Intestine After Oral Delivery to Inhibit Local SGLT1 Oral delivery of LX2761 results in very low systemic exposure in mice Source: Goodwin NC et al 2017 J Med Chem 109 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 111: LX2761 - No Increase in Urinary Glucose Excretion
LX2761 - No Increase in Urinary Glucose Excretion 24-hour urine glucose on day 1 and day 2 after oral delivery with a single dose in mice Source: Goodwin NC et al 2017 J Med Chem 110 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 112: LX2761 Blunted Glucose Excursions in Preclinical Testing
LX2761 Blunted Glucose Excursions in Preclinical Testing Data from oral glucose tolerance tests in rats Source: Powell DR et al 2017 J Pharmacol Exp Ther 111 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 113: Decreased Glucose Excursions 15 Hours After the Last Dose
Decreased Glucose Excursions When Oral Glucose was Administered 15 Hours After the Last Dose of LX2761 Note: The adult male C57 mice studied were fed ad lib between the last oral dose of LX2761 and the OGTT Source: Powell DR et al 2017 J Pharmacol Exp Ther 112 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 114: LX2761 and Sitagliptin Synergistically Increase Postprandial GLP-1
LX2761 and DPP-4 Inhibitor Sitagliptin Synergistically Increase Postprandial GLP-1 Levels in Preclinical Testing ➢ Adult male mice received vehicle, LX2761 and/or sitagliptin by oral delivery ➢ Each mouse received 4 g/kg glucose by oral delivery Source: Powell DR et al 2017 J Pharmacol Exp Ther 113
Slide 115: LX2761 – Key Takeaways
LX2761 – Key Takeaways ➢Potent, oral, locally-acting SGLT1 inhibitor ➢Robust preclinical efficacy and good safety profile ▪ Reduces PPG ▪ No increase in UGE, consistent with local action ▪ Synergy with DDP-4 inhibitor in preserving active GLP-1 ➢ Phase 1a clinical trials completed in healthy subject
Slide 116: LX9211 - Neuropathic Pain
April 10, 2018 LX9211 - Neuropathic Pain Discovering Breakthrough Treatments for Human Disease 115 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 117: R&D in the Pain Market – Overview
R&D in the Pain Market – Overview In contrast, oncology has >2,000 clinical programs (1,700 NCEs) 220 clinical programs Only 125 NCEs Most approved pain products since 2007 87% are non-opioid have been receptors reformulations or have pre-2007 market history 2 approved NCEs for pain in a decade (mil
Slide 118: LX9211 - A Novel Approach for Neuropathic Pain: AAK1 Inhibitor
LX9211- A Novel Therapeutic Approach for Neuropathic Pain: Adaptor Associated Kinase-1 (AAK1) Inhibitor ➢ Discovered in Lexicon’s neuroscience drug discovery alliance with Bristol-Myers Squibb ➢ Lexicon has acquired exclusive development and commercialization rights ➢ Potent, highly-selective, oral
Slide 119: Diabetic Neuropathic Pain Disease - Overview
Diabetic Neuropathic Pain Disease - Overview ➢A late-stage complication in patients with diabetes mellitus, affects approximately 15% of patients. ➢Complicates diabetes treatment by limiting the patient’s ability to exercise, which improves glucose management ➢Severely interferes with sleep, which c
Slide 120: Genome 5000 Program - AAK1 Knockout Mice Have Anti-Nociceptive Phenotype
Lexicon’s Genome 5000 Program - AAK1 Knockout Mice Have Anti-Nociceptive Phenotype Mouse Spinal Nerve Ligation Model Source: Kostich et al 2016, J Pharmacol Exp Ther 119 © 2018 Lexicon Pharmaceuticals, Inc.
Slide 121: LX9211 Reduces Streptozotocin-induced Diabetic Neuropathic Pain in Rats
AAK1 Inhibitor LX9211 Reduces Streptozotocin-induced Diabetic Neuropathic Pain in Rats Inhibition of Mechanical Allodynia (%) 150 140 130 120 110 **** 100 **** **** **** 90 80 70 60 **** **** 50 40 **** **** **** 30 20 **** * 10 * 0 -10 0 1.5 3.5 5.5 Time After Treatment (h) Vehicle in Non-diabetic
Slide 122: LX9211 Does Not Impair Motoric Coordination in the Rat
LX9211 Does Not Impair Motoric Coordination in the Rat - Rotarod Performance Test 300 * Riding TIme (s) 200 ** **** 100 0 1 3 5 Time After Treatment (h) Vehicle LX9211 (3 mg/kg) LX9211 (30 mg/kg) Gabapentin (100 mg/kg) *P<0.05, **P<0.01, ****P=0.0001 compared to vehicle Source: Unpublished data from
Slide 123: AAK1 Inhibitors - Mechanisms of Action
AAK1 Inhibitors - Mechanisms of Action ➢ Mechanism involves α2 adrenergic pathway ➢ Mechanism thought to involve GABAergic pathway ➢ Target does not have the same motor side effects seen with gabapentinoids ➢ Spinal dorsal horn key site of action (central nervous system target) ➢ Mechanism does not
Slide 124: LX9211 Key Takeaways
LX9211- A Potent and Selective AAK1 Inhibitor for Neuropathic Pain: Key Takeaways ➢ High potency and specificity for AAK1 inhibition ➢ Robust target engagement and efficacy ➢ Superior profile to the current standard of care ➢ Excellent brain penetration ➢ Opioid target sparing ➢ Phase 1a clinical st
Slide 125: Financial Overview
April 10, 2018 Financial Overview Jeffrey L. Wade, J.D. Executive Vice President, Corporate and Administrative Affairs and Chief Financial Officer Precision Science. Pioneering Medicine. Patient Driven. 124 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 126: 2017 Financials
2017 Financials Selected Income Sheet Data: 2017 2016 Revenue $90.3M1 $83.3M Operating Expenses2 R&D $156.8M $178.2M SG&A $66.2M $43.0M Total Operating Expenses $227.0M $220.5M Net Loss $(129.1)M $(141.4)M Net Loss Per Common Share $(1.23) $(1.36) Selected Balance Sheet Data: As of Dec 31, 2017 Cash
Slide 127: 2018 Financial Guidance
2018 Financial Guidance 2018 Financial Selected Income Sheet Data: Guidance Revenue Revenue from collaborations $30-$40M At least double year- Net product revenue over-year Operating Expenses1 R&D $125-$135M SG&A $80-$90M Total Operating Expenses $205-$225M Non-Cash Expenses ~$17M Net Cash Used in O
Slide 128: 2018 Marks a Year of Transition - Sotagliflozin
2018 Marks a Year of Transition - Sotagliflozin Investments in sotagliflozin through 2018 may begin to yield returns in 2019 and 2020 Regulatory Development Sales Milestones Milestones Milestones and Royalties • $220M – • $110M – • $990M – Sales Milestones linked to Milestones linked to milestones f
Slide 129: Investment in the Future – Commercial and R&D
Investment in the Future – Commercial and R&D • Commercialization - Investments in XERMELO commercialization and medical affairs activities, with a view towards achieving positive cash flow on the brand in the next 12-24 months - Initiation of investments in sotagliflozin U.S. T1D commercialization
Slide 130: Q&A Session #2
April 10, 2018 Q&A Session #2 Precision Science. Pioneering Medicine. Patient Driven. 129 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.
Slide 131: Closing Remarks
April 10, 2018 Closing Remarks Lonnel Coats President and Chief Executive Officer Precision Science. Pioneering Medicine. Patient Driven. 130 Precision Science. Pioneering Medicine. Patient Driven. © 2018 Lexicon Pharmaceuticals, Inc.