Impact of Functioning Metastatic Neuroendocrine Tumors

Clinical Overview and Treatment Advances in Carcinoid Syndrome Sponsored by Lexicon Pharmaceuticals Impact of Functioning Metastatic Neuroendocrine Tumors Evaluation & Management 1

Presentation objectives By the end of this presentation, attendees will have learned about: Epidemiology and clinical characteristics of neuroendocrine tumors The role of serotonin in carcinoid syndrome The complications of carcinoid syndrome Carcinoid syndrome diarrhea management 3 Introduction to Neuroendocrine Tumors (NETs) 2

NETs: Not Your Typical Tumors Family of malignancies originating from neuroendocrine cells throughout the body 1 Often misunderstood and often present at an advanced stage 1 Increasingly common 1 Can be aggressive, treatment resistant, and potentially life threatening 1,2 Induce debilitating hormonal syndromes NET=neuroendocrine tumor. 5 Carcinoid Syndrome Is an Ultra-Orphan Disease ~13,000 Patients Are Currently Living With Carcinoid Syndrome in the United States NETs 1 ~103,000 patients GEP-NETs ~61% 2 ~62,500 patients Non-GEP-NETs ~39% 3 ~40,000 patients Patients with functioning carcinoid tumors 10%-20% 4,5,a ~13,000 Patients Nonfunctioning carcinoid tumors ~80% ~50,000 patients Bronchopulmonary ~69% 3 ~27,000 patients a Calculation based on 20%. 1. Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. 2. Lawrence B, et al. Endocrinol Metab Clin North Am. 2011;40(1):1-18. 3. Frilling A, et al. Endocr Relat Cancer. 2012;19(5): R163-R185. 4. National Cancer Institute. Gastrointestinal carcinoid tumors treatment for health professionals (PDQ ). https://www.cancer.gov/types/gi-carcinoid-tumors/hp/gi-carcinoid-treatment-pdq. Accessed February 7, 2017. 5. Horton KM, et al. AJR Am J Roentgenol. 6 2004;182(3):559-567. 6 3

Pathophysiology and Complications Arising from Serotonin in Carcinoid Syndrome Diarrhea Serotonin is overproduced intracellularly by functioning NETs Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin production 29 mnet cell Systemic circulation/blood stream Secretion 31 TPH is robustly expressed in functioning NETs and the resulting serotonin overproduction triggers carcinoid syndrome 14,32 Somatostatin and its receptors (SSTR2 and SSTR5) serve to block the secretion of serotonin, though NET cells may reduce SSTR concentration on the cell surface 31,32 Serotonin is converted from tryptophan by TPH and subsequently secreted by NETs into systemic circulation, where it is converted to 5-HIAA 15 mnet=metastatic NET; NETs=neuroendocrine tumors. 8 4

Excess serotonin has short- and long-term consequences known as Carcinoid Syndrome Overall health 36 Among patients with metastatic or advanced neuroendocrine tumors (NETs), those with carcinoid syndrome have a poorer prognosis than those with NETs alone. Short-term effects 5,15,33 Life-altering diarrhea Urgent bowel movements Flushing in the skin Long-term effects 15,33,35 Tissue fibrosis Heart (carcinoid heart disease) Lung/pulmonary Mesentery Carcinoid Syndrome 9 Carcinoid syndrome diarrhea is often debilitating and sometimes life-threatening Diarrhea occurs in >70% patients with carcinoid syndrome and may occur several times daily 5,36 Fluid loss from severe diarrhea may result in dehydration and serious health consequences 38 : 9% develop severe, life-threatening diarrhea 39 Patients can experience significant weight loss and hypoproteinemia 38 BM=bowel movement. 10 5

Approaches to Management for NETs and Carcinoid Syndrome Diarrhea SSAs have been the standard of care in the management of NETs and Carcinoid Syndrome diarrhea Systemic circulation/blood stream SSAs inhibit the downstream release of serotonin but do not directly inhibit serotonin production SSAs bind primarily to SSTRs 2 and 5 on the cell surface 40 They block the extracellular secretion of serotonin and other hormones 41,42 SSAs are recommended for the treatment of symptomatic and asymptomatic NETs 44 SSAs are commonly used for tumor and symptom management in patients with NETs 44 mnet=metastatic NET; NET=neuroendocrine tumor; SSA=somatostatin analog; SSTR=somatostatin receptor; TPH=tryptophan hydroxylase. SSA 12 6

Despite a variety of treatment options, therapies that target a root cause of carcinoid syndrome are necessary Modification of SSA dose such as shortening the treatment interval or increasing the dose are often employed however: 51 - Many patient develop tachyphylaxis potentially due to decreased receptor concentration 32 - Escalation is typically at doses that are not FDA approved 51 - There is a lack of prospective well-designed clinical evidence to support this strategy Self-administered short-acting SSA injections may also be utilized to try to reduce diarrhea, although this approach generally requires multiple daily injections 51 Patients often use non-specific treatments to halt gastric motility yet continue to remain syndromic 13 Summary NETs are a diverse family of potentially malignant neoplasms with a steadily rising incidence rate 5,2 Carcinoid syndrome is induced by the secretion of serotonin from functional NETs and is often misdiagnosed 15,16 Potentially devastating short- and long-term effects of carcinoid syndrome include life-altering diarrhea and carcinoid heart disease, respectively 5 Carcinoid syndrome treatment is imperative regardless of tumor status, as patients have long life spans and exhibit significant disease burden 36 Despite non-specific options historically, patients require additional management of their carcinoid syndrome diarrhea 52,53 NET=neuroendocrine tumor. 14 7

Thank you First in class: tryptophan hydroxylase inhibitor 1,2 Introducing XERMELO The first and only oral treatment for carcinoid syndrome diarrhea 1,2 8

XERMELO (telotristat ethyl) A tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Please see Important Safety Information throughout this presentation. Introducing Rebecca C., 62* Diagnosed with GI NET Diagnosed with carcinoid syndrome Syndrome Intensified 2012 2013 2014 2015 Underwent surgery Sandostatin 30 mg/4 wk *Representative of a typical patient in the TELESTAR TRIAL. This is not an actual patient. GI=gastrointestinal; NET=neuroendocrine tumor; wk=week. 18 9

Rebecca s chief complaints and current therapy Chief complaints: Diarrhea Patient experiences urgent bowel movements that occasionally occur throughout the night Frequent bathroom trips lead to disruptions in the workplace and at social events Upon further probing, patient reveals that the frequency of her bowel movements has increased to 6 daily Physical exam findings: Frequent injections from SSA administration produced scar tissue in both buttocks Baseline laboratory values: u5-hiaa Levels: 91mg/24hrs Current therapy: Octreotide 30 mg/4 weeks Short-acting SSA therapy PRN Imodium/Lomotil PRN PRN=as needed; SSA=somatostatin analogue; u5-hiaa=urinary 5-hydroxyindoleacetic acid. 19 Considerations for next steps Chief complaint of diarrhea (frequency and impact to patient lifestyle) Mode of SSA administration Patient currently at maximum FDA-approved dose for Sandostatin LAR Elevated levels of u-5hiaa Upon further dialogue, the patient was started on XERMELO for the treatment of carcinoid syndrome diarrhea SSA=somatostatin analog; LAR=long-acting release; u5-hiaa=urinary 5-hydroxyindoleacetic acid. 20 10

TELESTAR A 12-week, double-blind, placebo-controlled, randomized, multicenter, Phase III pivotal trial TELESTAR: Study design 1 XERMELO is approved based on the results of TELESTAR, a 12-week, double-blind, placebo-controlled, randomized, multicenter Phase III trial 1 Primary endpoint: Change in number of daily bowel movements. Patients were allowed to use rescue medication (short-acting octreotide) and antidiarrheals for symptomatic relief The TELESTAR study included a 36-week open-label extension investigating a higher than recommended dose of XERMELO 1 TELESTAR=Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome; mnet=metastatic neuroendocrine tumor; SSA=somatostatin analog. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 22 11

TELESTAR: Baseline characteristics 1 SD=standard deviation; BM=bowel movement; u5-hiaa=urinary 5-hydroxyindoleacetic acid; SSA=somatostatin analog; H=hour. Reference: 1. Kulke MH, Hörsch D,Caplin ME, et al. J Clin Oncol. Published Online: October 28, 2016 (doi:10.1200/jco.2016.69.2780). 23 XERMELO (telotristat ethyl) Mechanism of action 12

XERMELO: The first and only oral TPH inhibitor to decrease the production of serotonin, an important driver of carcinoid syndrome diarrhea 1,2 XERMELO + SSA decreases both the production of serotonin within the metastatic neuroendocrine (mnet) cell and the release of serotonin outside the cell 1-3 OUTSIDE THE mnet CELL INSIDE THE mnet CELL TPH INHIBITION AND DECREASED INTRACELLULAR SEROTONIN PRODUCTION RESULT IN 1 u5-hiaa IS A BIOMARKER IN CARCINOID SYNDROME AND IS INDICATIVE OF SEROTONIN LEVELS 5,6 References: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017.. 2. Molina-Cerrillo J, Alonso-Gordoa T, Martínez-Sáez O, Grande E. Oncologist. 2016;21:701-707. 3. Sandostatin LAR Depot Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; July 2014. 4. Appetecchia M, Baldelli R. J Exp Clin Cancer Res. 2010;29:19. 5. van der Horst-Schrivers ANA, Post WJ, Kema IP, et al. Eur J Cancer. 2007;43:2651-2657. 6. Bartholomew TK, Garcia Hernandez J, Rossi RE, et al. Urinary 5-hydroxyindoleacetic acid in serotonin-producing neuroendocrine tumors: correlation with disease eatures and survival. Poster presented at: European Neuroendocrine Tumor Society 11th Annual Conference; March 5-7, 2014; Barcelona, Spain. 25 TELESTAR: 24-hour u5-hiaa levels decreased with XERMELO but not with SSA alone 1 u5-hiaa did not decrease with SSA alone 1 Reductions observed following 6 and 12 weeks of treatment 1 u5-hiaa=urinary 5-hydroxyindoleacetic acid; SSA=somatostatin analog. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 26 13

XERMELO provided significant and superior reductions in mean daily bowel movements vs SSA alone (P<0.001) 1 Over 12 weeks, XERMELO + SSA delivered superior reductions in bowel-movement frequency vs SSA alone (P<0.001) 1 XERMELO + SSA provided early and sustained reductions in bowel-movement frequency, observed as early as 1 to 3 weeks and maintained throughout the 12-week study 1 SSA=somatostatin analog. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 27 89% of patients receiving XERMELO + SSA experienced improvement in bowel-movement frequency 1 Reductions in daily bowel-movement frequency with XERMELO + SSA vs SSA alone XERMELO + SSA reduced overall average bowel-movement frequency by 2 per day in 8x more patients than SSA Alone: 33% vs 4%, respectively 1 SSA=somatostatin analog. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 28 14

XERMELO + SSA reduced the use of short-acting rescue injection beyond SSA alone PATIENTS RECEIVING SSA ALONE REQUIRED MORE THAN TWICE AS MANY AVERAGE DAILY RESCUE INJECTIONS AS DID PATIENTS RECEIVING XERMELO + SSA: 0.7 VS 0.3 AVERAGE DAILY INJECTIONS, RESPECTIVELY 1 If combination treatment with XERMELO and short-acting octreotide is needed, administer short-acting octreotide at least 30 minutes after administering XERMELO SSA=somatostatin analog. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 29 XERMELO: Safety profile 1 *Incidence of 5% in the XERMELO treatment group and at an incidence greater than placebo. Reference: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 30 15

XERMELO + Standard of Care Is Estimated to Have Minimal Budget Impact Inadequately Controlled Patient Population (Current SOC) SSA Outcomes Increase dose of LAR Increase SSA rescue use Increased incidence of CS diarrhea HCRU Budgetary Impact Year 1: $18.9M $20.4M PPPM $9.4K $10.1K PMPM $0.16 $0.17 Net PMPM $0.01 (Future SOC) SSA + TE Increase cost with Xermelo Decrease SSA rescue use Decrease incidence of CS diarrhea HCRU Population Time horizon: 3 years up to 5 years Health plan population:10m members with carcinoid syndrome (0.0042%): N=420 Members without adequately controlled carcinoid syndrome (39.92%): N=168 Data on file. SOC, Standard of Care HCRU, Health Care Related Utilization 31 XERMELO Delivers Value VALUE ~90% of payers surveyed incorporate both benefit and cost into their value assessments 1 Benefit Reduces carcinoid syndrome diarrhea symptoms Oral route of administration Cost Minimal budget impact ($0.01 PMPM) XERMELO Value XERMELO an FDA-approved combination therapy with SSA for patients with metastatic NETs and carcinoid syndrome diarrhea who are inadequately controlled by their current SSA therapy is an efficacious therapy that may fill the void left by costly, off-label dose escalation a Compared with costs associated with inadequately controlled carcinoid syndrome diarrhea (eg, ambulatory care, ER visits, inpatient stays, pharmacy cost). 3 1. Abedi S. Defining value: the payer perspective. http://www.pharmexec.com/defining-value-payer-perspective. Published January 5, 2016. Accessed May 2, 2017. 2. XERMELO [prescribing information]. The Woodlands, TX; Lexicon Pharmaceuticals, Inc.; February 2017. 3. Data on file. 32 16

Important Safety Information Warnings and Precautions: XERMELO may cause constipation, which can be serious. Monitor for signs and symptoms of constipation and/or severe, persistent, or worsening abdominal pain in patients taking XERMELO. Discontinue XERMELO if severe constipation or severe, persistent, or worsening abdominal pain develops. Adverse Reactions: The most common adverse reactions ( 5%) include nausea, headache, increased gamma-glutamyl-transferase, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. Drug Interactions: If necessary, consider increasing the dose of concomitant CYP3A4 substrates, as XERMELO may decrease their systemic exposure. For more information about XERMELO, please see the full Prescribing Information. 33 Rebecca at week 12 on TELESTAR BM frequency Achieved a week 12 reduction similar to the study population u5-hiaa A reduction in u-5hiaa levels was achieved at week 12 Current therapy: XERMELO 250 mg Octreotide 30 mg/4 weeks Imodium/Lomotil PRN Treatment-emergent side effects: Grade 1 headache Grade 2 nausea AS SYMPTOMS IMPROVE, IT IS CRUCIAL TO MAINTAIN A CONTINUING DIALOGUE WITH PATIENTS SURROUNDING THE FREQUENCY AND IMPACT OF DAILY BOWEL MOVEMENTS u5-hiaa=urinary 5-hydroxyindoleacetic acid; BM=bowel movement; PRN=as needed.. 34 17

XERMELO: Dosing and Adherence It is important for your patients to take XERMELO every day 1 : XERMELO works by reducing serotonin, thereby reducing carcinoid syndrome diarrhea XERMELO bioavailability is increased with food; therefore, it should be administered as 250 mg tablets 3 times daily with meals If a dose is missed, patients should be advised not to take extra doses in an attempt to compensate Reference: XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 35 XERMELO: The first and only oral treatment for carcinoid syndrome diarrhea 1,2 Through inhibition of tryptophan hydroxylase, XERMELO decreases the production of serotonin and the frequency of carcinoid syndrome diarrhea 1,2 89% of patients receiving XERMELO + SSA experienced improvement in bowel-movement frequency vs 69% of patients receiving SSA alone 1 XERMELO provided superior and significant reductions in daily bowel movements averaged over 12 weeks ( 1.4 with XERMELO 250 mg vs 0.6 with SSA alone; P<0.001) 1 XERMELO + SSA provided early and sustained reductions in bowel-movement frequency, observed as early as 1 to 3 weeks and maintained throughout the 12-week study 1 The most common adverse reactions ( 5%) include nausea, headache, increased gamma-glutamyl-transferase, depression, flatulence, decreased appetite, peripheral edema, and pyrexia 1 u5-hiaa=urinary 5-hydroxyindoleacetic acid; SSA=somatostatin analog. References: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 2. Molina-Cerrillo J, Alonso-Gordoa T, Martínez-Sáez O, Grande E. Oncologist. 2016;21:701-707. 36 18

XERMELO: The first and only oral treatment for carcinoid syndrome diarrhea 1,2 THANK YOU For more information call 1(844) XERMELO or visit www.xermelo.com References: 1. XERMELO Prescribing Information. The Woodlands, TX: Lexicon Pharmaceuticals, Inc.; February 2017. 2. Molina-Cerrillo J, Alonso-Gordoa T, Martínez-Sáez O, Grande E. Oncologist. 2016;21:701-707. 37 How to Ask A Question Type your question in the Questions area 19