Telotristat Ethyl (etiprate) : a new kid on the block Dr. Christos G. Toumpanakis MD PhD FRCP

Telotristat Ethyl (etiprate) : a new kid on the block Dr. Christos G. Toumpanakis MD PhD FRCP Consultant in Gastroenterology/Neuroendocrine Tumours Hon. Senior Lecturer University College of London Neuroendocrine Tumour Unit - ENETS Centre of Excellence ROYAL FREE HOSPITAL, London,UK

IPSEN Honoraria for lectures Educational Grants for RFH NET Unit Advisory Board NOVARTIS Honoraria for lectures Educational Grants for RFH NET Unit Advisory Board LEXICON Advisory Board

Contents Refractory carcinoid syndrome Implications Current options Telotristat ethyl : Mode of action Summary of preclinical data and phase I data Phase II trials Phase III trials Positioning of Telotristat in NETs therapeutic algorithm

MIDGUT NETs (in 5% of bronchial NETs and 1% of pancreatic NETs) a. Carcinoid syndrome Flushing, diarrhoea, bronchospasm, Carcinoid heart disease 20 30 % of patients with liver metastases 5% of patients with carcinoid syndrome do not have liver metastases b. Carcinoid crisis Severe symptoms of carcinoid syndrome + hypotension during procedures that involve GA, as well as in TAE, and when the patient is on inotropes Refractory Carcinoid syndrome : ongoing symptoms, despite maximum conventional doses of somatostatin analogues (SSTA)

Are my patient s symptoms really due to Refractory Carcinoid Syndrome? OTHER CAUSES OF DIARRHOEA Steatorrhoea Small bowel bacterial overgrowth Bile acid malabsorption Mesenteric ischaemia OTHER CAUSES OF FLUSHING Menopause Anxiety attacks Medications (morphine analogues)

Refractory Carcinoid Syndrome & risk for development and / or progression of CHD Multivariate model, in a prospective study of 252 patients. Development and progression of CHD were linked to 5-HIAA levels. 5-HIAA > 300 μmol/l is independent predictor for development and progression of CHD (2-3 fold increase in risk). The same risk was noted in patients with > 3 flushing episodes / day. Denney et al, J Am Coll Cardiol 1998 Moller et al, NEJM 2003 Bhattacharyya et al, Am J cardiol 2011

Carcinoid Heart Disease It represents the development of fibrotic plaques on the heart valves. It DOES NOT mean development of myocardial metastases. Reported in the past in 40-50% of patients with carcinoid syndrome,, recent prevalence : about 20%, (midgut NETs with hepatic or retroperitoneal metastases, ovarian NETs and bronchial NETs). Its development is associated with 30 50% reduction in the expected survival of those patients. The median survival improved from 1.5 years in the 1980s to 4.4 years in the late 1990s.

Gastrointestinal neuroendocrine tumors treated with high dose octreotide-lar: A systematic literature review Michael S Broder, David Beenhouwer, Jonathan R Strosberg, Maureen P Neary, Dasha Cherepanov, World J Gastroenterol 2015 Feb Octreotide LAR dose Results Valle et all (2001) Dose escalation Improvement of symptoms Woltering et all (2006) 20mg/30mg/60mg Flushing not controlled in 0% (20 mg), 11.1% (30 mg), vs 7.1% (60 mg), diarrhea not controlled in 0% of pts. (20 mg), 27.8% (30 mg), vs 30.8% (60 mg) groups Ferolla et all (2012) 30mg every 3 weeks Complete normalization 40% Partial symptom control in 60% Strosberg at all (2013) Wolin at all (2013) (phase III study with pasireotide) 30mg every 3 weeks 40mg / 60 mg 40mg 62% improvement of diarrhoea 56% improvement of flushing 27% symptoms improvement in month 6

Interferon Alpha for carcinoid syndrome symptoms control RFH Interferon Data 24 pts, in combination with SSTA - Diarrhoea improved 45% - Flushing improved in 54% Of the 19 patients given alpha-interferon in combination with octreotide, 72% showed significant reduction in urinary 5- HIAA for a median of 10 months. A symptomatic improvement was seen in 49%. The combination was well tolerated. - No statistically significant decrease of 5-HIAA levels - 27% of patients discontinued treatment at 3 months, due to AE Mirvis et al, Anticancer Research 2015 Janson & Oberg, Acta Oncol 1993

EVEROLIMUS FOR REFRACTORY CARCINOID SYNDROME Control of carcinoid syndrome with everolimus (CASE REPORT) Capdevilla J et al. Ann Oncol 2011 CgA 5-HIAA After a month of treatment, the symptoms of carcinoid syndrome improved with a reduction in the flushing episodes to 1 2 per day, an improvement in diarrhea and a significant decrease in 5-HIAA levels (up to 60%). Symptomatic Control of Neuroendocrine Tumours with Everolimus. Bainbridge et al, Horm Cancer 2015 Everolimus plus octreotide LAR resulted in greater reductions in serum chromogranin A (p treatment=0 0041) and urine 5- hydroxyindoleacetic acid (p treatment <0 0001) compared with placebo plus octreotide LAR. RADIANT-2, Pavel et al, Lancet 2011 7/10 patients who were syndromic had improvements in symptomology, with a mean duration of symptom control 13.9 months. 6/10 had reduced stool frequency, 3/7 had a reduction of asthenia, and 5/7 had reduced frequency and severity of flushing. Sixty percent of patients experienced any grade toxicities, including the following: 40% grade 1/2 stomatitis, 7% grade 3/4 stomatitis, 20% grade 1/2 rash, 13% diarrhoea, and one case of pneumonitis

Control of carcinoid syndrome symptoms with PRRT RFH PRRT data 35 patients Percentages of patients who reported improvement in pain and diarrhoea score after PRRT. Saima Khan et al. J Nucl Med 2011 Koffas et al, ENETS & DDW 2016

No enough data for sunitinib or systemic chemotherapy for symptoms control in refractory carcinoid syndrome

Transarterial Hepatic Embolization and Chemoembolization Symptomatic benefit (40-80%) Partial response : ~ 50%? Survival benefit Brown et al J Vasc Interv Radiol 1999;10(4):397-403 Chamberlain et al J Am Coll Surg 2000;190:432-445 Morbidity (carcinoid crisis, fever, pain, hepatic failure, intestinal ischaemia) Mortality i.v. octreotide infusion pre- and post therapy Careful selection of patients Toumpanakis et al, Best Pract Res Clin End Metab 2007

Phase III study of pasireotide LAR vs octreotide LAR in patients with metastatic midgut NET Blinded treatment period of 6 months NET patients with carcinoid syndrome symptoms inadequately controlled by maximum doses of currently available SSAs 1:1 randomisation Pasireotide LAR 60mg IM every 28 days x 6 months with dose to 40mg for tolerability (n=53) Octreotide LAR 40mg IM every 28 days x 6 months with dose to 30mg for tolerability (n=57) Primary endpoint: symptom control (month 6) Secondary endpoints: tumour response, PFS, safety Trial was terminated early based on interim analysis demonstrating futility for primary endpoint (symptom response at month 6) Wolin et al, Drug Des Devel Ther. 2015 Sep 3;9:5075-86

It seems that THERE IS an unmet need

Telotristat etiprate: A peripherally-acting serotonin synthesis inhibitor Telotristat etiprate is a novel, orallydelivered inhibitor of tryptophan hydroxylase (TPH) that reduces serotonin production: Absorbed into peripheral circulation Does not cross the bloodbrain barrier Lapuerta P, et al. Clinical Investigation (Lond.) 2015; 5(5): 447 456

Telotristat etiprate : Molecular structure Telotristat etiprate is an ethyl ester pro-drug which is hydrolyzed to its active moiety LP-778902 both in vivo and in vitro Telotristat etiprate conversion Lapuerta P, et al. Clinical Investigation (Lond.) 2015; 5(5): 447 456

Telotristat etiprate: Mode of action TPH Catalyzes the First Step of Serotonin Synthesis Tryptophan Hydroxylase (TPH) Tryptophan Telotristat Etiprate 5-Hydroxytryptophan 5-HI AA (5-Hydroxyindoleacetic acid) Serotonin (5-Hydroxytryptamine, 5-HT) TPH catalyzes the first step of serotonin synthesis 2013 Lexicon Pharmaceuticals, Inc. Slide 10

Ιn addition to SSA, telotristat etiprate inhibits serotonin production and alleviates symptoms Serotonin hormonal syndrome flushing, diarrhoea... 5-HIAA Urine Serotonin Tryptophan- Hydroxylase Tryptophan 5-Hydroxytryptophan (5-HTP) NET-Cell Telotristat etiprate SSTR 5-HIAA: 5-hydroxyindole acetic acid SSA somatostatin analogue SSTR somatostatin receptor Serotonin (5-HT) SSA

Preclinical summary Reduction of peripheral serotonin levels in KO mice did not adversely affect physiologic function Telotristat etiprate reduces peripheral serotonin levels without affecting brain serotonin levels

Summary of phase 1 clinical results Single and multiple dose phase 1 studies involving 88 subjects demonstrated that telotristat etiprate was tolerated up to the highest dose tested over 14 days (1,500 mg) Adverse events were minimal, generally mild in intensity, and evenly distributed throughout all dose groups Statistically significant reductions in biomarkers of interest were observed at doses from 500 mg to the maximum dose of 1,500 mg (500 mg TID): 20-30% reduction in blood serotonin 50-60% reduction in 24-hour urinary 5-HIAA Lapuerta P et al. Clin. Invest. (Lond.) 2015;5(5): 447 456. Lexicon pharmaceutical, 2013

Telotristat etiprate: phase 2 studies Two Phase 2 studies examined the safety and efficacy of telotristat etiprate in patients with carcinoid syndrome not adequately controlled by somatostatin analogues Inadequate control was defined as average bowel movement frequency 4 episodes per day during a baseline assessment period 1 2 LX1606.202 conducted in the USA, placebo- controlled, 28- day study with several different doses: 150 mg, 250 mg, 350 mg and 500 mg, TID LX1606.203 conducted in Europe, open-label, 12-week study with titrated dose level: 150 mg, 250 mg, 350 mg and 500 mg, TID Lapuerta P, et al. Clinical Investigation (Lond.) 2015; 5(5): 447 456. Kulke MH, et al. Endocr. Relat. Cancer 2014 ; 21 (5): 705 714. Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

LX1606.202: Endpoints Primary efficacy analysis Reduction in bowel movements (baseline 4-10 bowel movements per day) Secondary efficacy analyses Reduction in 24-hour urine 5-HIAA (u5-hiaa), a biomarker for serotonin synthesis Report of adequate relief Flushing, pain, bloating, urgency, stool consistency, nausea Kulke MH, et al. Endocr. Relat. Cancer 2014 ;21(5): 705 714.

LX1606.202: Positive top-line results with telotristat etiprate Clinical Response (at least 30% reduction in bowel movements for at least 2 weeks) Biochemical Response (at least 50% reduction or normalization in u5- HIAA) Adequate Relief at Week 4 Placebo Telotristat etiprate n R R/n n R R/n 5 0 0% 18 5 28% 5 0 0% 16 9 56% 4 0 0% 13 6 46% R The = number results of in patients terms of achieving biochemical a response response, clinical response and n patient = number reported of patients adequate available relief for analysis of symptoms were reported only in telotristat etiprate treatment group and not in the placebo group Lapuerta P et al. Clinical Investigation (Lond.) 2015; 5 (5): 447 456. Kulke MH, et al. Endocr. Relat. Cancer 2014 ;21(5):705 714.

LX1606.203: Phase 2 European open label study in carcinoid syndrome Primary objective Evaluate the safety and tolerability of Telotristat etiprate in patients with symptomatic carcinoid syndrome Secondary objectives Assess the change in: Number of daily bowel movements Stool form/consistency Urgency to defecate Sensation/severity of nausea Subjective global assessment of symptoms associated with carcinoid syndrome Subjective assessment of abdominal pain or discomfort Number of cutaneous flushing episodes Urinary 5-HIAA levels Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

LX1606.203: Patients experienced reductions in bowel movement frequency Mean BM frequency -43.5% change from BL at Weeks 11-12 There was a significant reduction in bowel movement frequency, from a baseline of 5.9 to a mean of 3.3 BMs/day at Week 11 12 (p < 0.001) Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

Mean Stool Form (6-point scale) LX1606.203: Stool consistency weekly average -19.5% change from BL at Weeks 11-12 Scale 0: None, 1:Hard, 2:Firm, 3:Soft, 4:Loose, 5: Watery Stool consistency improved significantly (p < 0.05). Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9. 27

Mean Daily Flushing Episodes LX1606.203: Flushing weekly average -36.6% change from baseline at Weeks 11-12 Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

Mean Daily Abdominal Pain/Discomfort Score (100 mm VAS) LX1606.203: Mean abdominal pain/discomfort Mean Abdominal Pain/Discomfort -18.4% change from baseline at Weeks 11-12 Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

Mean U5-HIAA (mg/24hours) LX1606.203: Urinary 5-HIAA weekly average Mean U5-HIAA value -71.9% change from baseline at Wks 11-12 Pavel M, et al. J. Clin. Endocrinol. Metab 2015; 100(4): 1511-9.

Messages from phase 2 studies 1 Telotristat etiprate significantly reduced BM frequency and associated abdominal pain in patients with breakthrough symptoms of carcinoid syndrome 2 Telotristat etiprate provided clinically meaningful reductions in flushing episodes 3 Telotristat etiprate significantly decreased serotonin levels, as determined by 24- hour urinary 5-HIAA, in patients with inadequately controlled carcinoid syndrome 4 Reduction of carcinoid syndrome associated symptoms correlates with reduction in 5-HIAA, which is consistent with inhibition of tumor serotonin production, the known mechanism of action of telotristat etiprate 5 Clinical response was not dependent on the type, or dose, of concomitant SSA 6 There is no evidence of loss of response to prolong (up to 12 weeks) telotristat etiprate therapy

Telotristat ethyl: phase 3 studies

TELESTAR LX1606.301 LX1606.303 LX1606.302 (Telotristat Etiprate for Carcinoid Syndrome Not Adequately Controlled on Somatostatin Analogue Therapy) ) TELECAST (Telotristat Etiprate for Carcinoid Syndrome Therapy) TELEPATH (Telotristat Etiprate Expanded Treatment for Patients with Carcinoid Syndrome)

TELESTAR Phase 3 Study Design 3- to 4- week runin (n=135) Run in: Evaluation of bowel movement (BM) frequency 1:1:1 R Placebo TID (n=45) Telotristat etiprate 250 mg TID (n=45) Telotristat etiprate 500 mg TID* (n=45) Telotristat etiprate 500 mg TID Evaluation of primary endpoint: Reduction in number of daily BMs from baseline (averaged over 12- week double-blind treatment phase) All patients required to be on SSA at enrollment and continue SSA therapy throughout study period

TELESTAR results : Reduction in Mean Daily Bowel Movement Frequency at Baseline and Week 12 29% 35% 17% Mild nausea: 15% Mild depression: 15-20%% n=35 n=36 n=37 35

Mean u5-hiaa Change From Baseline, mg/24 Hours Phase III TELESTAR Mean change in u5-hiaa (mg/24 hours) from baseline to week 12 1 20 10 0 11.47-10 -20-30 -40-40.13-50 -57.73-60 Placebo (n=29) Telotristat ethyl 250mg (n=32) Telotristat ethyl 500mg (n=31) All patients continued SSA therapy throughout the study period. Data include only patients for whom both baseline and week 12 assessments were available. Wilcoxan rank-sum test showed significant differences for each telotristat ethyl dose vs placebo (P<0.001) Baseline 5-HIAA levels across treatment arms ranged from 80.96-92.65 mg/24 h

Phase III TELESTAR: AEs of interest 1 Category Placebo* Telotristat ethyl 250 mg* Telotristat ethyl 500 mg* Patients, n 45 45 45 135 Total Nausea, n (%) 5 (11.1) 6 (13.3) 13 (28.9) 24 (17.8) Severe nausea, n (%) 1 (2.2) 1 (2.2) 0 2 (1.5) Discontinuation due to nausea, n (%) 1 (2.2) 0 0 1 (0.7) Depression, n (%) 3 (6.7) 1 (2.2) 6 (13.3) 10 (7.4) Depressed mood, n (%) 0 1 (2.2) 2 (4.4) 3 (2.2) Severe depression or depressed mood, n Discontinuation due to depression or depressed mood, n 0 0 0 0 0 0 0 0 *All patients continued SSA therapy throughout the study period.

Phase III TELESTAR: conclusions Telotristat ethyl significantly reduced BM frequency in patients with carcinoid syndrome inadequately controlled with SSA therapy 1 Patients receiving telotristat ethyl demonstrated more durable responses compared with placebo and the difference was statistically significant 1 Telotristat ethyl significantly decreased 24-hour u5-hiaa in a dose-dependent manner in patients with inadequately controlled carcinoid syndrome 1 Reductions in flushing and abdominal pain were greater on treatment with telotristat ethyl (not statistically significant) 1 Inhibition of u-5hiaa is consistent with the proposed mechanism of action of telotristat ethyl Telotristat ethyl was well tolerated in the TELESTAR study 1

RANDOMISATION LX1606.302 TELEPATH Study LX1606.303 TELECAST Study design Patients with histopathologicallyconfirmed, well-differentiated, metastatic NET; with history of carcinoid N=60 Phase 3 Telotristat etiprate 250 mg + placebo TID orally Telotristat etiprate 500 mg + placebo TID orally Telotristat etiprate 500 mg TID + SSA syndrome Placebo TID orally 0 12 48 Double- blind Treatment phase Open-label Extension phase Primary endpoint: Incidence of treatment-emergent AEs, % change in urinary 5-hydroxyindoleacetic acid level

TELECAST Primary Safety Endpoint: Incidence of Treatment-emergent Adverse Events Telotristat Telotristat Category, n (%) Placebo tid ethyl ethyl (n=26) 250 mg tid 500 mg tid (n=25) (n=25) Any TEAE 21 (80.8) 25 (100) 21(84.0) Gastrointestinal disorders 15 (57.7) 16 (64.0) 9 (36.0) General disorders and administration-site conditions 6 (23.1) 7 (28.0) 4 (16.0) Infections and infestations 5 (19.2) 8 (32.0) 4 (16.0) Treatment-related TEAEs 8 (30.8) 10 (40.0) 11 (44.0) Serious TEAEs* 5 (19.2) 1 (4.0) 2 (8.0) Serious treatment-related TEAEs 0 0 0 Study discontinuation due to TEAEs 1 (3.8) 2 (8.0) 0 TEAE resulting in death 0 0 0 *Serious TEAEs: placebo - disease progression, cerebrovascular accident, bronchiectasis, dyspnea, and urethral stent insertion; telotristat ethyl 250 mg - disease progression; telotristat ethyl 500 mg - ascites and disease progression Discontinuations: placebo - disease progression; telotristat ethyl 250 mg upper abdominal pain, diarrhea; telotristat ethyl 500 mg - NA 40

TELECAST - Adverse Events of Interest Category, n (%) Depression-related TEAEs Depressed mood Decreased interest Depression Hepatic enzyme elevations Elevated gamma-glutamyl transferase Elevated alanine aminotransferase Placebo tid (n=26) 2 (7.7) 2 (7.7) 1 (3.8) 0 0 0 0 Telotristat ethyl 250 mg tid (n=25) 1 (4.0) 1 (4.0)* 0 0 2 (8.0) 1 (4.0) 1 (4.0) Telotristat ethyl 500 mg tid (n=25) 1 (4.0) 0 0 1 (4.0) 3 (12.0) 1 (4.0) 0 Any gastrointestinal-related TEAE Abdominal pain Diarrhea Nausea 15 (57.7) 4 (15.4) 5 (19.2) 4 (15.4) 16 (64.0) 8 (32.0) 4 (16.0) 3 (12.0) 9 (36.0) 0 2 (8.0) 2 (8.0) *Patient was reported to have concomitant TEAEs of anemia and pyrexia that contributed to depressed mood. Patient had underlying depression that was treated with paroxetine at Baseline. All events of depression, nausea, and hepatic enzyme elevations were mild or moderate in intensity, and none resulted in treatment discontinuation. Gastrointestinal-related TEAEs were less frequent with telotristat ethyl 500 mg than with placebo or telotristat ethyl 250 mg. TEAE, treatment-emergent adverse event; tid, 3 times per day

TELESTAR / TELECAST durable response Durable response defined as 30% reduction in bowel movements frequency for 50% of doubleblind study period Placebo (n=26) 250 mg (n=25) 500 mg (n=25) Treatment difference durable response rate (95% CL) 0.4 (0.2, 0.6) 0.4 (0.2, 0.6) Pavel et al. NANETS 2015 p-value 0.001 0.001

TELECAST summary and conclusion Both primary safety and efficacy endpoints of the DBT period of the TELECAST study were met The safety results of this study support those observed in previous trials: Depression-related events and elevations in hepatic enzymes did not lead to study discontinuation There was a statistically significant reduction in u5-hiaa levels and BM frequency with telotristat ethyl in patients with CS, consistent with the results of the TELESTAR Phase 3 study Durable response was observed in 40% of patients receiving telotristat ethyl 250 mg tid and telotristat ethyl 500 mg tid Telotristat ethyl represents a new potential treatment approach for patients with CS

LX1606.302 TELEPATH Design Patients from studies: LX1606-202 LX1606-203 LX1606-301 (TELESTAR) LX1606-303 (TELECAST) could continue or be switched on telotristat etiprate in the LX1606 302 study N=160* Phase 3 Telotristat etiprate 250 mg daily orally Telotristat etiprate 500 mg daily orally Primary endpoint: incidence of treatmentemergent AEs at week 50 Study duration This study is a roll-over extension study (compasionate use) for patients in the TELESTAR and TELECAST studies and earlier phase 2 studies

Telotristat and Carcinoid Heart Disease Two patients with CHD after TVR (mechanical and biological prosthesis) After telotristat was commenced: Significant decrease in 5-HIAA levels No recurrence/new valve involvement by CHD in the 1 st patient Regression of TVR in the 2 nd patient (moderate TR to mild-mod TR) Dr Simona Glasberg Neuroendocrine Tumors Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (anecdotal data) Two patients, with CHD In one patient with moderate TR; 5-HIAA decreased substantially and CHD remained stable, not requiring valve replacement. The other underwent replacement of TV and PV with bioprosthetic valves and developed early recurrence of valvulopathy on both valves. Commenced on telotristat, and whilst a a re-operation was considered due to mod-severe TR and mod PR, there has been no progression on telotristat and surgery has not been deemed necessary. Dr Jerome S Zacks, Center for Carcinoid and Neuroendocrine Tumors, Icahn Medical School at The Mount Sinai Medical Center, New York, NY (ENETS 2016)

Telotristat ethyl: positioning in NETs therapeutical algorithm

Exclude other causes Carcinoid syndrome Resistant to SSTA No radiological progression Radiological progression Optimize SSTs Add telotristat Ethyl Add Interferon-A TAE Debulking surgery PRRT? Everolimus Predominantly Liver disease TAE? SIRT

Carcinoid syndrome With Carcinoid Heart Disease at presentation Without Carcinoid Heart Disease at presentation Somatostatin Analogues Maximum dose of somatostatin analogues +/- Telotristat Ethyl If 5-HIAA still > 300 Add Telotristat Ethyl

Thank you