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1 Farnesoid-X Receptor Agonists: a New Class of Drugs for the Treatment of PBC? An International Study Evaluating the Addition of Obeticholic Acid (INT-747) to Ursodeoxycholic Acid An International Study Andrew Mason, Velimir Luketic, Keith Lindor, Gideon Hirschfield, Stuart Gordon, Marlyn Mayo, Kris Kowdley, Albert Parés, Michael Trauner, Erin Castelloe, Cathi Sciacca, Tessa Beecher Jones, Mark Pruzanski, David Shapiro For the Obeticholic Acid [INT 747] PBC Investigator Group U. Alberta, Virginia Commonwealth U., Mayo Clinic, U. Toronto, Henry Ford Clinic, U. Texas SW, Virginia Mason Med Center, U. Barcelona, U. Graz, Intercept Pharmaceuticals.

2 Disclosure/Conflict of Interest Statement I have financial relationship(s) within the last 12 months relevant to my presentation: Full Time Employee with Intercept Pharmaceuticals, Inc. AND My presentation focuses on the investigational use of: Obeticholic Acid and Placebo

3 Bile Acids: from Simple Detergents to Pleotrophic Homeostatic Regulators Detergents in gut Solubilize fats in intestine absorption Farnesoid X Receptor Liver, bile ducts, fat Nuclear receptor for bile acid signaling Natural ligand: Chenodeoxycholic acid Bile acid synthesis regulation Feedback via FGF 19 & SHP Hepatic Triglyceride, VLDL Synthesis Makishima Science 1999; 284: 1362 Wanatabe JCI 2004; 113: Hepatic regeneration, intestinal bacterial overgrowth/translocation protection Modulation of insulin sensitivity & adiposity Cariou J Biolog Chem 2006; 281: TGR 5 Liver, fat, enteroendocrine cells G Protein Coupled Receptor cell membrane Mediates intracellular conversion of T4 to T3 GLP 1 & Insulin Obeticholic Acid FXR Agonist Wanatabe Nature 2006; 439: Thomas Cell Metabolism 2009; 10:

4 6α-Ethyl Chenodeoxycholic Acid - INT-747 Obeticholic Acid [OCA] OCA 6α ethyl chenodeoxycholic acid CDCA chenodeoxycholic acid UDCA ursodeoxycholic acid FXR EC 50 (agonist) μm 8.66 μm No activity ~ 2 log FXR agonism Pelliciari R. J.Med.Chem 2002

5 6α-Ethyl Chenodeoxycholic Acid - INT-747 Obeticholic Acid Obeticholic Acid [oh bet" i kol' ik] INT-747 6a-ethyl chenodeoxycholic acid 3α,7α-dihydroxy-6α-ethyl-5βcholan-24-oic acid No meaningful activity vs. Other Nuclear Receptors Broad enzyme & receptor pharmacology screen EC50 for TGR5: 20 µm Conjugated + glycine & taurine Equipotent FXR agonists to parent

6 Normal Volunteers Plasma Concentrations Enterohepatic Circulation After last dose (12 days of dosing) ng/ml ECDCA Glyco-6-ECDCA Tauro-6-ECDCA Time (hrs) Shapiro D. Hepatology 2009; 50 (Suppl S4): 198 [Abstract: 992]

7 Preclinical Studies Overview Numerous animal models evaluated BDL, estrogen, lithocholic acid, CCl 4, ANIT, thioacetamide injury Effects consistent with FXR agonism Induced FXR target genes SHP induction and Cyp7α1 and Cyp8β1 repression Cholerectic Anti fibrotic Changes in α1 collagen, αsma, TGFβ1, MMP 2, TIMP 1, and TIMP 2 Histology fibrosis, reversal of cirrhosis, Portal hypertension

8 Anti-Cholestatic Effects of OCA Lithocholic acid (LCA) model Bile Flow Infusion of : LCA alone -o- [b] or LCA + INT [c] Histology - rats treated with: a. Vehicle b. LCA alone c. LCA plus INT-747 d. LCA + CDCA Data from C. Clerici Pellicciari et al., J. Med. Chem., 2002;45:

9 OCA Attenuates Portal Hypertension Rat Bile Duct Ligation Model 20 P< P< mm Hg Sham BDL BDL+INT-747 Vairappan B.Hepatology 2009; 50 (S4): (Abstract: 70)

10 OCA Improves Insulin Sensitivity in Type 2 DM + NAFLD Patients 2 step insulin infusion euglycemic clamps 60 & 120 µu insulin x m 2 body surface area/min Dose related in FGF 19 & weight GDR (mg/kg/min) µu insulin x m 2 SA/min 120 µu insulin x m 2 SA/min p=0.04 Day 0 Day 43 GDR (mg/kg/min) p=0.036 Day 0 Day 43 Placebo (N=17) 25 mg (N= 15) 50 mg (N=12) Both doses vs placebo: p=0.048 Both doses vs placebo: p=0.022 Sanyal A. Hepatology 2009; 50(S4): 398A

11 PBC Ongoing Medical Needs Ursodeoxycholic Acid Only approved drug for PBC Therapy has had a clear impact on PBC But significant proportion of patients have an inadequate response & need better therapy Many drugs evaluated, none clearly effective Poupon R, J Hepatol : Silveira M, Lindor K, Clin Liver Dis 2008; 12: Kaplan N, Gershwin, E N Engl J Med 2005;353:

12 Drugs Evaluated in PBC Drug Efficacy Safety References Rifampicin Improves pruritus Drug induced hepatitis Bach Gastroenterol 1992; 102: 2007 Prince Gut 2002; 50: 436 Azathioprine Unclear Leukopenia, neoplasia Crowe Gastroenterol 1980; 78: 1005 Chlorambucil Biochemical Bone marrow suppression Hoofnagle Gastroenterol 1986; 91: 1327 Prednisolone Histological Osteoporosis; Cushing s Syndrome Budesonide Histological Bone density Portal v thrombosis Cyclosporine Survival Renal function & hypertension Methotrexate None Marrow suppression, fatigue, pulmonary fibrosis Mycophenalate mofetil None Anemia, leukopenia, dypnea, chest pain. Rituximab Pilot study Mucocutaneous - pemphigus, Stevens- Johnson, toxic epidermal necrolysis Leuschner J Hepatol 1996; 25: 49 Rautiainen Hepatol 2005; 41: 747 Hemfling Hepatol 2003; 38: 196 Wiesner N Engl J Med : 1419 Bach Am J Gastrol 2003; 98: 187 Coombes Hepatol 2005; 42: 1184 Talawalkar J Clin Gastroent 2005; 39: 168 Meyers Hepatol 2007; 46; 550A

13 Dose Response Study Design Addition to UDCA UDCA N=35/group Placebo OCA 10 mg Baseline Follow-Up OCA 25 mg OCA 50 mg Screening Baseline 1-4 weeks predose Double Blind Phase 12 weeks Follow-Up Phase 2 weeks

14 Primary Objectives & Inclusion Criteria Objectives Assess effects of INT 747 added to ursodeoxycholic acid on Alkaline phosphatase levels Safety Inclusion Criteria Males or females; years Proven or likely PBC At least 2 of 3 needed: History of increased AP levels for at least 6 months Positive AMA titer or PBC specific anti nuclear antibodies Liver biopsy consistent with PBC Screening AP value between x ULN

15 Primary Objectives & Inclusion Criteria Objectives Assess effects of INT 747 added to ursodeoxycholic acid on Alkaline phosphatase levels Safety Inclusion Criteria Males or females; yrs Proven or likely PBC At least 2 of 3 needed: History of increased AP levels for at least 6 months Positive AMA titer or PBC specific anti nuclear antibodies Liver biopsy consistent with PBC Alkaline Phosphatase: xuln

16 Key Medical Exclusion Criteria Specific drugs in 3 months before screening: Colchicine, methotrexate, azathioprine, or systemic corticosteroids. History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or poorly controlled ascites) Screening conjugated bilirubin >2 x ULN Screening ALT or AST value >5 x ULN Screening serum creatinine value >1.5 mg/dl (133µmol/L) Other concomitant liver diseases (HCV, HBV) infection, PSC and/or other autoimmune liver disease Pregnancy

17 Study Centers 8 Countries, 33 Centers 165 patients enrolled Geography USA: 56% Canada: 26% Europe: 18%

18 Patient Numbers Screened Screened N=221 Randomized Randomized N=165 Failed to Qualify N=56 Outcome Completed N=136 Discontinued N=27 Withdrew Consent/Lost N=2 Analysis ITT mitt for AP N=161 Excluded* N=4 *: If no post baseline visit

19 PBC Diagnosis % % Pbo 10mg 25mg 50mg Total Definite (3 Criteria) % Probable (2 Criteria) %

20 Demographics Pbo n=38 10mg n= 38 25mg n= 48 50mg n= 41 Total N= 165 Male 5% 0% 6% 7% 5% Female 95% 100% 94% 93% 95% Caucasian 89% 97% 98% 98% 96% African 3% - - 2% 1% Asian 3% 3% - - 1% Other 5% - 2% - 2% Age 55y 56y 56y 54y 55y BMI (kg/m 2 ) UDCA (mg/kg)

21 Alkaline Phosphatase Baseline Placebo n=37 10mg n=38 25mg n=47 50mg n=39 Total N=151 AP x ULN

22 RESULTS Efficacy: Alkaline Phosphatase

23 % Δ Alkaline Phosphatase p < p < p < Mean values + SEM Mean % Change in AP Placebo 10 mg 25 mg 50 mg n=37 n=38 n=47 n=39

24 % Δ By Visit Alkaline Phosphatase - ITT EOS Follow up % Δ Placebo 10 mg 25 mg 50 mg 30 OCA vs. Pbo: p<0.001 p< Off-Study Rx

25 Absolute Δ - Alkaline Phosphatase 0 p < p < p < Mean values + SEM 20 Change in AP (U/L) Placebo 10 mg 25 mg 50 mg n=37 n=38 n=47 n=39

26 Alkaline Phosphatase Mean values + SEM AP (U/L) vs. Pbo: All: p< Placebo (n=37) 10 mg (n=38) 25 mg (n=47) 50 mg (n=39) Day 0 Day 85 EOS

27 RESULTS Liver Enzymes

28 γ-glutamyl Transpeptidase - γgt Day 85 EOS p< all doses Placebo(n=38) 10 mg (n=38) 25 mg (n=48) 50 mg (n=41) GGT (U/L) % Change: Pbo: mg: 48 25mg: 63 50mg: 57 ULN 0 Baseline Day of Visit 85-EOS

29 Alanine Transaminase - ALT 70 ULN Placebo(n=38) mg (n=38) 25 mg (n=48) ALT (U/L) mg (n=41) % Change: Pbo: 0 10mg: 28 25mg: 35 50mg: Baseline 85-EOS Day 85 EOS p< & 25mg p< mg Day of Visit

30 Aspartate Transaminase - AST AST (U/L) 70 ULN Placebo(n=38) 10 mg (n=38) 25 mg (n=48) 50 mg (n=41) % Change: Pbo: 0 10mg: 17 25mg: 16 50mg: Baseline 85-EOS Day 85 EOS p< & 25 mg p= mg Day of Visit

31 Safety & Tolerability

32 AEs > 5% in any Group Pbo (%) 10mg (%) 25mg (%) 50mg (%) Total Total % Pruritus % Headache % Fatigue % Constipation % Diarrhea % Nausea % Abdo Distension % Dry Eye % Oropharyngeal Pain % Pain, extremities % Vomiting % Pyrexia % UTI %

33 AEs > 5% in any Group Pbo (%) 10mg (%) 25mg (%) 50mg (%) Total Total % Pruritus % Headache % Fatigue % Constipation % Diarrhea % Nausea % Abdo Distension % Dry Eye % Oropharyngeal Pain % Pain, extremities % Vomiting % Pyrexia % UTI %

34 Pruritus as AE Incidence by Dose % Placebo 10mg 25mg 50mg

35 Pruritus - Severity Mild Moderate Severe % Placebo 10mg 25mg 50mg

36 Pruritus - Discontinuations 30 Placebo 10mg 25mg 50mg 20 % 10 0 Placebo 10mg 25mg 50mg

37 Discontinuations for AEs Any AE Pruritus % % Placebo 10mg 25mg 50mg 0 Placebo 10mg 25mg 50mg

38 Serious AEs Group AE Relationship to Study Drug Placebo Dyspnea Unlikely 10 mg 25 mg 50 mg Growth of Parotid Gland Tumor (diagnosed pre study) Angioedema Angina Secondary to Epinephrine Gastrointestinal Bleeding Jaundice PBC Flare Chest Pain Unlikely Unlikely Unlikely [Completed Study] Possible Possible Probable Possible

39 Conclusions: OCA + UDCA Highly significant effects on Alkaline Phosphatase Significant decreases in: GGT, ALT, AST No clear dose response relationship Safety & Tolerability Pruritus Principal AE shows dose response relationship 50mg unlikely starting dose in PBC Ongoing Phase 2 Studies Long Term Safety Extension Monotherapy study Merits further evaluation Phase 3 planned

40 Thank You - Patients & Investigators.

41 Study Sites N. America Country Investigator Study Coordinator Location Bruce Bacon Judy Thompson St. Louis, MO Henry Bodenheimer Gabrielle Gaspard New York, NY Stuart Gordon Diana Thornbury Detroit, MI Kris Kowdley Cheryl Saunders Seattle, WA Cynthia Levy Joy Peter Gainsville, FL Keith Lindor Jan Petz Rochester, MN USA Velimir Luketic Denice Shelton Richmond, VA Marlyn Mayo Giselle Huet Dallas, TX Arthur McCullough Ruth Sargent Cleveland, OH Flavia Mendes John Morgan Miami, FL Joseph Odin Jaunita Jones New York, NY Lawton Shick Veronika Testa Boston, MA John Vierling Jana Lee Houston, TX Canada Alexander Aspinall Lynn Schindel Calgary, Alberta Gideon Hirschfield Catalina Coltescu Toronto, Ontario Andrew Mason Adam Henley Edmonton, Alberta Gerald Minuk Kim Hawkins Winnipeg, Manitoba Catherine Vincent Christina Benjamin Montreal, Quebec

42 Study Sites Europe Country Investigator Study Coordinator Location United Kingdom Andrew Burroughs Matteo Garcovich London Roger Chapman Madeleine Thyssen Oxford Peter Hayes Lesley Briody Edinburgh David Jones Hattie Murdoch/Jenny Bainbridge Newcastle James Neuberger Jo Grayer Birmingham Michael Manns & Kinan Rifai Janina Kirschner Hannover Germany The Netherlands France Christian Rust N/A Munich Christoph Schramm Kirsten Aue Hamburg Stefan Zeuzem Melanie Moschitz Frankfurt Ulrich Beuers Lucas Wenniger Amsterdam Karel van Erpecum N/A Utrecht Henk van Buuren Melek Polat Utku Rotterdam Raoul Poupon Farid Gaouar Paris Christian Trepo Benedicte Soret Lyon Austria Michael Trauner Martin Wagner Graz Spain Albert Parés Rosana Ahuir Barcelona

43

44 Pruritus Development with Time 10mg Pbo 50mg 25mg

45 Pruritus Interventions Pruritus N=111, 67% Dose Modification N=43 Bile Acid Resin at Baseline N=19 Bile Acid Resin Added N=40 Completed N=31, 66% Completed N=17, 89% Completed N=32, 80% Discontinued N=12, 26% Discontinued N=2, 11% Discontinued N=7, 18%