Corporate Presentation June 2016

Transcription

1 Corporate Presentation June

2 Safe Harbor Statement This presentation contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of important risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the initiation, cost, timing, progress and results of our development activities, preclinical studies and clinical trials; our ability to successfully commercialize Ocaliva (obeticholic acid) in PBC and our ability to maintain our regulatory approval in the United States for Ocaliva in PBC; the timing of and our ability to obtain and maintain regulatory approval of Ocaliva for PBC in jurisdictions outside the United States; the timing of and our ability to obtain and maintain regulatory approval of OCA in indications other than PBC and any other product candidates we may develop such as INT-767; conditions that may be imposed by regulatory authorities on our marketing approvals for our product candidates such as the need for clinical outcomes data (and not just results based on achievement of a surrogate endpoint), and any related restrictions, limitations, and/or warnings in the label of any approved product candidates; our plans to research, develop and commercialize our product candidates; our ability to obtain and maintain intellectual property protection for our product candidates; our ability to successfully commercialize OCA in indications other than PBC and our other product candidates; the size and growth of the markets for our product candidates and our ability to serve those markets; the rate and degree of market acceptance of any of our products; the success of competing drugs that are or become available; the election by our collaborators to pursue research, development and commercialization activities; our ability to attract collaborators with development, regulatory and commercialization expertise; regulatory developments in the United States and other countries; the performance of third-party suppliers and manufacturers; our need for and ability to obtain additional financing; our estimates regarding expenses, future revenues and capital requirements and the accuracy thereof; our ability to retain key scientific or management personnel; and other factors discussed under the heading "Risk Factors" contained in Intercept s Annual Report, Quarterly Reports and other filings with the Securities and Exchange Commission. All information in this presentation is as of the date hereof, and Intercept undertakes no duty to update this information unless required by law. 2

3 Building a Specialty Focused Business in Non-Viral Progressive Liver Diseases Novel therapeutic approach in non-viral, progressive liver diseases OCA is a farnesoid X receptor (FXR) agonist Worldwide rights (outside of Japan, China and Korea) Patent terms projected to expire at various times through 2033 PBC: Ocaliva now approved for Primary Biliary Cholangitis Approved May 27, 2016 for the treatment of PBC in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA Positive data from Phase 3 POISE trial and two placebo-controlled Phase 2 trials Confirmatory outcomes trial ongoing with post-marketing completion Breakthrough therapy designation from FDA for NASH w/ liver fibrosis NASH: Significant Market Opportunity Phase 3 REGENERATE trial initiated in September 2015 Phase 2 CONTROL NASH Statin Trial initiated December 2015 Broad NASH clinical development program planned Significant Upside from Further OCA Indications and Pipeline OCA in development for additional non-viral, progressive liver diseases INT-767 Phase 1 initiated November

4 Pipeline Focused on Progressive Liver Diseases with High Unmet Need OCA Product / Population Primary Biliary Cholangitis Preclinical Phase 1 Phase 2 Phase 3 Approved Nonalcoholic Steatohepatitis Primary Sclerosing Cholangitis Biliary Atresia INT-767 Fibrosis INT-777 Type 2 Diabetes Own worldwide rights to all programs (except Japan, China & Korea for OCA) 4

5 Recent Milestones OCA PBC NASH FDA Advisory Committee Meeting (17-0 in favor of approval) April 2016 FDA Approval of Ocaliva May 2016 REGENERATE Phase 3 trial initiated Sep 2015 Phase 2 CONTROL NASH Statin Trial initiated Dec 2015 PSC Expanded Enrollment Centers in Phase 2 AESOP Trial Nov 2015 Biliary Atresia Phase 2 trial initiated Oct 2015 INT-767 Phase 1 trial initiated Nov

6 Planned Milestones and Anticipated Timing PBC Anticipated Decision in EU YE 16 OCA NASH Complete enrollment of Phase 2 CONTROL trial YE 16 Complete enrollment of Phase 3 REGNERATE trial 1H 17 PSC Complete enrollment of Phase 2 AESOP trial YE 16 INT-767 Complete SAD/MAD Phase 1 trial 2H 16 6

7 Unique Focus on Bile Acid Chemistry Bile Acids: Role in Digestion Bile Acids: Cell Signalling Bile acids are synthesized from cholesterol in the liver Facilitate dietary absorption of lipids and nutrients based on their natural detergent properties Released by gallbladder into gut during digestion Reabsorbed & conserved (enterohepatic recirculation) Dedicated bile acid receptors (e.g., FXR): act as hormones regulating multiple biological pathways Key regulators of liver, intestinal & kidney function Modulate metabolic, inflammatory & immune pathways 7

8 FXR is Central to a Multitude of Pathways INFLAMMATION NF-κB TNFα, IL-1β, IL-17, IFN-γ CRP FIBROSIS Stellate cell activation (α-sma) Stellate cell apoptosis (TIMP-1) Fibrogenesis (TGF-β1) Matrix degradation (MMP-2) ATHEROSCLEROSIS Vasodilation (enos) Inflammation (COX-2, inos) Calcification (JNK) Smooth muscle cell migration LIPID METABOLISM Triglyceride synthesis (SREBP-1c) Triglyceride clearance (apoc-iii) HDL-C (SR-B1, CETP) LDL-C (CETP) GLUCOSE METABOLISM Insulin signaling (FGF19) Insulin sensitivity (IRS-1, IRS-2 ) Insulin production (KLF11, GLUT-2) Hepatic gluconeogenesis (PEPCK) BILE ACID HOMEOSTASIS Bile acid synthesis (CYP7A1) Bile acid uptake (NTCP) Bile acid secretion (BSEP) Bile acid absorption (ASBT) In vitro/in vivo studies do not necessarily correlate with clinical response. 8

9 Ocaliva for PBC 9

10 Primary Biliary Cholangitis (PBC) PREVALENCE: Disease of women (10:1) 1 in 1,000 women >40 years old DIAGNOSIS: Non-invasive diagnosis (blood test) Elevated alkaline phosphatase (ALP) & anti-mitochondrial antibody (AMA) Pruritus (itching) and fatigue are signature symptoms 10

11 Alkaline Phosphatase is a Key Prognostic Marker in PBC An increase in Alkaline Phosphatase (ALP) is observed early in the disease and continues throughout the disease until late stage. Hepatocellular damage can be seen with increases in AST, ALT, GGT An increase in serum bilirubin occurs late in disease Cholestasis (toxic bile acid accumulation) Hepatocellular damage Inflammation Fibrosis Cirrhosis Healthy Liver Serum ALP Clinical use as diagnostic/prognostic Cirrhotic Liver AST, ALT, GGT Bilirubin Albumin, platelets Poupon R. Hepatology. 2010; 52: Selmi C. Lancet 2011; 377:

12 Two Methods for Staging PBC Stage 4 (Cirrhosis) Staged by Histology (Ludwig) 1 Child Pugh B/C "Decompensated" 3% Child Pugh A "Compensated" 13% Stage 3 17% Stage 1 36% Abnormal bilirubin and albumin Abnormal bilirubin or albumin Staged by Rotterdam 2 Advanced 9% Moderately Advanced 24% Stage 2 31% Early 67% Normal bilirubin and albumin Data from Lammers et al. Gastroenterology. 2014, 1: For patients wtih available biopsy (25% of patients unavailable); Ludwig et al. Virchows Arch A Pathol Anat Histol Stage 1: Portal inflammation with or without florid bile duct lesions. Stage 2: Gradual increase of periportal lesions extending into the hepatic parenchyma. Stage 3: Distortion of the hepatic architecture with numerous fibrosis septa. Stage 4: Cirrhosis with the existence of regenerative nodules; Child-Pugh distribution assumptions based on: Kim et al. Korean J Hepatol. 2010, Malham World et al. J Gasto. 2011, Kochel-Jankowska et al. J Physiol Pharmacol. 2013, Kikuchi World et al. J Hepatol. 2013, Chen Ann et al. Hepatol. 2013, Nilsson et al. HBP (Oxford). 2010, Su et al. Liver Int. 2008, Aboutwerat et al. Biochim Biophys Acta. 2003; 2: ter Borg et al. Am J Gastro baseline values for patients w/ available data 12

13 Ocaliva (Obeticholic acid): NOW FDA APPROVED Granted accelerated approval in PBC in combination with ursodeoxycholic (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA Approval based on a reduction in alkaline phosphatase (ALP) First new therapy for PBC patients in nearly 20 years 13

14 Ocaliva Met the Primary Endpoint of Phase 3 POISE Trial Primary Composite 12 months Responder rate [95% CI] Components of Primary 12 months 1 Ocaliva 10mg* (N = 73) 48% [36, 60] ALP less than 1.67x ULN 55% N=40 Decrease in ALP of at least 15% 78% N=57 Total bilirubin less < ULN 82% N=60 Ocaliva Titration* (N=70) 46% [34, 58] 47% N=33 77% N=54 89% N=62 Placebo* (N=70) 10% [4,19] 16% N=12 29% N=21 78% N=57 EFFICACY: Primary endpoint: ALP < 1.67x ULN (with 15% reduction) & normal bilirubin) Ocaliva met the primary endpoint at every time point assessed during the trial; as early as 2 weeks p< vs. placebo in both 12 months Ocaliva met secondary endpoints: GGT, ALT, AST and total bilirubin (p< vs. placebo) Enrollment: 217 patients at 59 centers in 13 countries. In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm. All patients allowed standard of care, including stable dose of ursodiol 1: Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[n=itt population]); percentage of patients with Month 12 values are 86%, 91% and 96% for the Ocaliva 10 mg, Ocaliva titration and placebo arms, respectively. 14

15 Ocaliva Safety and Tolerability Pruritus, generally mild to moderate, was the most frequently reported AE 8 total discontinuations; 0 placebo, 7 in OCA 10mg, 1 in OCA titration Dose titration resulted in the lowest incidence of pruritus in PBC patients to date Pruritus severity no different than placebo after 6 months of OCA (assessed by a visual analog scale); >95% continued in open-label LTSE Additional side effects observed during the trial included fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia thyroid function abnormality, and eczema. 15

16 Ocaliva Post-Marketing Commitments COBALT Phase 4 PBC confirmatory clinical outcomes trial initiated Primary composite endpoint of clinical outcomes Potential modifications, in consultation with FDA, to include: A broader cross section of PBC patients (early, moderately advanced and advanced disease as defined by the Rotterdam criteria) PBC with Child-Pugh Classes B and C hepatic impairment An arm to evaluate safety/efficacy of Ocaliva monotherapy Develop and characterize a formulation of Ocaliva to allow for once daily dosing for patient with hepatic impairment 16

17 Global PBC Opportunity Global Prevalence / OCA Candidate Assumptions US ROW 290k 276k Prevalence (rate / ~2016 pop.) 1,2 0.04% 0.035% Access to healthcare 3,4 89.6% 100% PBC Diagnostic rate (2016) 5 47% 49% Under treater care 5 91% 88% Treated w/ UDCA % 112k 112k UDCA discontinue Intolerant/failure 5 8.0% Inadequate responder ALP >ULN 5,6 71.0% 134k 119k 112k Adequate responder ALP <ULN 5,6 29.0% 130k 116k 55k 48k 46k 55k 50k 47k Prevalence Access Diagnosed Under treater care UDCA Treated / UDCA discontinue intolerance or failure US EU5 Canada ANZ ROE 72k 29k 37k 30k 15k 15k UDCA treated uncontrolled (ALP > ULN) UDCA treated uncontrolled (ALP > 1.67) * * 1: Kim et al. J. Gastroenterology. 2000; 119(6): : CDA Epidemiology Research 3: US Census Bureau 2015 *: Does not include intolerant patients 4: OCED Health Data : Intercept Market Research 6: Lammers el al Gastroenterology Dec;147(6): Estimates based on FYE

18 ~19,000 PBC Patients In US Initial Launch Focus 0.04% 47% 1 Launch will focus on patients matching POISE criteria 9% 3 130k 91% 93% 2 64% 33% 55k 50k 47k 30k 15k 4k Prevalence Diagnosed Under treater care UDCA Treated / UDCA discontinue intolerance or failure UDCA treated uncontrolled (ALP > ULN) UDCA treated uncontrolled (ALP > 1.67) UDCA discontinue tolerability/failure * * 1. Access to healthcare assumed in calculation at 88.6% 2. 8% of patients under treater care are intolerant or discontinued due to failure on UCDA. 85% of patients under treater care are currently treated with UDCA: 3. UDCA discontinue patients represent 9% of patients who are either UDCA treated or UDCA intolerant or discontinue ICPT Market Research Estimates based on FYE

19 Our plan for a successful Ocaliva launch in PBC Communicate the tremendous scientific innovation for Ocaliva Achieve broad payer coverage Prioritize high volume prescribers Establish a strong patient support system 19

20 US Commercial Update Commercial Managed Markets Education Efforts 45 Territory Business Managers have profiled >4,000 physicians covering 70-80% of patients w/ PBC 100% 90% Our goal is to gain coverage for the patients who meet the POISE criteria Medicaid 9% Va/DoD, 1% Multiple physician and patient awareness efforts underway US Treated Patients w/ PBC 80% 70% 60% 50% 40% 30% 20% 10% 0% First 30 days Remaining physicians visited by YE 2016 Medicare 30% Commercial ~60% Formulary decisions expected in 2H

21 Interconnect Our Personalized Patient Support Program MD Prescribes OCALIVA for PBC Interconnect Support Services Specialty Pharmacy Network Patient Conduct Benefit Investigation Assist with appeals Administer financial assistance programs Patient education Compliance and persistency Confirm coverage Distribute product Report data Care Coordinator - Single Point of Contact Interconnect financial assistance programs includes: A $0 copay program for patients with commercial insurance. Access to Ocaliva at no cost for eligible uninsured or underinsured patients. Interconnect can also help refer patients with Medicare or Medicaid to an independent non-profit organization that provides financial assistance to PBC patients 21

22 The NASH Opportunity 22

23 NASH: A Worldwide Health Issue Changes in the lifestyle and diet of the global population are fuelling a worldwide epidemic of obesity and the increasing prevalence of NAFLD/NASH NASH linked to increased dietary consumption of fructose and PUFAs 1 NASH expected to become the leading cause of liver transplant by Growing NASH-related HCC among liver transplants (8% in 2008 to 14% in 2012) 2, with up to 40% of HCC in non-cirrhotic patients 3,4 1: Wree, A. et al. Nat. Rev. Gastroenterol. Hepatol. 10, (2013) 2: Wong et al. Hepatology 2014; 59(6): : Tateishi et al. J of Gastroenterology. June : Dyson et al. J. Hepatology 2014; 60(1):

24 NAFLD: Progression to NASH w/ Fibrosis Over an average follow-up period of ~6 years 1,2 : NAFLD: Progression to NASH 2 NASH: Progression to Cirrhosis 2 50% 40% 44% 37% 50% 40% 35% 30% 20% 10% 0% Developed NASH Developed NASH + Fibrosis 22% Developed NASH w/ Stage 3 Fibrosis 30% 20% 10% 0% 10% 9% F1 F2 F3 1: McPherson et al, Journal of Hep, 2015; 2: 108 patients had serial biopsies (mean 6.4 years to repeat biopsy): 27 patients with baseline NAFLD and 81 patients with baseline NASH 24

25 Liver Fibrosis: Associated with Long-term Outcomes Liver Fibrosis, But No Other Histologic Features, Associates With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease Paul Angulo, MD, David E. Kleiner, MD, PhD, Sanne Dam-Larsen, MD, PhD, Leon A. Adams, MBBS, PhD, Einar S. Bjornsson, MD, Phunchai Charatcharoenwitthaya, MD, Peter R. Mills, MD, Jill C. Keach, Heather D. Lafferty, MB, ChB, Alisha Stahler, Svanhildur Haflidadottir, MD, Flemming Bendtsen, MD, PhD x Hazard Ratio of Death or Liver Transplant 1, Fibrosis Stage 4 3.8x Fibrosis Stage 3 2.9x 2.6x Fibrosis Stage 2 Current Smoker 1.9x 1.6x Fibrosis Stage 1 Diabetes 0.3x Statin Use 1: Angulo et al, Gastroenterology 2015; 2: Retrospective analysis of 619 patients diagnosed with NAFLD over median follow-up of 12.6 years 25

26 Broad and Comprehensive NASH clinical plan for OCA Trial Description Status Phase 3 REGENERATE Efficacy & Safety in NASH w/ Fibrosis Initiated September 2015 Phase 2 Underway/Planned CONTROL OCA & Statin Effects on LDL and Lipid Metabolism Initiated December 2015 Cirrhosis Program Efficacy & Safety in NASH w/ Cirrhosis & Portal hypertension In planning Non-Invasive Dedicated Non-Invasive Technology Evaluation in NASH In planning Pediatric NASH Efficacy & Safety in Pediatric NASH Patients In planning NASH Registry In planning Phase 2 completed FLINT Efficacy & Safety in Non-Cirrhotic NASH Tetri et al. The Lancet 2015; 385: Japanese NASH Efficacy & Safety in Japanese NASH Patients Conducted by Sumitomo Dainippon Diabetes/NAFLD Diabetes + NAFLD Euglycemic Clamp Mudaliar et al, Gastroenterology 2013; 145:

27 Phase 2 FLINT Trial Conclusions Administration of 25mg OCA for 72 weeks resulted in the following: Met the primary endpoint of improved liver histology All components of NAS improved Significant improvement in liver fibrosis Reduced markers of liver function Body weight decreased but HOMA-IR did not improve OCA was generally well tolerated based on safety and tolerability data Incidence of AEs in OCA/placebo groups similar except pruritus OCA increased total and LDL-cholesterol and slightly decreased HDL-cholesterol Phase 3 trial initiated in September

28 Fibrosis Improvement and Progression OCA Pbo 40% 35% 30% Improvement in Fibrosis 35% P=0.004 Fibrosis Progression 25% 20% 15% 10% 5% 0% 19% N=102 N=98 > 1-stage Improvement 17% P= % N=92 N=83 Fibrosis Resolution 15% Not. sig. N=67 N=68 18% Progressed to Bridging Not. sig. 2% 5% N=101 N=97 Progressed to Cirrhosis Intercept Subgroup Analyses 1: Data from FLINT trial published online in Tetri et al. The Lancet and Supplementary Appendix on November 7, : All p-values compared to placebo. P-values calculated with the Cochran-Mantel-Haenszel test, stratified by clinic and diabetes status. 28

29 NASH Resolution: Baseline NASH-Only Analysis ~20% of FLINT patients did not have definite NASH at baseline Post-hoc analysis excluding patients without baseline NASH demonstrates significant response vs. placebo on NASH resolution 25% 20% 15% 10% 5% 22% P=0.0832, Not. sig. % of Patients w/ NASH Resolution OCA 13% 19% P= % Pbo 0% N=102 N=98 All Completers N=94 N=87 All Completers with Definite or Borderline NASH at Baseline Intercept Subgroup Analysis 1: Data from FLINT study published online in Tetri et al. The Lancet and Supplementary Appendix on November 7, Of FLINT patients assessed for secondary endpoints, 10% (19/200) did not have definite/borderline-nash at baseline 2: All p-values compared to placebo. P-values calculated with the Cochran-Mantel-Haenszel test, stratified by clinic and diabetes status. 29

30 REGENERATE: Randomized Global Phase 3 Trial to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment 1,400 Patients Placebo OCA 10 mg OCA 25 mg 72 week Interim Analysis* Co-primary endpoints: Fibrosis Improvement with no worsening of NASH NASH Resolution with no worsening of fibrosis ~300 sites Initiated Sept 2015 Entry Criteria 1 : Biopsy-confirmed NASH Fibrosis stage 2 or stage 3 *Interim histology analysis at 72 weeks in 1,400 patients planned to serve as basis for filing for approval Complete enrollment for interim analysis 1H A small group of NASH patients with stage 1 early liver fibrosis with an increased risk of rapid progression due to concomitant diabetes, obesity or active liver inflammation (ALT >1.5X ULN) will also be enrolled, but not included in the primary endpoint analyses 30

31 REGENERATE: Randomized Global Phase 3 Trial to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment 1,400 Patients Placebo OCA 10 mg OCA 25 mg ~2,000 patients ~300 sites Initiated Sept 2015 Entry Criteria 1 : Biopsy-confirmed NASH Fibrosis stage 2 or stage 3 72 week Interim Analysis Co-primary endpoints: Fibrosis Improvement with no worsening of NASH NASH Resolution with no worsening of fibrosis End of Study Event-Driven Final Analysis* Interim histology analysis at 72 weeks in 1,400 patients planned to serve as basis for filing for approval (complete enrollment 1H 2017) *EOS endpoint: Occurrence of pre-specified number of adverse liver-related clinical events 1 A small group of NASH patients with stage 1 early liver fibrosis with an increased risk of rapid progression due to concomitant diabetes, obesity or active liver inflammation (ALT >1.5X ULN) will also be enrolled, but not included in the primary endpoint analyses 31

32 First Quarter 2016 Financial Results Quarter ended 12/31/2015 Quarter ended 3/31/2016 Cash Position $628.1 $556.9 Adjusted Operating Expense $76.6 $ Operating Expense Guidance $ $ Non-recurring Charge* NA $45 *Settlement payment; Anticipated cash payment to be made in the second quarter of All values in millions 32

33 Appendix 33

34 Appendix: The PSC Opportunity 34

35 Primary Sclerosing Cholangitis (PSC): Overview EPIDEMIOLOGY: PSC is an autoimmune cholestatic liver disease Prevalence is ~1/3 of PBC 1 Occurs ~70% in men 1 ~75% of PSC patients have IBD, principally ulcerative colitis 1 DISEASE COURSE: Typically more complicated & aggressive than PBC 2 Biliary obstructions & infections Cholangiocarcinoma & liver cancer Hirschfield, et al; The Lancet. June 2013 TREATMENT: Orphan indication with high unmet need: no approved treatment Urso often used, although not recommended by AASLD 3 Studies have shown that ALP < 1.5x ULN correlates with improved outcomes 4 1: Bambha et al. Gastroenterology 2003; 125: : Robbins and Cotran pathological basis of disease 3: Chapman et al. Hepatology 2010; 51: : Al Mamari, et al. J Hepatol 2013;58:

36 PSC Phase 2 Trial 75 patients (target) Primary endpoints: change from baseline in ALP; safety Initiated in December

37 Appendix: NASH 37

38 FDA Pulls Approval of Fibrate in Combo with Statins in April 2016 Due to Lack of Outcomes Benefit Based on several large cardiovascular outcome trials including AIM-HIGH, ACCORD, and HPS2- THRIVE the FDA has determined that the benefits of niacin ER tablets and fenofibric-acid [delayedrelease] capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn," a document filed in the Federal Registry states Sources:

39 PPAR α / δ Agonists: Decrease in LDL Not Better than Statins Changes in LDL (%) Atorvastatin GFT505 GOLDEN MBX-8025 Fenofibrate GFT505 S2 Bezafibrate -11.2% -7.0% -24.0% -22.0% -20.6% -40.0% All PPAR α / δ agonists show comparable LDL reduction with statins showing the greatest reduction in LDL Note: Atorvastatin: CARDS study. 10mg dose versus placebo. GFT505: GOLDEN study. 120 mg dose versus placebo. Includes effect of statins in both groups. MBX-8025: Study M at 100 mg dose at last observation after week 8. Change in LDL at baseline. Fenofibrate: Pooled cohort data from label. Change in LDL versus placebo. Duration of study treatment was 3 to 6 months. FIELD study data compared versus placebo after 4 months of treatment. Bezafibrate: BIP study. Average change in LDL versus placebo. GFT S1 and S2: CARIOU, B. et al. Diabetes Care 34: , Evaluated the metabolic effects and tolerability of GFT505 in abdominally obese patients with either combined dyslipidemia or prediabetes. S2=47 patients on 80mg/day for 28 days. 39

40 PPAR α / δ Agonists: Glucose Metabolism Not Better than Fibrates / SOC Changes in HbA1c (%) Glucophage (metformin) Actos (pioglitazone) Jardiance (empagliflozin) Bezafibrate Fenofibrate Januvia (sitagliptin) GFT505 Change from baseline -0.90% -0.80% -0.76% -0.70% -0.60% -0.46% -1.40% Note: Glucophage (metformin): FDA label. 29 week study with up to 2550 mg/day dose. Actos (pioglitazone): FDA label. 26 week study with 45mg/day dose. Jardiance (empagliflozin): FDA label. 24 week study with 25mg/day dose. Fenofibrate: Diabetes Care. 2010;33(10): doi: /dc day study with 200 mg/day dose in pre-diabetic patient population. Januvia (sitagliptin): FDA label. 24 week study with 100mg/day dose. Bezafibrate: J-BENEFIT study. 24 week study with 400mg/day dose. GFT505: GOLDEN study. 52 week study with 120mg/day dose in diabetic patient population. 40

41 NASH Regulatory Considerations: Breakthrough Therapy Designation Breakthrough therapy designation for OCA received from FDA in January 2015 Precedent setting for treatment of NASH with liver fibrosis FDA recognition of serious and life-threatening condition Credible evidence of a substantial improvement on a clinically significant endpoint Based on clinical efficacy and safety data from FLINT and Phase 2 NAFLD trial No approved products for NASH Phase 3 program developed based on harmonized input from FDA and EMA 30% of BTD Requests Granted 1 4 BTDs Granted in GI/IE Division 1 4 Reason for BTD Denials 2 70% 211 Requests 30% 59 Lack of Efficacy 66% Lack of Safety 16% Other 18% 1: Data includes all BTD requests through 11/30/2014. Cited from FDA CDER New Drug Review, December 11, (slides) 2: Janet Woodcock interview by BioCentury. November 21, (link) 41

42 FLINT Trial: Key Baseline Characteristics 1 Demographics Type 2 Diabetes Histologic Assessment (mean) Concomitant Medication Lipids (mmol/l mg/dl 3 ) OCA Age: 52 y.o. Male: 30% Hispanic: 16% 53% Diabetic Insulin (pmol/l): 201±226 (mean) BMI: 35 (mean) NAS: 5.3 Fibrosis:1.9 F3 2 : 33% of pts Anti-diabetic: 48% Vitamin E: 21% Lipid-lowering: 51% Total Chol: 4.9 (190 mg/dl) 3 LDL-C: 2.9 (112 mg/dl) 3 HDL-C: 1.1 (42 mg/dl) 3 Trigs: 2.2 (196 mg/dl) 3 Placebo Age: 51 y.o. Male: 37% Hispanic: 15% 52% Diabetic Insulin (pmol/l): 138±129 (mean) BMI: 34 (mean) NAS: 5.1 Fibrosis:1.8 F3 2 : 30% of pts Anti-diabetic: 51% Vitamin E: 23% Lipid-lowering: 45% Total Chol: 4.8 (187 mg/dl) 3 LDL-C: 2.9 (111 mg/dl) 3 HDL-C: 1.1 (44 mg/dl) 3 Trigs: 2.0 (178 mg/dl) 3 1: Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, : Selected baseline percentages based on completer population. 3: Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides. 42

43 FLINT: Primary and Secondary Histological Endpoints 70% 60% 50% 61% 53% 45% 46% % of Patients w/ Improvement OCA Pbo P= P=0.001 P=0.006 P=0.03 P=0.004 not. sig. not. sig. 40% 30% 20% 10% 21% 38% 35% 31% 35% 19% 22% 13% 13% 12% 0% Primary Endpoint Steatosis Lobular Inflammation Ballooning Fibrosis NASH resolution Portal Inflammation 1: Data from Tetri et al. The Lancet. Published online November 7, : All p-values compared to placebo. P-values calculated with the Cochran-Mantel-Haenszel test, stratified by clinic and diabetes status. 43

44 FLINT: Response Rates in Higher Risk Patient Groups 60% 50% 40% P= % % of Patients Meeting Primary Endpoint OCA Pbo P<0.05 P<0.05 P<0.05 P<0.05 P< % 52% 49% 49% 44% 30% 20% 21% 19% 17% 27% 23% 10% 8% 0% N=110 N=109 N=59 N=57 N=60 N=48 N=63 N=64 N=65 N=71 N=52 N=36 Primary Endpoint Diabetes Ins. Res - Adv. Beta Cell Loss ALT 60 Fibrosis F3 BMI 35 1: Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, : All p-values compared to placebo. P-value boundary for subgroup analyses based on 95% confidence interval of published odds ratio. 44

45 FLINT: Liver Enzymes and Weight ALT ALP GGT Weight 1: Data from Tetri et al. The Lancet. Published online November 7, : All p-values compared to placebo. *p<

46 FLINT: Lipid Concentrations mg/dl mg/dl mg/dl mg/dl : Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, : All p-values compared to placebo. *p<0.05 3: Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides. 46

47 FLINT: HOMA-IR Variability HOMA-IR in Print 1 HOMA-IR Changes in FLINT 2,3 200% Biological Variation of HOMA-IR in T2D...Consequently, at any level of HOMA-IR, a subsequent sample must increase by >90% or decrease by >47% to be considered significantly different from the first FLINT Baseline HOMA-IR 61±74 40±42 Mean Change from Baseline (%) 150% 100% 50% 0% -50% Baseline Week 72 Week 96 0 OCA Pbo -100% 1: Jayagopal et al.diabetes Care November 2002 vol. 25 no : Data from Tetri et al. The Lancet and Supplementary Appendix. Published online Nov 7, : Labels denote mean values and standard deviation. -150% n=283 n=257 n=242 OCA Pbo 47

48 FLINT: Frequent ( 5%) and Selected AEs Incidence of AEs in OCA/placebo groups similar for all symptoms except pruritus Pruritus in the OCA group occurred more frequently (23% vs 6%, p < ), at a higher grade (predominantly moderate pruritus) and resulted in one patient discontinuation Incidence of severe or life-threatening events also not different between groups All severe or life threatening CV events and 2 patient deaths deemed to be unrelated to treatment Adverse Events OCA Pbo Pruritus (any) 33 9 Nausea/Vomiting/Diarrhea Abdominal Pain 7 9 CV Death MI/Stroke 1 1 CVD/Angina 1 1 Other CV : Data from Tetri et al. The Lancet. Published online November 7, All p-values compared to placebo. 2: Both deaths were deemed to be unrelated to treatment. 3: Other CV events includes congestive heart failure, cardiomyopathy, arrhythmia. 48

49 Comparison of NASH Clinical Trial Endpoints FLINT (OCA) LEAN (Victoza) Golden (GFT505) Simtuzumab Enrollment Primary Endpoint 2-point NAS decrease & no worsening of fibrosis 1 combination of the disappearance of active steatohepatitis and no worsening in fibrosis 7 reversing histological steatohepatitis without worsening of fibrosis 8 in morphometric quantitative collagen 1 NASH Resolution pattern of injury, independent of lesion scores 2,3,4,5,6 (secondary endpoint) disappearance of ballooning 7 Elimination of either steatosis or inflammation Not or ballooning8, 9, 10 applicable No worsening of fibrosis no increase in fibrosis score no increase in fibrosis score 7 Allows increase in fibrosis score: Baseline F0/F1 patients can increase to F2 and still meet endpoint 8 Unspecified in CPA 1 No assessment of staging score 1 Note: The information in the table above is based on the publicly available sources listed below. 7: Armstrong, et al. BMJ Open 2013; 3(11) 1: Clinicaltrials.gov 4: Lavine et al. JAMA 2011; 305(16): : Clinicaltrialsregister.eu 2: Chalasani et al. Journal of Hep; 2008; 48(5): : Sanyal et al. Hepatology 2011; 54(1): : Ratziu et al. Alim. Pharm & Therap. 2007; 26(6): : Kistler et al. Am J Gastroenterology; : Tandra et al. J Hepatol 2011; 55(3): : Bedossa et al. Hepatology 2012; 56(5):

50 CONTROL: Combination of OCA And Statins for Monitoring Of Lipids Atorvastatin 10mg Atorvastatin 20mg Titrated Atorvastatin Statin Use per EU/US Guidelines N=80 Placebo OCA 5 mg OCA 10 mg OCA 25 mg OCA 10 mg OCA 25 mg 2-year Open Label Extension Study Baseline lipid profile Week 16 Objectives: Evaluate the impact of varying doses of OCA on LDL and lipid metabolism Evaluate the impact of low doses of statin therapy to modulate LDL in combination with OCA treatment Timing: Initiated Dec

51 Phase 2 Efficacy and Safety Study in Cirrhosis due to NASH Standard of Care Patients with cirrhosis due to NASH and Portal Hypertension Placebo OCA OCA Baseline HVPG Objectives: To understand the safety and tolerability of OCA in NASH patients with cirrhosis and portal hypertension To evaluate the effect of OCA in reducing portal pressure as assessed by hepatic venous pressure gradient (HVPG) Interim endpoint HVPG Exploratory long term follow up for outcomes Timeline: Study initiation est. 2016, pending regulatory feedback 51

52 Phase 2b Sumitomo Dainippon Pharma NASH Trial FLINT SDP Duration 72 weeks Endpoint Histological Improvement 2-point Improvement in NAFLD Activity Score w/ no worsening of Fibrosis Arms 25mg, Placebo 10, 20, 40mg, Placebo Enrollment There were distinct differences in baseline characteristics in the SDP trial population when compared to the Western patients in the FLINT trial 52

53 Summary of SDP Phase 2b Trial Results Study Results ITT Analysis? 1 Placebo N=50 10mg N=50 20mg N=50 40mg N=50 NAS improvement 2 points with no worsening of fibrosis 10 (20%) 11 (22%) p = (28%) p = (38%) p = p = No difference was seen in fibrosis improvement in the OCA groups compared to placebo Completer Analysis 4 Dose dependent effects were observed 51% of patients in the 40mg dose vs. 22% in the placebo group meeting the primary endpoint (p=0.0061) Safety & Tolerability: Pruritus discontinuations Placebo: 0, 10mg: 0, 20mg: 2, 40mg: 5 patients Lipid parameters, including LDL-C, HDL-C and triglycerides, appeared to be consistent with previously reported lipid changes in Western NASH patients 1: ITT analysis included all randomized patients who received treatment (50 per group), and patients who discontinued or did not have a repeat biopsy were treated as non-responders 2: Primary efficacy analysis is a stratified Cochran-Armitage test with multiple contrast coefficients. Statistical significance is based on a p-value < : Secondary efficacy analysis is a CMH (Cochran-Mantel-Haenszel) test stratified by baseline fibrosis stage for pairwise comparison of each OCA group vs. placebo group. The multiplicity was not adjusted. 4: A pre-specified completer analysis was conducted on the patients who had biopsies at both baseline and 72 weeks (45, 44, 44 and 37 patients in the placebo, 10mg, 20mg and 40mg OCA groups, respectively). 53

54 Appendix: PBC 54

55 POISE: Primary Efficacy Objective Linked to Outcomes As part of accelerated approval strategy, Intercept sponsored the largest independent meta-analysis of PBC patient data (N=4,845) Independent researchers confirmed ALP/bilirubin 1 is highly predictive of outcomes Responder Global PBC Study Group published in December HR (95% CI): 3.53 ( ) p=3.3x10-34 Non-Responder 1: ALP < 1.67x ULN and normal bilirubin after 1 year of UDCA. 2: Lammers et al. Gastroenterology. December : Lammers, EASL, AASLD (graph) 55

56 OCA Clinical Development in PBC All trials randomized, double-blind, placebo-controlled with long-term safety extension (LTSE) phases Trial Description Duration N= Dose Status Phase OCA 12 weeks UDCA + OCA 12 weeks mg or 50mg 10mg, 25mg or 50mg Completed: met primary and secondary endpoints Completed: met primary and secondary endpoints Phase 3 / 4 POISE UDCA + OCA 1 year 217 COBALT Long-term confirmatory outcomes Up to 8 years 350 (target) 5mg or 10mg 5mg or 10mg DB completed: met primary & secondary endpoints; >95% enrolled in LTSE Enrolling 56

57 POISE: Frequent AEs ( 5%) Placebo (n=73) Titration OCA (n=70) 10 mg OCA (n=73) n (%) n (%) n (%) Pruritus 28 (38%) 39 (56%) 50 (68%) Fatigue 10 (14%) 11 (16%) 17 (23%) Nasopharyngitis 13 (18%) 17 (24%) 13 (18%) Nausea 9 (12%) 4 (6%) 8 (11%) Diarrhoea 8 (11%) 2 (3%) 8 (11%) Arthralgia 3 (4%) 4 (6%) 7 (10%) Headache 13 (18%) 12 (17%) 6 (8%) Oropharyngeal pain 1 (1%) 5 (7%) 6 (8%) Cough 5 (7%) 4 (6%) 6 (8%) Constipation 4 (5%) 5 (7%) 5 (7%) Oedema peripheral 2 (3%) 2 (3%) 5 (7%) Influenza 4 (5%) 5 (7%) 4 (5%) Abdominal pain upper 5 (7%) 5 (7%) 4 (5%) Back pain 8 (11%) 4 (6%) 4 (5%) Upper respiratory tract infection 8 (11%) 4 (6%) 4 (5%) Urinary tract infection 8 (11%) 4 (6%) 4 (5%) Rash 3 (4%) 3 (4%) 4 (5%) 57