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.

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.

ANDMy presentation focuses on the investigational use

of:Obeticholic Acid and Placebo

Bile Acids: from Simple Detergents to Pleotrophic Homeostatic Regulators• Detergents in gut ‐ Solubilize fats in intestine → absorption

• Farnesoid‐X Receptor – Liver, bile ducts, fatNuclear receptor for bile acid signaling

• Makishima Science 1999; 284: 1362

Natural ligand: Chenodeoxycholic acid 

Bile acid synthesis regulation

Feedback via FGF‐19 & SHP

↓ Hepatic Triglyceride, VLDL Synthesis• Wanatabe JCI 2004; 113: 1408‐1411

Hepatic regeneration, intestinal bacterial overgrowth/translocation protection

Modulation of insulin sensitivity & adiposity• Cariou J Biolog Chem 2006; 281:11039–11049

• TGR‐5 – Liver, fat, enteroendocrine cells – G‐Protein Coupled Receptor ‐ cell membrane

Mediates intracellular conversion of T4 to T3• Wanatabe Nature 2006; 439: 484‐489

↑ GLP‐1 & Insulin• Thomas Cell Metabolism 2009; 10: 167‐177

Obeticholic Acid

FXR Agonist

OCA6α‐ethyl chenodeoxycholic acid

CDCAchenodeoxycholic acid

UDCAursodeoxycholic acid

FXR EC50(agonist)

0.099 μM 8.66 μM No activity

Pelliciari R. J.Med.Chem 2002

~ 2 log FXR agonism

6α-Ethyl Chenodeoxycholic Acid - INT-747

Obeticholic Acid [OCA]

6α-Ethyl Chenodeoxycholic Acid - INT-747

Obeticholic Acid

Obeticholic Acid [oh bet" i kol' ik]

INT-7476a-ethyl chenodeoxycholic acid

3α,7α-dihydroxy-6α-ethyl-5βcholan-24-oic acid

No meaningful activity vs. Other Nuclear ReceptorsBroad enzyme & receptor 

pharmacology screen EC50 for TGR5: 20 µMConjugated + glycine & taurine

Equipotent FXR agonists to parent

Normal Volunteers – Plasma Concentrations –Enterohepatic Circulation

0 25 50 75 100 1250

100

200

300

400

500

Glyco-6-ECDCATauro-6-ECDCA

6-ECDCA

Time (hrs)

ng/m

l

After last dose (12 days of dosing)

Shapiro D. Hepatology 2009; 50 (Suppl S4): 198 [Abstract: 992]

Preclinical Studies Overview• Numerous animal models evaluated

BDL, estrogen, lithocholic acid, CCl4, ANIT, thioacetamide injuryEffects 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‐2Histology ‐ fibrosis, reversal of cirrhosis, Portal hypertension

Histology - rats treated with:a. Vehicleb. LCA alonec. LCA plus INT-747d. LCA + CDCA

Bile Flow Infusion of :• LCA alone -o- [b] or • LCA + INT-747 -●- [c]

Data from C. Clerici Pellicciari et al., J. Med. Chem., 2002;45:3569–3572

Anti-Cholestatic Effects of OCALithocholic acid (LCA) model

Vairappan B.Hepatology 2009; 50 (S4): 336-337 (Abstract: 70)

Sham BDL BDL+INT-747

0

5

10

15

20

mm

Hg

P<0.0001 P<0.001

Rat Bile Duct Ligation Model

OCA Attenuates Portal Hypertension

OCA Improves Insulin Sensitivity in Type 2 DM + NAFLD Patients• 2 step insulin infusion euglycemic clamps

60 & 120 µU insulin x m2 body surface area/min

• Dose related ↑ in FGF‐19 & ↓weight

Day 0 Day 4301

2.5

3.0

3.5

4.0

4.5

5.0

GD

R (m

g/kg

/min

)

Day 0 Day 4304

5.5

6.0

6.5

7.0

7.5

8.0

8.5

Placebo (N=17)25 mg (N= 15)50 mg (N=12)

GD

R (m

g/kg

/min

)

Sanyal A. Hepatology 2009; 50(S4): 398A

p=0.04

Both doses vs placebo: p=0.048 Both doses vs placebo: p=0.022

p=0.036

60 µU insulin x m2 SA/min 120 µU insulin x m2 SA/min

PBC Ongoing Medical Needs

• Ursodeoxycholic AcidOnly 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 2010 52:745-758Silveira M, Lindor K, Clin Liver Dis 2008; 12: 425-443

Kaplan N, Gershwin, E N Engl J Med 2005;353:1261-73

Drugs Evaluated in PBCDrug Efficacy Safety References

Rifampicin Improves pruritus Drug induced hepatitis Bach Gastroenterol 1992; 102: 2007Prince 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

Leuschner J Hepatol 1996; 25: 49

Budesonide Histological ↓ Bone density Portal v thrombosis

Rautiainen Hepatol 2005; 41: 747Hemfling Hepatol 2003; 38: 196

Cyclosporine Survival ↓ Renal function & hypertension

Wiesner N Engl J Med 1009 322: 1419

Methotrexate None Marrow suppression, fatigue, pulmonary fibrosis

Bach Am J Gastrol 2003; 98: 187Coombes Hepatol 2005; 42: 1184

Mycophenalate mofetil None Anemia, leukopenia, dypnea, chest pain.

Talawalkar J Clin Gastroent 2005; 39: 168

Rituximab Pilot study Mucocutaneous -pemphigus, Stevens-Johnson, toxic epidermal necrolysis

Meyers Hepatol 2007; 46; 550A

Screening

Baseline 1-4 weeks predose

Double Blind Phase 12 weeks

Follow-Up Phase 2 weeks

Placebo

OCA 10 mg

OCA 50 mg

0 2 4 8 12 14

N=35/group

Baseline Follow-Up

UDCA

OCA 25 mg

Dose Response Study Design – Addition to UDCA 

Primary Objectives & Inclusion Criteria

Objectives• Assess effects of INT‐747 added to ursodeoxycholic acid on

• Alkaline phosphatase levels• Safety

Inclusion Criteria• Males or females; 18 ‐ 70 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 1.5 ‐ 10 x ULN

Primary Objectives & Inclusion Criteria

Objectives• Assess effects of INT‐747 added to ursodeoxycholic acid on

• Alkaline phosphatase levels• Safety

Inclusion Criteria• Males or females; 18 ‐ 70 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:  1.5 ‐ 10 x ULN

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., varicealbleeds, 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

Study Centers

•8 Countries, 33 Centers

•165 patients enrolled

•Geography• USA:        56%

• Canada:  26%

• Europe:  18%

Patient Numbers

Outcome

Randomized

ScreenedScreened

N=221

Randomized

N=165

Completed

N=136Discontinued

N=27

Withdrew Consent/Lost

N=2

Failed to Qualify

N=56

AnalysisITT

mITT 

for AP

N=161

Excluded*N=4

*: If no post baseline visit

PBC Diagnosis ‐ %

% Pbo 10mg 25mg 50mg Total

Definite (3 Criteria) 71 61 69 59 65%

Probable (2 Criteria) 29 39 31 41 35%

DemographicsPbon=38

10mgn= 38

25mgn= 48

50mgn= 41

TotalN= 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 55yBMI (kg/m2) 27.4 27.8 27.4 26.4 27.2

UDCA (mg/kg) 15.9 15.9 15.6 16.3 15.9

Alkaline Phosphatase – Baseline

Placebon=37

10mgn=38

25mgn=47

50mgn=39

TotalN=151

AP 276.4 294.4 289.4 286.1 286.6

x ULN 2.4 2.5 2.5 2.4 2.4

RESULTS

‐ Efficacy: Alkaline Phosphatase

Placebo 10 mg 25 mg 50 mg‐30

‐20

‐10

0

n=37 n=38 n=47 n=39

p < 0.0001 p < 0.0001 p < 0.0001

25

‐2.5

Mean % Change in AP

% Δ – Alkaline Phosphatase

Mean values + SEM

  15 29 57 85‐EOS Follow‐up

‐40

‐30

‐20

‐10

0

Placebo

10 mg

25 mg50 mg%

Δ

% Δ By Visit – Alkaline Phosphatase - ITT

Off-StudyRx

OCA vs. Pbo: p<0.001 p<0.05

Placebo 10 mg 25 mg 50 mg‐100

‐80

‐60

‐40

‐20

0

n=37 n=38 n=47 n=39

p < 0.0001 p < 0.0001 p < 0.0001Ch

ange

 in AP (U/L)

Absolute Δ - Alkaline Phosphatase

Mean values + SEM

Day 0 Day 85‐EOS0

100200

250

300 Placebo (n=37)

25 mg (n=47)50 mg (n=39)

10 mg (n=38)

AP (U/L)

Alkaline Phosphatase

Mean values + SEM

vs. Pbo:All: p<0.0001

RESULTS

Liver Enzymes

Baseline 85-EOS0

100

200

300

400Placebo(n=38)

10 mg (n=38)

25 mg (n=48)50 mg (n=41)

ULN

Day 85‐EOSp<0.0001 ‐ all doses

Day of Visit

GG

T (U

/L)

γ-Glutamyl Transpeptidase - γGT

% Change: Pbo:    +  710mg: ‐ 4825mg: ‐ 6350mg: ‐ 57

Baseline 85-EOS0

1530

40

50

60

70

Placebo(n=38)

10 mg (n=38)

25 mg (n=48)50 mg (n=41)

ULN

Day 85‐EOSp<0.0001 ‐ 10 & 25mgp<0.005 ‐ 50mg

Day of Visit

ALT

(U/L

)Alanine Transaminase - ALT

% Change: Pbo:        010mg: ‐ 2825mg: ‐ 3550mg: ‐ 21

Aspartate Transaminase - AST

% Change: Pbo:        010mg: ‐ 1725mg: ‐ 1650mg: ‐ 9

Baseline 85-EOS0

1530

40

50

60

70

Placebo(n=38)

10 mg (n=38)

25 mg (n=48)50 mg (n=41)

ULN

Day 85‐EOSp<0.005 ‐ 10 & 25 mgp=0.06 ‐ 50 mg

Day of Visit

AST

(U/L

)

Safety & Tolerability

  Pbo (%) 10mg (%) 25mg (%) 50mg (%) TotalTotal 84 89 98 100 93%Pruritus 50 47 85 80 67%Headache 11 8 10 17 12%Fatigue 13 18 6 12 12%Constipation 8 8 8 7 8%Diarrhea 8 8 8 7 8%Nausea 3 11 6 10 7%Abdo Distension 3 5 0 10 4%Dry Eye 3 0 6 5 4%Oropharyngeal Pain 3 5 8 0 4%Pain, extremities 0 0 2 10 3%Vomiting 0 0 6 0 2%Pyrexia 0 8 0 0 2%UTI 8 0 0 0 2%

AEs > 5% in any Group

  Pbo (%) 10mg (%) 25mg (%) 50mg (%) TotalTotal 84 89 98 100 93%Pruritus 50 47 85 80 67%Headache 11 8 10 17 12%Fatigue 13 18 6 12 12%Constipation 8 8 8 7 8%Diarrhea 8 8 8 7 8%Nausea 3 11 6 10 7%Abdo Distension 3 5 0 10 4%Dry Eye 3 0 6 5 4%Oropharyngeal Pain 3 5 8 0 4%Pain, extremities 0 0 2 10 3%Vomiting 0 0 6 0 2%Pyrexia 0 8 0 0 2%UTI 8 0 0 0 2%

AEs > 5% in any Group

Placebo 10mg 25mg 50mg0

25

50

75

100

%Pruritus as AE – Incidence by Dose

Placebo 10mg 25mg 50mg0

20

40

60

80

100MildModerateSevere

%Pruritus - Severity

Pruritus - Discontinuations

Placebo 10mg 25mg 50mg0

10

20

30

Placebo10mg25mg50mg

%

Placebo 10mg 25mg 50mg0

10

20

30

%

Placebo 10mg 25mg 50mg0

10

20

30

%

Discontinuations for AEs

Any AE Pruritus

Serious AEs

Group AE  Relationship to Study Drug

Placebo • Dyspnea Unlikely

10 mg ‐

25 mg  • Growth of Parotid Gland Tumor (diagnosed pre study)

Unlikely

50 mg

• Angioedema• Angina Secondary to Epinephrine

UnlikelyUnlikely

[Completed Study]

• Gastrointestinal Bleeding Possible

• Jaundice Possible

• PBC Flare Probable

• Chest Pain Possible

Conclusions:  OCA + UDCA

• Highly significant effects on Alkaline Phosphatase• Significant decreases in: GGT, ALT, AST

• No clear dose response relationship

• Safety & TolerabilityPruritus – Principal AE ‐ shows dose response relationship

• 50mg – unlikely starting dose in PBC

• Ongoing Phase 2 StudiesLong Term Safety Extension

Monotherapy study

• Merits further evaluation – Phase 3 planned

Thank You -Patients & Investigators.

Study Sites – N. AmericaCountry Investigator Study Coordinator Location  

USA

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

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

Study Sites – EuropeCountry   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 

Germany 

Michael Manns & Kinan Rifai Janina Kirschner Hannover 

Christian Rust N/A  Munich Christoph Schramm Kirsten Aue Hamburg 

Stefan Zeuzem Melanie Moschitz Frankfurt 

The Netherlands Ulrich Beuers Lucas Wenniger Amsterdam 

Karel van Erpecum N/A  Utrecht Henk van Buuren Melek Polat‐Utku  Rotterdam 

France Raoul Poupon Farid Gaouar Paris Christian Trepo Benedicte Soret  Lyon 

Austria  Michael Trauner Martin Wagner Graz 

Spain  Albert Parés Rosana Ahuir   Barcelona 

Pruritus – Development with Time

Pbo

50mg

10mg

25mg

Pruritus Interventions

PruritusN=111, 67%

Dose Modification

N=43

Bile Acid Resinat Baseline

N=19

Bile Acid ResinAddedN=40

CompletedN=32, 80%

DiscontinuedN=7, 18%

CompletedN=17, 89%

Discontinued N=2, 11%

CompletedN=31, 66%

DiscontinuedN=12, 26%

PruritusN=111, 67%

Dose Modification

N=43

Bile Acid Resinat Baseline

N=19

Bile Acid ResinAddedN=40

DiscontinuedN=12, 26%