Program Disclosure. This activity is supported by an educational grant from Intercept Pharmaceuticals.

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2 Program Disclosure This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint providership of Purdue University College of Pharmacy and the Chronic Liver Disease Foundation. Purdue University College of Pharmacy, an equal access/equal opportunity institution, is accredited by the ACCME to provide continuing medical education for physicians. This activity is supported by an educational grant from Intercept Pharmaceuticals.

3 Educational Objectives Examine current and emerging data relating to the diagnosis of PBC. Develop evidence-based treatment plans for patients with PBC using the latest clinical evidence. Identify disease-related symptoms and long-term medical management strategies to improve patient quality of life.

4 CLDF National Primary Biliary Cholangitis (PBC) Coalition The Chronic Liver Disease Foundation (CLDF) is pleased to invite you to become a member of a nationwide coalition of certified providers designed to improve the screening and treatment of patients with Primary Biliary Cholangitis (PBC). It is critically important that community specialists understand the importance of screening, diagnosis and appropriate management of PBC, as well as locating qualified specialists for PBC Linkage to Care. Upon completing CLDF curriculum delivered via this live meeting, an online module or an e-monograph, healthcare providers will receive a certificate of competency and will be offered enrollment into the CLDF National PBC Coalition.

5 Your Role If interested in becoming a member, please opt in on the form provided in your meeting folder. Your name will be included in the Resource Directory on the ACG Coalition website. Additional benefits include: Patient Registry Participation Market Research Phase IV Opportunities Latest Data on PBC Community Speaker Bureau Patient Advocacy and Outreach via Town Hall Meetings

6 Primary Biliary Cholangitis (PBC)

7 PBC is a Chronic, Progressive Autoimmune Disease Factors possibly associated with onset and perpetuation of bile-duct injury in PBC Genetics Immune response Bile duct damage Environment PBC is characterized by destruction of the interlobular and septal bile ducts that may lead to cirrhosis Poupon R. J Hepatol. 2010;52(5): ; Selmi C, et al. Lancet. 2011;377(9777): ; Carey EJ, et al. Lancet. 2015;386(10003):

8 PBC Phenotype Age Usually >45 years Gender Serology Immunoglobulin Female > Male (9:1) AMA in ~95%; disease-specific ANA in ~30%-50%; ASMA may be present IgM typically elevated MRCP Liver Histology Coexisting IBD Normal Lymphocytic infiltrate; inflammatory duct lesion; granuloma may be present Not typical Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth-muscle antibody; IBD, inflammatory bowel disease; MRCP, magnetic resonance cholangiography; PBC, primary biliary cholangitis. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:

9 PBC Prevalence Boonstra K, Kunst A, Stadhouders P, et al. Rising incidence and prevalence of primary biliary cirrhosis: a large population-base study. Liver International. 2014;34:e35.

10 Concomitant Autoimmune Disease in Women with PBC Frequency (%) Sjögren s syndrome 7-34 Raynaud s syndrome 9-13 Hashimoto s thyroiditis Rheumatoid arthritis 3-8 Psoriasis 6 Scleroderma or CREST* 1-2 Inflammatory bowel disease 1 Any autoimmune disease *CREST (calcinosis, Raynaud s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) Carey EJ, Ali AH, Lindor KD. Primary Biliary Cirrhosis. The Lancet Oct.; 386(10003):

11 Diagnostic Considerations Spectrum of Autoimmune Liver Injuries 1 Autoimmune hepatitis 1 Primary biliary cholangitis 1 Primary sclerosing cholangitis 1 IgG4-related disease 2 Differential for Cholestatic Liver Biochemistry 3 Drug-induced liver injury Inherited cholestasis Idiopathic ductopenia Malignant infiltration Nonalcoholic fatty liver disease Biliary obstruction Primary biliary cholangitis Primary sclerosing cholangitis Sarcoidosis 1. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36: ; 2. Joshi D, et al. Aliment Pharmacol Ther. 2014;40: ; 3. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:

12 Diagnosis of PBC: Is Biopsy Needed? If: Increased AMA ALP >1.5 x ULN AST <5 x ULN Then: Positive predictive value for PBC >98% Sensitivity 80%, specificity 92% Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; ULN, upper limit of normal Zein CO, Angulo P, Lindor K. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis?; Clin Gastro and Hepatol 2003;1(2):89-95.

13 Evaluation of Patients with Cholestatic Profile + PBC* AMA ANA + ** Specific PBC Nonspecific Ultrasound; immunoglobulins; medications; thyroid; celiac screen; lipids; bone density; Sjögren s screen *** MRCP +/- liver biopsy if MRCP nondiagnostic *0.5% 1% of healthy individuals are AMA+; **>85% patients with AMA PBC are ANA+; ***Differential is among PSC, antibody- negative PBC, and alternate ductopenic disorders. Abbreviations: AMA, antimitochondrial antibody; ANA, antinuclear antibody; MRCP, magnetic resonance cholangiography; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis. Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:

14 Interpretation of AMA, ANA, and Immunoglobulin Testing in PBC AMA ANA Positive in >90% of patients with PBC, depending on assay 1 In the correct context, AMA reactivity, with an elevated ALP and no significant elevation in AST, is associated with a >95% PPV of histologic PBC 2 2 ANA immunofluorescent patterns are specific to PBC: multiple nuclear dots and perinuclear/rim-like membranous 3 gp210 and sp100 Automated ANA assays will likely not detect these reactivities Laboratories should perform immunofluorescence if ELISA-based assays for gp210 and sp100 are not available Immunoglobulins Elevated IgM is a sensitive but not specific characteristic of PBC 1 Elevated IgG is primarily observed in AIH 1 Abbreviations: PPV, positive predictive value; AIH, autoimmune hepatitis; IgM, immunoglobin M; IgG, immunoglobin G 1. Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36: ; 2. Zein CO, et al. Clin Gastroenterol Hepatol. 2003;1:89-95; 3. Zeman MV, Hirschfield GM. Can J Gastroenterol. 2010;24:

15 Overlap or Crossover Scenarios Immunoserologic Overlap Positive ANA/ASMA titers and elevated IgG in AMApositive PBC AMA-positive AIH Radiologic Overlap Clinical features of AIH with cholangiographic abnormalities consistent with inflammatory cholangiopathy Biochemical Overlap AST/ALT >5 x ULN in PBC or PSC ALP >3 x ULN in AIH (GGT >5 x ULN in children) Histologic Overlap Lymphoplasmacytic infiltrate and interface hepatitis with bile-duct lesions consistent with either PBC or PSC Also, varying combinations of the above, including temporal variations: consecutive vs sequential presentations Abbreviation: GGT, gamma-glutamyl transferase Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:

16 Survival Rates, Elastography and PBC Abbreviation: LSM, liver stiffness measurement Corpechot C, Carrat F, Poujol-Robert A, et al. Hepatology. 2012; 56(1):

17 Higher APRI is Associated with Poorer Transplant-Free/Overall Survival in PBC Abbreviation: APRI, aspartate aminotransferase/platelet ratio. Trivedi PJ, Bruns T, Cheung A, et al. Optimizing risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response. J Hepatol. 2014;60(6):

18 Disease Management

19 Pruritus Is Common Among PBC Patients Prevalence reported as high as 69% 1 Unknown etiology 1,2 Bile salts, endogenous opioids, histamine, serotonin, progesterone/ estrogen, and autotaxin/lysophosphatidic acid are suspected pruritogens 2 Diurnal variation most intense itch in the late evening 2 Localization reported at limbs soles of feet, palms of hands 2 Exacerbated by pregnancy or contact with wool/heat 3 1. Imam MH, et al. J Gastroenterol Hepatol. 2012;27(7): ; 2. Beuers U, et al. Hepatology. 2014;60(1): ; 3. Lindor KD, et al. Hepatology. 2009;50(1):

20 Stepwise Approach to Pruritus Cholestyramine (4-16 g/day) Anion exchange resin Difficult posology Bloating, constipation or diarrhea, nausea Rifampin ( mg/day) PXR agonist, lowers autotaxin 10% risk of hepatitis usually occurring in the first 2 months Naltrexone (12.5 to 50 mg/day) Opioid antagonist Loss of appetite, irritability, GI side effects Sertraline ( mg/day) SSRI Somnolence, nausea, dizziness, fatigue Abbreviations: SSRI, selective serotonin reuptake inhibitor; PXR pregnane X receptor, AASLD and EASL guidelines 2009.

21 Assessing and Managing Fatigue Though fatigue caused by PBC may not be reversible, associated causes of fatigue should be actively excluded or identified and managed 1,2 Rule Out: Associated causes of fatigue (disease or medication): Anemia 2 Depression 2 Sleep disorder 2 Hypothyroidism 1-3 Medications that can cause or contribute to fatigue (eg, excessive antihypertensive medication) 1 Consider Fatigue Management Strategies: Fatigue may be improved by: Maintaining regular physical activity 4,5 Modafinil ( mg) 6,7 Methotrexate for patients with severe fatigue 8 1. European Association for the Study of the Liver. J Hepatol. 2009;51(2): ; 2. Lindor KD, et al. Hepatology. 2009;50(1): ; 3. Elta GH, et al. Dig Dis Sci. 1983;28(11): ; 4. Cook NF, et al. Br J Nurs. 1997;6(14): ; 5. Graydon JE, et al. Cancer Nurs. 1995;18(1):23-28; 6. Jones DEJ, et al. Aliment Pharmacol Ther. 2007;25(4): ; 7. Ian Gan S, et al. Dig Dis Sci. 2009;54(10): ; 8. Babatin MA, et al. Aliment Pharmacol Ther. 2006;24(5):

22 The Absence of Symptoms at Diagnosis May Not Predict Prognosis Examination of the natural history of a 770-patient cohort in Northeast England (incident cases, ) % asymptomatic at diagnosis Median survival time from diagnosis was not significantly different between patients who were symptomatic and asymptomatic at diagnosis 1 The relationship between symptom severity and disease progression can vary by patient 2 Proportion Surviving Initially asymptomatic patients Initially symptomatic patients P = Time from Diagnosis (Yr) No. at risk Prince MI, et al. Gut. 2004;53: ; 2. Lindor KD, et al. Hepatology. 2009;50:

23 PBC Approved Therapies

24 First Line: Ursodeoxycholic Acid/Ursodiol (UDCA) Orally administered, naturally occurring, hydrophilic secondary bile acid Dose: mg/kg/day Improvement in liver tests may be seen within a few weeks and 90% of the improvement usually occurs within 6-9 months After 1 year of treatment, the number of patients with biochemical response according to Paris Criteria was 66% and according to Barcelona Criteria was 62% (Kuiper et al) Up to 40% treated with UDCA have a suboptimal response Abbreviation: UDSA, ursodeoxycholic acid Kuiper, et al. Gastroenterology 2009; 136(4):

25 Therapeutic Effects: UDCA Improves TB, ALP, GGT, AST and ALT Improves survival free of liver transplantation UDCA mg/kg/day Improves cholesterol, IgM Delays development of esophageal varices Delays histological progression Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; IgM, immunoglobulin M; TB, total bilirubin; UDCA, ursodeoxycholic acid. Levy C and Lindor KD. In: Zakim and Boyer's Hepatology: A Textbook of Liver Disease. Elsevier Inc;2011: Graphic courtesy of Dr. Cynthia Levy.

26 UDCA: Transplant-free Survival Based on Bilirubin and Alkaline Phosphatase Levels at 1 Year Follow-up Transplant-free survival (%) a-b: P.001 c-d: P.001 a b c d Normal bilirubin and ALP 2.0 x ULN Normal bilirubin and ALP > 2.0 x ULN Abnormal bilirubin and ALP 2.0 x ULN Abnormal bilirubin and ALP > 2.0 x ULN Time (years) a b c d Lammers, et al. Gastroenterology. 2014; 147:

27 GLOBE Score to Predict Outcomes of PBC Patients Receiving UDCA International collaborative meta-analysis >4000 patients with PBC from 15 centers in 8 European and North American countries On UDCA for at least 1 year Median follow-up 7.8 years Risk score developed and validated to predict transplant-free survival Lammers WJ, et al. Gastroenterology. 2015;149:

28 GLOBE Score: Online Calculation ALP at 1 year Total Bilirubin at 1 year Albumin at 1 year Age at initiation of UDCA GLOBE Platelets at 1 year Predicts 3-, 5- and 10-year survival compared to age-matched population

29 Second Line: Obeticholic Acid (OCA) FXR Agonist Bile Acid Homeostasis Inflammation Pathways Decreases BA synthesis Decreases BA uptake Decreases BA absorption Increases BA secretion Downregulates NF-KB, TNF Decreases IgM and CRP CHOLERESIS Abbreviations: BA, bile acid; NF-KB, nuclear factor kappa beta; TNF, tumor necrosis factor; CRP, C-reactive protein

30 Screening OCA in Patients with PBC: POISE Study Design Placebo (n=73) OCA 10 mg (n=73) OCA 5 mg OCA 5-10 mg dose adjustment option OCA 5 mg Titrate to OCA 10 mg (n=33) Remain at OCA 5 mg (n=36) Months in Open-Label Phase 0 W2 M3 M6 M9 M12 OCA titration at 6 months: Subjects in OCA titration arm titrated from 5 mg to 10 mg at Month 6 if they met any of the following criteria at the Month 6 assessment: The primary endpoint (ALP < 1.67xULN or bilirubin ULN) was not achieved No evidence of tolerability issues, e.g. pruritus Modified from Nevens F et al. N Engl J Med 2016;375:

31 Primary Objective and Patient Population To assess the proportion of patients achieving ALP <1.67 x ULN and a decrease of 15% and total bilirubin ULN Inclusion PBC diagnosis (EASL and AASLD guidelines) ALP 1.67 x ULN and/or total bilirubin >ULN to <2 x ULN Stable UDCA or unable to tolerate UDCA Exclusion Concomitant liver diseases, decompensation, severe pruritus requiring treatment Randomization Strata UDCA (yes/no) Paris 1: ALP >3x ULN and/or AST >2x ULN and/or total bilirubin >ULN Nevens F et al. N Engl J Med. 2016;375:

32 Patients with Response (%) Primary Endpoint in the Double-blind and Open-label Extension Phases Placebo Obeticholic acid, 5-10 mg Obeticholic acid,10 mg 100 Double-Blind Phase Open-Label Phase 5 mg Dose adjustment Month in Double-Blind Phase Month in Open-Label Phase No. of Patients Placebo Obeticholic acid, 5-10 mg Obeticholic acid, 10 mg Nevens F, et al. N Engl J Med. 2016;375:

33 Alkaline Phosphatase (U/liter) Alkaline Phosphatase in the Double-blind and Open-label Phases Placebo Obeticholic acid, 5-10 mg Obeticholic acid, 10 mg A Alkaline Phosphatase Double-Blind Phase Open-Label Phase mg Dose adjustment x ULN 100 ULN 0 Baseline Month in Double-Blind Phase Month in Open-Label Phase No. of Patients Placebo Obeticholic acid, 5-10 mg Obeticholic acid, 10 mg Nevens F, et al. N Engl J Med. 2016;375:

34 Totla Bilirubin (mg/dl) Total Bilirubin During the Double-blind and Open-label Phases B Total Bilirubin 1.4 Double-Blind Phase Open-Label Phase 5 mg Dose adjustment ULN Baseline Month in Double-Blind Phase Month in Open-Label Phase Nevens F, et al. N Engl J Med. 2016;375:

35 Findings on Obeticholic Acid in PBC: POISE Obeticholic acid is associated with statistically significant, clinically meaningful improvements 1 Biochemical criteria correlated with clinical benefit (alkaline phosphatase and bilirubin) Markers of inflammation (C-reactive protein) and apoptosis (CK18) Efficacy and safety of obeticholic acid Demonstrated when analyzed according to disease severity/response criteria 2 Consistent across patient subgroups 3 Age at diagnosis Disease duration Baseline alkaline phosphatase levels Abbreviation: PBC, primary biliary cirrhosis. 1. Nevens F, et al. Hepatology. 2014;60(suppl):347A-348A; 2. Luketic VA, et al. Hepatology. 2014;60(suppl):355A-356A; 3. Andreone P, et al. Hepatology. 2014;60(suppl):360A.

36 Adverse Events in POISE and Open-Label Extension Event Placebo N=73 n (%) OCA 5-10 mg N=70 n (%) OCA 10 mg N=73 n (%) Open Label N=193 n (%) Pruritus 28 (38) 39 (56) 50 (68) 138 (72) Nasopharyngitis 13 (18) 17 (24) 13 (18) 45 (23) Headache 13 (18) 12 (17) 6 (8) 36 (19) Fatigue 10 (14) 11 (16) 17 (23) 50 (26) Nausea 9 (12) 4 (6) 8 (11) 28 (15) Serious Adverse Events 3 (4) 11 (16) 8 (11) 27 (14) Modified from Nevens F, et al. N Engl J Med. 2016;375:

37 LS Mean (SE) Change from Baseline in Pruritus VAS Score Changes in Pruritus Over Time Double Blind Phase 30 Placebo ± UDCA (N=73) Obeticholic acid, 5-10 mg ± UDCA (N=70) Obeticholic acid, 10 mg ± UDCA (N=73) *** 20 ** * Month Abbreviations: VAS, visual analog scale; LS, least squares Nevens F, et al. N Engl J Med. 2016;375:

38 Overall Findings The effect of OCA was consistent and independent of age at diagnosis, duration of PBC and baseline ALP. Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA after 1 year. Thus, starting patients on OCA 5 mg with titration to 10 mg based on the clinical response appears to be an appropriate dosing strategy. OCA given to individuals with PBC with an inadequate response to, or unable to tolerate UDCA, produced a significant clinically meaningful improvement in liver biochemistry, which has been shown to correlate strongly with clinical benefit. Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Nevens F, et al. N Engl J Med. 2016;375:

39 Summary PBC is most common in middle-aged women Taking a good history is essential Diagnosis can typically be made based on persistent cholestatic liver profile and AMA positivity after other common liver diseases have been excluded

40 Long-term Management of Patients with PBC Liver tests every 3-6 months consider OCA if non response to UDCA Thyroid status (TSH) annually DEXA at baseline and every 2-4 years Monitor for associated autoimmune conditions In the presence of severe cholestasis assess levels of vitamins A and D. May need to administer Vit K prior to procedures Upper endoscopy every 1-3 years if cirrhotic or Mayo risk score >4.1 Ultrasound ± AFP every 6 months in patients with known or suspected cirrhosis Abbreviations: TSH, thyroid stimulating hormone; DEXA, dual energy X-ray absorptiometry; AFP, alpha fetoprotein Lindor K, et al. Hepatology 2009;50: ; EASL clinical guidelines. J Hepatology 2009; Japanese guidelines Hepatology Research 2014.