Kris V. Kowdley, MD Director - PowerPoint Presentation

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2. Kris V. Kowdley, MDDirectorLiver Care Network and Organ Care ResearchSwedish Medical CenterSeattle, WashingtonSeth N. Sclair, MDClinical Assistant ProfessorDivision of Gastroenterology and Liver DiseaseCase Western Reserve UniversitySchool of MedicineUniversity Hospitals Cleveland Medical Center Cleveland, OhioPresented by

3. Content AreasDiagnostic considerationsInitial treatment with ursodeoxycholic acidAssessing response to ursodeoxycholic acidObeticholic acidInvestigational treatmentsManaging symptoms and complications

4. Diagnostic ConsiderationsAutoimmune hepatitis1Primary biliary cirrhosis1Primary sclerosing cholangitis1IgG4-related disease2Drug-induced liver injuryInherited cholestasisIdiopathic ductopeniaMalignant infiltrationNonalcoholic fatty liver diseaseObstructive biliary lesionPrimary biliary cholangitisPrimary sclerosing cholangitisSarcoidosisTrivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.Joshi D, et al. Aliment Pharmacol Ther. 2014;40:1251-1261.Hirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712.Spectrum of AutoimmuneLiver Injuries1Differential for CholestaticLiver Biochemistry3

5. What Are the Diagnostic Markers in Primary Biliary Cholangitis?Primary biliary cholangitis (PBC) is the most common adult autoimmuneliver diseaseThe overwhelming majority of patients are women in middle age who have circulating antimitochondrial antibodies Cholestasis is usually reflected as a predominant rise in alkalinephosphatase levelAt presentation, most patients are largely asymptomaticOver time, however, symptoms such as pruritus and fatigue significantly impact patient quality of life

6. PBC PhenotypeTrivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth-muscle antibody; IBD, inflammatory bowel disease; MRCP, magnetic resonance cholangiography; PBC, primary biliary cholangitis.

7. Take a Good HistorySymptom burden1,2PruritusFatigueSicca syndrome: dry eyes/mouthAbdominal painArthralgiasRemember: some patients remain asymptomaticRelevant medical history1Autoimmunity (personal or family)SmokingRecurrent urinary tract infectionPruritus during pregnancyHirschfield GM, et al. Best Pract Res Clin Gastroenterol. 2011;25:701-712.Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.

8. Interpretation of AMA, ANA, and Immunoglobulin Testingin PBCAMAPositive in >90% of patients with PBC, depending on assay1In the correct context, AMA reactivity, with an elevated ALP and no significant elevation in AST, is associated with a >95% PPV of histologic PBC2ANA2 ANA immunofluorescent patterns are specific to PBC: multiple nuclear dots andperinuclear/rim-like membranous3 Automated ANA assays will likely not detect these reactivitiesLaboratories should perform immunofluorescence if ELISA-based assays for gp210 and sp100 arenot availableImmunoglobulins Elevated IgM is a sensitive but not specific characteristic of PBC1Elevated IgG is primarily observed in AIH1Trivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.Zein CO, et al. Clin Gastroenterol Hepatol. 2003;1:89-95.Zeman MV, et al. Can J Gastroenterol. 2010;24:225–231.AIH, autoimmune hepatitis; ALP, alkaline phosphatase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IgM, immunoglobulin M; PPV, positive predictive value.

9. “Overlap” or “Crossover” ScenariosAlso, varying combinations of the above, including temporal variations: consecutive vs sequential presentationsTrivedi PJ, et al. Aliment Pharmacol Ther. 2012;36:517-533.AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASMA, anti-smooth-muscle antibody; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; IgG, immunoglobulin G; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal.Positive ANA/ASMA titers and elevated IgG in AMA-positive PBCAMA-positive AIHImmunoserologic OverlapAST/ALT >5 x ULN in PBC or PSCALP >3 x ULN in AIH(GGT >5 x ULN in children)Biochemical OverlapClinical features of AIH with cholangiographic abnormalities consistent with inflammatory cholangiopathyRadiologic OverlapLymphoplasmacytic infiltrate and interface hepatitis with bile-duct lesions consistent with either PBC or PSCHistologic Overlap

10. Predictive Significance of Alkaline Phosphataseand Bilirubin ValuesLammers WJ, et al. Gastroenterology. 2014;147:1338-1349.ALP, alkaline phosphatase; ULN, upper limit of normal.ALP ≤2 x ULNALP >2 x ULN

11. Influence of PBC-Specific Antinuclear Antibodies onDisease PrognosisRetrospective/prospective Japanese cohort study to assess significance of ANAs for progression of PBC (N = 276)Prevalence of anti-gp210 in PBC = 26.1%Anti-gp210 antibodies strongest ANA predictor for progression to end-stage hepatic failureOdds ratio 33.777 (95% CI, 5.930−636.745)Frequency of death significantly higher in patients positive for anti-gp210 than negative (P = 1.3 x 10-7)Nakamura M, et al. Hepatology. 2007;45:118-127.ANA, antinuclear antibody; CI, confidence interval.

12. Influence of PBC-Specific Antinuclear Antibodies onDisease PrognosisStudy of ANA significance in Greek and Spanish patients with PBC (N = 362)Prevalence of gp210 = 10.4%Bogdanos D, et al. Hepatology. 2007;45(6):1583.ALP, alkaline phosphatase; ANA, antinuclear antibody.Baseline Levelgp210 Positivegp210 NegativeBilirubin (mg/dL)1.4 ± 0.70.8 ± 0.4ALP (U/L)895 ± 340612 ± 423

13. Autoimmune Liver Disease—Patient EvaluationGraphic courtesy of Dr. Gideon Hirschfield.AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; MRCP, magnetic resonance cholangiography; ULN, upper limit of normalCholestatic ProfileALP/GGT ; ALT/AST <5 x ULNPBC? PSC?Hepatic ProfileALT/AST ; no significant ALP AIH?Symptoms HistoryAILD is usually entertained after common liver disease(alcohol, viral, metabolic, drug-induced) is excludedDoppler ultrasoundMRI (MRCP) Serum immunoglobulinsAutoantibodiesExclusion of drug-induced liver injuryExclusion of Wilson’s diseaseUtility of liver biopsy

14. Evaluation of Patients With Cholestatic Profile*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.PBC*−ANA+**SpecificPBCNon-specific−***MRCP+/- liver biopsy if MRCP non-diagnostic+AMAUltrasound; immunoglobulins; medications; thyroid; celiac screen; lipids; bone density; Sjögren’s screenAMA, antimitochondrial antibody; ANA, antinuclear antibody; MRCP, magnetic resonance cholangiography; PBC, primary biliary cholangitis.

15. Overall Management of PBCStart ursodeoxycholic acid (UDCA) and assess responseDetermine stage of diseaseInstitute HCC and variceal screening for cirrhoticsAssess and addressOsteoporosisFat-soluble vitamin deficiencyFatiguePruritusSicca syndromeBe aware of extrahepatic manifestationsCommon: thyroid disease, renal disease, gallstones, arthritisUncommon: lichen planus, ulcerative colitis, anemiasLindor KD, et al. Hepatology. 2009;50:291-308.HCC, hepatocellular carcinoma; PBC, primary biliary cirrhosis.

16. UDCA—Current Standard-of-Care for PrimaryBiliary CholangitisUDCA is 1 of 2 therapies approved by FDA for PBCObeticholic acid approved in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCARecommended adult dosage is 13−15 mg/kg/dayTypically administered in 2 divided dosesLindor KD, et al. Hepatology. 2009;50:291-308.FDA, US Food and Drug Administration; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid or ursodiol.

17. Medical Approaches to PBC: UDCAPoupon RE, et al. Gastroenterology. 1997; 113:884-890.Survival Free of Transplantation (Combined Data)UDCAPlacebo  UDCA27323611627522087Probability of Survival (%)1.00.502448MonthsUDCAPlacebo  UDCA

18. Effect of UDCA on Mortality and Liver Transplantation RiskLong-term UDCA reduces deathand OLT1,2UDCA normalizes survival rates when given at early stages of PBC3However, survival in patients with late-stage disease is reduced3Poupon RE, et al. N Engl J Med. 1994;330:1342-1347.Poupon RE, et al. Gastroenterology. 1997;113:884-890.Corpechot C, et al. Gastroenterology. 2005;128:297-303.CI, confidence interval; OLT, orthotopic liver transplantation; PBC, primary biliary cholangitis; RR, relative risk; UDCA, ursodeoxycholic acid or ursodiol.EndpointRR (95% CI)P valueDeath or OLT10.32(0.14−0.74).005OLT-free survival21.92(1.30−2.82)<.001

19. What Are Appropriate Baseline Factors and Treatment Endpoints to Assess Risk of Progression in PBC?High confidence and applicabilityBaseline and on-treatment ALP, bilirubinBaseline and on-treatment AST/platelet ratioOn-treatment biochemical response criteriaIntermediate confidence and applicabilityPresenting ageBaseline disease-specific ANABaseline and on-treatment transient elastographyIndeterminate confidence and applicabilityGender and baseline symptom profileBaseline and on-treatment novel histologic scoresOn-treatment direct portal pressure measurementTrivedi PJ, et al. Hepatology. 2016;63(2):644-659.ALP, alkaline phosphatase; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELF, enhanced liver fibrosis; PBC, primary biliary cirrhosis.

20. Established Response Criteria Models for UDCAParés A, et al. Gastroenterology. 2006;130:715-720.Corpechot C, et al. Hepatology. 2008;48:871-877.Kuiper EM, et al. Gastroenterology. 2009;136:1281-1287.Kumagi T, et al. Am J Gastroenterol. 2010;105:2186-2194.ALP, alkaline phosphatase; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid or ursodiol; ULN, upper limit of normal.ALP decreased by >40% from baseline or normalized after1 year UDCABarcelona1(2006)All 3 of the following: ALP ≤3 x ULN; AST ≤2 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA Paris-I2(2008)Albumin and bilirubin normalization when 1 or both were abnormal at baseline; albumin OR bilirubin normalization when both were abnormal at baseline after 1 year UDCARotterdam3(2009)ALP <1.67 x ULN after 2 years UDCAToronto4(2010)

21. Modifications of Biochemical Response Criteria ModelsCorpechot C. J Hepatol. 2011;55:1361-1367.Zhang LN, et al. Hepatology. 2013;58:264-272.Barcelona, Paris-I, or Toronto criteria met at 6 months UDCAAll 3 of the following: ALP ≤1.5 x ULN; AST ≤1.5 x ULN; and bilirubin ≤1 mg/dL after 1 year UDCA Paris-II1(2011)Early Biochemical Response2(2013)ALP, alkaline phosphatase; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid or ursodiol; ULN, upper limit of normal.

22. GLOBE Score3(2015)UK-PBC Risk Score2(2015)Optimized Response Criteria ModelsTrivedi PJ, et al. J Hepatol. 2014;60:1249-1258.Carbone M, et al. Hepatology. 2016;63(3):930-950.Lammers WJ, et al. Gastroenterology. 2015;149(7):1804-1812.ALP, alkaline phosphatase; ALT, alanine aminotransferase; APRI, AST/platelet ratio index; AST, aspartate aminotransferase; UDCA, ursodeoxycholic acid or ursodiol.Biochemical response (Barcelona, Paris-I/II, or Toronto) and APRI ≤0.54 after 1 year UDCABiochemical + APRI1(2014) Prognostic index comprising baseline albumin and platelet count, plus bilirubin, ALT or AST, and ALP after 1 year UDCA Prognostic index comprising baseline age, and bilirubin, ALP, albumin,and platelet count after 1 year UDCA

23. GLOBE Score CalculationScore comprisingage at start of UDCAbeta coefficients of identified variablesnatural logarithm transformation of BILI, ALP, ALB, and PLT after 1 yearof UDCAbaseline survival estimateLammers WJ, et al. Gastroenterology. 2015;149(7):1804-1812.ALB, albumin; ALP, alkaline phosphatase; BILI, bilirubin, LLN, lower limit of normal; NL, normal logarithm; PLT, platelet count; ULN, upper limit of normal.Online calculator available at: http://www.globalpbc.com/globe.(0.044378 * age at start of UDCA therapy + 0.93982 * NL(BILIxULN) at 1 year)) + (0.335648 * NL(ALPxULN at 1 year))—2.266708 * ALBxLLN at 1 year—0.002581 * PLT at 1 year) + 1.216865

24. GLOBE Score—Transplant-Free Survival ThresholdLammers WJ, et al. Gastroenterology. 2015;149(7):1804-1812.Derivation cohortTransplant-Free Survival Rates for Patients with GLOBE Score >0.30Transplant-Free Survival Rates for Patients with GLOBE Score ≤0.30

25. PBC Follow-up Algorithm—UDCA Nonrespondersat 12 Months*Trivedi PJ, et al. Hepatology. 2016;63(2):644-659.ALT/AST >5 x ULN?YesNoGenderManWomanConsider need for second-lineagent/clinical trialsLiver biopsy: assess severity of interface hepatitis and consider “overlap” syndromeConsider HCC surveillanceIf cirrhotic, considerHCC surveillanceALT, alanine aminotransferase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid or ursodiol; ULN, upper limit of normal.*Consider earlier assessment of response for patients with phenotype associated with nonresponse: baseline LSM ≥9 kPa, presenting age <50 years, oranti-gp210 positive

26. APRI, AST/platelet ratio index; HCC, hepatocellular carcinoma; LSM, liver stiffness measurement; PBC, primary biliary cirrhosis;UDCA, ursodeoxycholic acid or ursodiol.PBC Follow-up Algorithm—UDCA Responders at 12 Months*Trivedi PJ, et al. Hepatology. 2016;63(2):644-659.GenderManWomanAPRI >0.54If cirrhotic, considerHCC surveillanceYesNoConsider need for second-lineagent/clinical trialsFollow-up with goals of sustained response, nonprogressive LSM, and symptom relief*Consider earlier assessment of response for patients with phenotype associated with nonresponse: baseline LSM ≥9 kPa, presenting age <50 years, oranti-gp210 positive

27. The Other Point of View—Findings From Cochrane ReviewMeta-analysis of 16 trialsNo significant differences in effect between UDCA and placebo or“no intervention” UDCA showed beneficial effect on liver biochemistry measures and histologic progressionRudic JS, et al. Cochrane Database Syst Rev. 2012;CD000551.EndpointRR (95% CI)All-cause mortality0.97(0.67−1.42)All-cause mortality or liver transplantation0.96(0.74−1.25)

28. Reported Incidence of UDCA Treatment FailurePells G, et al. J Hepatol. 2013;59:67-73.Corpechot C, et al. J Hepatol. 2011;55:1361-1367.Kuiper EM, et al. Gastroenterology. 2009;136:1281-1287.Corpechot C, et al. Hepatology. 2008;48:871-877.*Depending on criteria used.StudyTreatment Failure (%)Pells et al, 20131 (UK-PBC group)60% of patients presenting at age <40 years10% of patients presenting at age >70 yearsCorpechot et al, 2011213%–37%*Kuiper et al, 2009334%–38%* Corpechot et al, 2008435%–39%*

29. What Can Clinicians Do Next for Patients With Suboptimal Response to UDCA?Query patient for adherence1Barriers to adherence: weight gain, loose stools, hair lossConfirm UDCA dosage 13–15 mg/kg1 Doubling UDCA dose has not shown benefit2Check for comorbid liver disease1Avoid coadministration of bile acid sequestrant1Second-line therapy with obeticholic acidLindor KD, et al. Hepatology. 2009;50:291-308.Angulo P, et al. Am J Gastroenterol. 2001;96:3152-3157.

30. Bile Acids as Enterohepatic HormonesGraphic courtesy of Michael Trauner, MD.FXR, farnesoid X receptor (nuclear bile acid receptor).GutFecesCholesterolBile AcidsBile MicrobiomeFXRFibroblast Growth Factor-19FXRFXR

31. Farnesoid X Receptor SignalingNeuschwander-Tetri BA. Curr Gastroenterol Rep. 2012;14:55-62.BSEP, bile salt export pump; FXR, farnesoid X receptor; MRP 2/3/4, multidrug resistant protein 2/3/4; NTCP, sodium/taurocholate cotransporting polypeptide;OATP, organic anion transporting polypeptide; OST α/β, organic soluble transporter α/β.Bile Acids (Primary ligands for FXR)↓ Bile Acid Synthesis and Uptake↑ Gene Expression(BSEP, MDR3, MRP 2/3/4, OST α/β)↓ Gene Expression(CYP7A1, NTCP, OATP)FXR (Hepatocytes, biliary epithelium, small bowel enterocytes, renal tubular cells, adrenal cells, adipocytes,beta cells)BindingDirect EffectsIndirect Effects↑ Bile Acid Efflux

32. OCA: Phase 3 POISE Trial—DesignWith permission from Nevens F, et al. Paper presented at: 49th EASL; April 9-13, 2014; London, UK. Abstract 0168. ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid or ursodiol; ULN, upper limit of normal; WNL, within normal limits.Positive response: ALP <1.67 x ULN and bilirubin WNL, and ≥15% ALP reductionScreening1−8 weeks M9Continue prestudy UDCA OCA 10 mg (n = 73)Placebo (n = 73)12 Months M12 M6W20OCA 5 mg M3OCA 10 mg (n = 33)Entry: ALP ≥1.67 x ULN and/or bilirubin >ULN but <2 x ULNOCA 5 mg (n = 36)

33. OCA: Phase 3 POISE Trial—Primary EndpointNevens F, et al for the POISE Study Group. N Engl J Med. 2016;375(7):631-643.Primary endpoint = Proportion of subjects achieving ALP <1.67 x ULN with bilirubin ≤ULN and ≥15% reduction in ALP*P <.0001 vs placeboALP, alkaline phosphatase; OCA, obeticholic acid; ULN, upper limit of normal.

34. OCA: Phase 3 POISE Trial—Change in Direct BilirubinWith permission from Nevens F, et al. Paper presented at: 49th EASL; April 9-13, 2014; London, UK. Abstract 0168. LS, least squares; OCA, obeticholic acid; SE, standard error.

35. OCA International Trials—Subjects Achieving Composite EndpointKowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.Subjects (%)3 months3 months3 months6 months12 monthsPhase IIOCA Phase IIOCA + UDCA Phase IIIOCA ± UDCA Primary Endpoint: Composite of ALP <1.67 x ULN, ≥15% ALP reduction, normal bilirubinPlacebo (n = 134)OCA Titrated (n = 70)OCA 10 mg (n = 131)*P <.05**P <.01***P <.0001 ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid or ursodiol; ULN, upper limit of normal.

36. OCA International Trials—Change in Alkaline PhosphataseKowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657.Graphic courtesy of Kris V. Kowdley, MD.Phase IIOCA Phase IIUDCA +OCA Phase IIIUDCA ± OCA ALP Change from Baseline (U/N)3 months3 months3 months6 months***P<.0001; values are least squares mean ± standard error Placebo (n = 134)OCA Titrated (n = 70)OCA 10 mg (n = 131)ALP, alkaline phosphatase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid or ursodiol.

37. OCA International Trials—Changes in Serum Liver Biochemical TestsKowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.ALT (U/L)AST (U/L)P IIOCAP IIUDCA + OCAP III± UDCA + OCAChange from Baseline3 mo3 mo3 mo6 mo12 mo3 mo3 mo3 mo6 mo12 mo*P<.05, **P<.01, ***P<.0001; values are least squares mean ± standard error.Placebo (n = 134)OCA Titrated (n = 70)OCA 10 mg (n = 131)P IIOCAP IIUDCA + OCAP III± UDCA + OCAALT, alanine aminotransferase; AST, aspartate aminotransferase; OCA, obeticholic acid; UDCA, ursodeoxycholic acid or ursodiol.

38. OCA International Trials—Absolute Change in Lipid Levels From BaselineTreatment with OCA has been associated with increase in LDL-C and decrease in HDL-C and triglyceridesClinical significance is unclearAbsolute differences are smallPatients had high HDL-C at baseline, typical for PBC patientsKowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657. Graphic courtesy of Kris V. Kowdley, MD.C, cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OCA, obeticholic acid; UDCA, ursodeoxycholic acid or ursodiol.Phase II OCAPhase II OCA + UDCAPhase IIIOCA ± UDCAPlacebo(n = 23)OCA10 mg(n = 20)Placebo(n = 38)OCA 10 mg(n = 38)Placebo(n = 73)Titration OCA (n = 70)OCA 10 mg(n = 73)LDL-C (mg/dL) -3.1 3.9 3.5 9.7 1.4 3.5 -1.9HDL-C (mg/dL) -1.5 -12.7 3.5 -9.7 -3.5 -11.2 -16.6Triglyceride (mg/dL) -1.8 -2.7 -8.9 -2.7 4.4 -5.3 -14.2

39. OCA International Trials—Summary of Adverse Events≥1 Treatment-emergent serious adverse eventOCA 10 mg (6%)None drug-relatedPlacebo (4%)Pruritus was the most common adverse event reported across alltreatment groupsMost pruritus treatment-emergent adverse events were mild or moderate in severityUptitrating OCA dose from 5 mg to 10 mg at 6 months mitigated the incidence of pruritus and improved tolerability as assessed by patient discontinuation rate dueto pruritus1% in titration group9% in 10-mg groupKowdley K, et al. Paper presented at: DDW 2015; May 16-19, 2015; Washington, DC. Abstract 657.OCA, obeticholic acid.

40. OCA: Drug InteractionsBile acid binding resinsTake OCA >4 hours before or after resinWarfarin↓ International normalized ratioCYP1A2 substrates with narrow therapeutic index↓ Clearance of CYP1A2 substratesOcaliva [package insert]. New York, NY: Intercept Pharmaceuticals, Inc.; 2016.CYP1A2, cytochrome P450 1A2 enzyme; OCA, obeticholic acid.

41. Peroxisome Proliferator-Activated Receptor Alpha ActivityRegulates bile acid synthesis and detoxificationModulates phospholipid secretion, which helps protect bile duct epithelium by formation of micellesZollner G, et al. Br J Pharmacol. 2009;156:7-27.

42. Fibroblast Growth Factor 19 SignalingFibroblast growth factor 19 (FGF19) is an endocrine hormonethat helps regulate bile acids, and carbohydrate, lipid, andenergy metabolism FGF19 also has a role in regulating hepatic cell proliferationFGF19-FGFR4 signaling is associated with hepatocellular tumorigenesisAn engineered FGF19 variant has been shown to be capable of targeting the bile acid homeostasis function, but not the proliferative functionLuo J, et al. Sci Transl Med. 2014;6(247):247ra100.

43. Drugs in Phase 2/3 Testing for PBCTarget/ClassDrugPhasePeroxisome proliferator-activated receptor alpha agonistBezafibrate3, ongoing Fenofibrate2Fibroblast growth factor 19 analogNGM2822

44. Bezafibrate + UDCA—Long-term Outcome in UDCA Nonresponders With DyslipidemiaProspective, randomized, controlled, multicenter study (N = 27)Continued administration of UDCA vs bezafibrate add-on to UDCA after ≥24 weeks; therapy continued through 8 yearsPrimary endpointsALP levelMayo risk score Total bilirubin, AST, albuminOther endpointsOverall survivalHCC incidenceCreatinine—safety endpointHosonuma K, et al. Am J Gastroenterol. 2015;110:423-431.ALP, alkaline phosphatase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid or ursodiol.

45. Bezafibrate + UDCA—Key Long-term Outcomes at 8 YearsMayo risk score (bezafibrate + UDCA vs UDCA)0.91 vs 1.42 (P <.05)Mortality rate and incidence of HCC were not significantly different between the 2 groupsCreatinine levels at 8 years (bezafibrate + UDCA vs UDCA)0.94 vs 0.56 mg/dL (P <.05)“We should pay close attention to adverse events during this long-term combination therapy”Hosonuma K, et al. Am J Gastroenterol. 2015;110:423-431.HCC, hepatocellular carcinoma; UDCA, ursodeoxycholic acid or ursodiol.

46. Fenofibrate—Phase 2 Findings in Patients With PBC and Incomplete Response to UDCAOpen-label study (n = 20)1ALP levels decreased significantly1Rebound in ALP levels occurred following fenofibrate discontinuation1 Fenofibrate is contraindicated in patientswith hepatic or severe renal dysfunction, including PBC2Levy C, et al. Aliment Pharmacol Ther. 2011;33:235-242.Tricor [PI]. North Chicago, IL: AbbVie Inc.; 2016.Comparison of ALP at Baseline andOn-Treatment Week 48ALP, alkaline phosphatase; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid or ursodiol.

47. NGM282—Phase 2 Findings of Engineered VariantFGF19 in PBCDouble-blind, placebo-controlled trial in patients with PBC and incomplete responseto UDCA (n = 45)Preliminary findingsALP, ALT, and AST levels decreased significantlyPruritus not exacerbatedAEs mild; most common being headache andlower GI symptomsGlobe Newswire. March 24, 2015. http://globenewswire.com/news-release/2015/03/24/718185/10126091/en/NGM-Biopharmaceuticals-Announces-Positive-Phase-2-Clinical-Data-in-Primary-Biliary-Cirrhosis-Patients-for-NGM282-a-First-in-Class-Investigational-Medicine.html.Comparison of ALP Reduction from Baseline at On-Treatment Day 28P = .009 vs placeboP = .003 vs placeboALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid or ursodiol.

48. Fatigue in Patients With PBCCommon at all stages of PBCAutonomic dysfunctionAccelerated reduction in muscle functionMitochondrial dysfunction?Griffiths L, et al. Dig Dis. 2014;32:615-625.PBC, primary biliary cholangitis.

49. Reduction in Fatigue Score After Modafinil for 12 Weeks in Patients With PBCSilveira M, et al. Hepatology. 2011;54(4 suppl):1211A-1212A.Change from BaselineModafinil 200 mg(n = 20)Placebo(n = 20)P ValueFisk Fatigue Impact Score-1.5-3.50.91Fatigue Severity Score-13-30.36PBC-40 fatigue domain-8-40.87PBC, primary biliary cholangitis

50. Pruritus in Patients With PBCOccurs early in cholestatic diseases,1 later in hepatocellular diseasesLocalized vs generalizedPalms and solesNo primary rash1Exacerbated by PressureHeat1 Circadian rhythm (worse in evenings)1,2Periodic exacerbations and improvements2Rishe E, et al. Acta Derm Venereol. 2008;88:34-37.Mayo MJ, et al. Primary biliary cirrhosis. In: Yamada T, ed. Textbook of Gastroenterology, 4th ed. Oxford, UK: Lippincott Williams & Wilkins; 2003.PBC, primary biliary cholangitis

51. Behavioral Modifications for Pruritus in Patients With PBCWear loose, absorbent clothesSeek cool (not dry) environmentUse cool emollients frequentlyAvoid pruritogenic medications (opioids)Trim nailsLimit sun/ultraviolet exposurePBC, primary biliary cholangitis.

52. Management of Pruritus—EASL GuidelinesEASL. J Hepatol. 2009;51:237-267.EASL, European Association for the Study of the Liver; EOW, every other week.Cholestyramine up to 4g x 4/dRifampicin 150 mg/dIncrease dose EOW up to 600 mg/dNaltrexone up to 50 mg/dSertraline up to 100 mg/dConsider experimental approach Consider transplantation

53. Sicca Syndrome Management—Dry MouthProfessional dental cleaning every6 monthsSugar-free candy/gumRinsing with waterSaliva substitutes Pilocarpine or cevimeline if refractory to all of the aboveLindor KD, et al. Hepatology. 2009;50:291-308. Graphic courtesy of National Institutes of Health.

54. Sicca Syndrome Management—Dry EyesArtificial tearsPilocarpine or cevimeline if refractory to artificial tearsCyclosporine eye drops if refractory to all of the above Tear duct plugsLindor KD, et al. Hepatology. 2009;50:291-308. Graphic courtesy of National Institutes of Health.

55. Surveillance for and Managing Risk of Osteoporosis in Patients With PBC1. Lindor KD, et al. Hepatology. 2009;50:291-308. 2. Cosman F, et al. Osteoporos Int. 2014;25:2359-2381. 3. Carmel AS, et al. Osteoporos Int. 2012;23:2479-2487. 4. Diab DL, et al. Ther Adv Musculoskelet Dis. 2013;5:107-111. 5. Fosamax [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.;2016.*Total from diet plus supplement.AASLD, American Association for the Study of Liver Diseases; DEXA, dual-energy X-ray absorptiometry; EGD, esophagogastroduodenoscopy; GERD, gastroesophageal reflux disease; PBC, primary biliary cholangitis; WHO, World Health Organization.AASLD Guidelines1SavvyPatientSavvy ClinicianDEXA every 2–3 yRadiation?WHO FRAXAlgorithm2Calcium 1000–1500 mg/d*Cardiovascular risk?Calcium 1200 mg/d*2Vitamin D 1000 IU/d*Vitamin D level yearlyEffective?Necessary?Vitamin D≥33 ng/mL3Alendronate 70 mg/wk if osteopenicJaw necrosis?Esophageal cancer?3–5 y on (or longer based on risk assessment), 1–2 y off4;EGD if GERD5

56. Rate of Nonresponse to Bisphosphonate Stratified by25-Hydroxy Vitamin D LevelReal-world setting, postmenopausal women with low BMD (N = 210)Patients with a mean 25(OH)D ≥33 ng/mL (predetermined cutoff level) were approximately 4.5-fold more likely to achieve favorable response (P <.0001)Carmel AS, et al. Osteoporos Int. 2012;23:2479-2487..25(OH)D, 25-hydroxy vitamin D; BMD, bone mineral density.25(OH)D Serum ConcentrationNonresponse<30 ng/mL79% (52/66)≥30 to <40 ng/mL50% (34/68)≥40 ng/mL33% (25/76)

57. Surveillance for Fat-Soluble Vitamin Deficiencies in Patients With PBCDecreased bile acid secretion may lead to impaired absorption of fat-soluble vitamins ADEK1Monitoring guidelinesAASLD: no specific recommendation2Medicare: no more than once annually3Reasonable practice: annual vitamin A, D, PT (surrogate marker for K)May need to increase frequency of surveillance with new bile acid pool-lowering therapiesPhillips JR, et al. Am J Gastroenterol. 2001;96:2745-2750.Lindor KD, et al. Hepatology. 2009;50:291-308. https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=29510&ContrId=269&ver=38&ContrVer=1&Date=08%2f04%2f2014&DocID=L29510&bc=AAAAAAgAAAAAAA%3d%3d&AASLD, American Association for the Study of Liver Diseases; ADEK, vitamins A, D, E, and K; PBC, primary biliary cholangitis; PT, prothrombin time.VitaminProportion of PBC Patients with Deficiency1(N = 180)A33.5%D13.2%E1.9%K7.8%

58. Surveillance for Hepatocellular Carcinoma in PatientsWith PBCAmerican Association for the Study of Liver DiseasePatients with cirrhosis should be screened every 6−12 months using ultrasound with(or without) alpha fetoprotein1,2Beware the older male nonresponder, even if not cirrhotic!3Lindor KD, et al. Hepatology. 2009;50:291-308.Bruix J, et al. Hepatology. 2011;53(3):1020-1022.Trivedi PJ, et al. Gut. 2016;65(2):321-329.

59. Factors Associated With HCC Risk in UDCA-Treated PBC Patients—Multivariate Analysis (N = 4565)Trivedi PJ, et al. Gut. 2016;65(2):321-329.3.42 (P <.0001) Paris-I not fulfilled2.41 (P <.0001) Male1.42 (P <.0001) Thrombocytopenia(per 50 x 103/mm3 decline)1.31 (P =.009)Age (per 10 years)HCC, hepatocellular carcinoma; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid or ursodiol.

60. Surveillance for VaricesPatients with cirrhosis should be screened every 1−3 yearsusing esophagogastroduodenoscopy1Interval based on decompensation2Varices with bleeding may occur in noncirrhotic PBC patients3Lindor KD, et al. Hepatology. 2009;50:291-308.Garcia-Tsao G, et al. Hepatology. 2007;46:922-938.Vlachogiannakos J, et al. Eur J Gastroenterol Hepatol. 2009;21:701-707.

61. Effectiveness of Screening for Esophageal Varices in Patients With Early-Stage PBCRetrospective chart review of PBC patients (N = 325)8/127 (6%) had esophageal varices when stage I or IIAli AH, et al. J Clin Gastroenterol. 2011;45(7):e66-e71.ALB, albumin; BILI, bilirubin; MABPT, Male sex, low ALB (<3.5 g/dL), elevated BILII level (≥1.2 mg/dL), and/or prolonged PT (≥12.9 s); PBC, primary biliary cholangitis;PT, prothrombin time.AASLDLevy et alAngulo et alMABPTCriteriaCirrhotic (stage IV) PBCMayo risk score ≥4.5 and/or platelets ≤140,000Mayo risk score ≥4Male sex,ALB <3.5 g/dL, BILI ≥1.2 mg/dL, and/or PT ≥12.9 secSensitivity53%90%93%95%Specificity85%56%32%47%

62. Be Aware of Extrahepatic AssociationsMayo MJ, et al. Primary biliary cirrhosis. In: Yamada T, ed. Textbook of Gastroenterology, 4th ed. Oxford, UK: Lippincott Williams & Wilkins; 2003.Human body graphic from: Lambert TS. Human Anatomy, Physiology and Hygiene. Hartford, CT: Brockett, Hutchinson & Co.;1854.DLC02, diffusing capacity for carbon dioxide.Arthropathy 4%–38%Rheumatoid arthritis 3%–26%Ulcerative colitis0.5%–1%Gallstones30%–50%Lichen planus 0.5%–6%Psoriasis 1%–13%Low DLC02 40%–50%Bacteriuria11%–35%Renal tubular acidosis20%–33%Raynaud’s7%–14%Autoimmune anemias1%–2%CREST, including esophageal dysmotility3%–6%Hypothyroidism 11%–32%Graves’ disease 3%–6%