Diagnosis and Management of PBC Cynthia Levy, MD, FAASLD University of Miami Miller School of Medicine Miami, Florida 1
Primary Biliary Cholangitis (PBC) Chronic cholestatic liver disease Autoimmune in nature Inflammation and destruction of small interlobular bile ducts Affects predominantly middle-aged females Rising incidence and prevalence Carey E, et al. Lancet. 2015.
PBC Diagnosis Unexplained Elevation of ALP 1.5x ULN Positive antimitochondrial antibody Non-suppurative destructive cholangitis on histology Two out of these 3 criteria are required for the diagnosis of PBC
Variant Syndromes AMA-negative PBC 50% will have antinuclear antibodies (ANA) PBC-specific ANA anti gp210, anti sp100 Same clinical presentation Overlap syndrome with autoimmune hepatitis Consider when ALP: transaminase ratio <1.5, IgG is elevated and smooth muscle antibodies are present with titer >1:80 Premature Ductopenic Variant 5-10% Very rapid onset of ductopenia, severe icteric cholestasis and fast progression towards cirrhosis
Clinical Features Vary Greatly Between Patients o Fatigue 1,2 o Pruritus 1,2 o Concurrent autoimmune diseases 1,2 o Reduced bone density 1,2 o Hypercholesterolemia 1,2 o Xanthoma and Xanthelasma 2,3 PBC can range from asymptomatic and slowly progressive to symptomatic and rapidly evolving. 1 1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609; 2. Carey EJ, et al. Lancet. 2015;386(10003):1565-1575; 3. Lindor KD, et al. Hepatology. 2009;50(1):291-308.
First Line Therapy: Ursodeoxycholic Acid o Orally administered, naturally occurring, hydrophilic secondary bile acid o Dose: 13-15 mg/kg/day o Improvement in liver tests may be seen within a few weeks and 90% of the improvement usually occurs within 6-9 months Lindor K, et al. Hepatology. 2009;50:291-308.
Therapeutic Effects UDCA Improves TB, ALP, GGT, AST and ALT Improves survival free of liver transplantation Improves cholesterol, IgM UDCA 13-15 mg/kg/day 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;2011:738-753. Graphic courtesy of Dr. Cynthia Levy.
Combined Effect of TB and ALP on Transplant-Free Survival Transplant-Free Survival (%) 100 80 60 40 20 0 0 a-b: P.001 c-d: P.001 ALP and TB at 1 Year Follow-up 5 10 15 Time (Years) a 2112 1482 887 504 b 681 489 337 228 c 271 193 153 137 d 400 345 302 283 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 Lammers, et al. Gastroenterology. 2014; 147:1338-1349.
Hazard Ratio for LT/Death According to ALP A Hazard Ratio for Liver Transplantation or Death 5 4 3 2 1 At Baseline* Hazard Ratio for Liver Transplantation or Death 5 4 3 2 1 At One Year Follow-up* 0 0 1 2 3 4 Thresholds (xuln) for Alkaline 5 Phosphatase Values 0 0 1 2 3 4 5 Thresholds (xuln) for Alkaline Phosphatase Values *3710/4635 patients were included for this analysis Lammers, et al. Gastro. 2014.
New Targets for Treatment of Cholestatic Diseases PPAR + MDR3 Trauner M. Hepatology. 2017.
OCA in Patients with PBC: POISE Study Design Placebo (n=73) Screening OCA 5 mg OCA 10 mg (n=73) Titrate to OCA 10 mg (n=33) Remain at OCA 5 mg (n=36) OCA 5 mg OCA 5-10 mg dose adjustment option 0 3 6 9 12 60 Months in Open-Label Phase 0 W2 M3 M6 M9 M12 Modified from Nevens F, et al. N Engl J Med. 2016;375:631-643.
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 Patients with Response (%) 80 60 40 20 0 0.5 3 6 9 12 3 6 9 12 Month in Double-Blind Phase Month in Open-Label Phase No. of Patients Placebo Obeticholic acid, 5 10 mg Obeticholic acid, 0 mg 73 70 73 73 70 73 73 70 73 73 70 73 73 70 73 64 63 64 60 62 59 59 62 61 59 60 59 Nevens F, et al. N Engl J Med. 2016;375:631-643.
Other Effects of OCA During POISE Trial Significant drop in ALP, AST, ALT, GGT, TB Significant reduction in inflammatory markers Reduction in HDL-cholesterol (20% in 10mg/day, 9% in 5-10 mg/day) No change in liver stiffness scores (50% had LS measured) Significant reduction in serum bile acid levels and increase in FGF 19 levels Main side effect: Pruritus è mitigated by starting at 5 mg/day and only titrating up IF well tolerated Nevens F, et al. NEJM. 2016.
Obeticholic Acid Is Approved: o In combination with UDCA for patients with PBC who have been treated with UDCA for > 1 year and have incomplete response o As monotherapy for patients with PBC who are intolerant to UDCA Improvement in survival free of liver transplantation has not yet been demonstrated. Conditional approval granted
Cumulative Incidence of Advanced Stages of PBC Cumulative Incidences 20% 15% 10% 5% 0% 20% A. Decompensated Cirrhosis UDCA OCA plus UDCA 1 5 10 15 Year C. Liver Transplants Cumulative Incidences 20% 15% 10% 5% 0% 20% B. Hepatocellular Carcinoma UDCA OCA plus UDCA 1 5 10 15 Year D. Liver-Related Deaths In patients with inadequate response to UDCA, OCA decreased 15-yr cumulative incidences of: Decompensated cirrhosis from 12.2% to 4.5% HCC from 9.1% to 4% Cumulative Incidences 15% 10% 5% 0% UDCA OCA plus UDCA 1 5 10 15 Year Cumulative Incidences 15% 10% 5% 0% UDCA OCA plus UDCA 1 5 10 15 Year OLT from 4.5% to 1.2% Liver-related deaths from 16.2% to 5.7% Samur S, et al. Hepatology. 2017.
Cost-Effectiveness Study of OCA in PBC o Treating 10,000 patients would prevent: 770 cases of decompensated cirrhosis,510 cases of HCC, 330 OLTs and 1050 liver-related deaths o Lifetime treatment cost of PBC increased from $63,100 to $902,200 (1,330%) with addition of OCA to UDCA o ICER: $473,400/QALY è NOT cost-effective o Recommended price reduction: 73% Samur S, et al. Hepatology. 2017.
WHO SHOULD RECEIVE ADJUVANT THERAPY? WHO IS AT RISK FOR PROGRESSION?
PBC - Risk Stratification Pre-Treatment After 1 year of treatment with UDCA Staging: Transient elastography, histology, enhanced liver fibrosis score Age, gender, ethnicity Anti gp 210, anti-centromere Variant syndromes Response to UDCA ALP, TB Mathematical models: Globe PBC, UK PBC Levy C. Hepatology. 2017.
Value of Liver Stiffness in PBC A Survival Without Adverse Outcome 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival According to Baseline LSM 9.6 kpa >9.6 kpa 0 1 2 3 4 5 6 7 Total Follow-up (Years) B Survival Without Adverse Outcome 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival According to LSM/ t 2.1 kpa/yr >2.1 kpa/yr 0 1 2 3 4 5 6 Extended Follow-up (Years) -LS > 9.6 at baseline associated with 5x increase in risk of adverse outcomes -LS increase >2.1 kpa/year associated with 8x increase in risk of adverse outcomes Corpechot, et al. Hepatology. 2012.
Novel Therapies Under Evaluation for PBC Compound NCT Mechanism of Action Status Bezafibrate Fenofibrate NCT01654731 NCT02823353 Pan PPAR agonist PPAR alpha agonist Phase 3, Europe has results Phase 2, China NGM 282 NCT02026401 FGF 19 analog Phase 2, has results LJN452 NCT02516605 FXR agonist Phase 2, recruiting MBX-8025 NCT02955602 PPAR delta agonist Phase 2, recruiting FFP104 NCT02193360 CD40 Inhibitor Phase 1/2 - Europe Abatacept NCT02078882 Inhibits T cell activation Phase 4, ongoing LUM001 NCT01904058 ASBT inhibitor Phase 2, complete; primary endpoint: itching GS9674 NCT02943447 FXR agonist Phase 2, recruiting GSK 672 NCT02966834 IBAT inhibitor Phase 2, recruiting; primary endpoint: itching Genfit PPAR delta agonist Phase 2, not yet recruiting
Bezafibrate+UDCA vs. Placebo+UDCA o 100 patients with incomplete response to UDCA o Randomized to BZF 400 mg/day or placebo, for 2 years o Primary endpoint* at 2 years: 30% BZF vs. 0% Placebo o Itch score, LSM and ELF all improved in BZF group 67% 70% 60% 50% 40% 30% 20% 10% 0% 0% normalization ALP BZF Placebo Corpechot C, et al. LB-4195, EASL. 2017.
Summary: Updated Management Strategy Imaging & Labs Pruritus Assess symptoms Fatigue Baseline Evaluation Staging* Sicca Syndrome New Diagnosis Initiate PBC-specific therapy DEXA UDCA 13-15 mg/kg/day Clinical evaluation Cirrhosis? MRS > 4.1? Thrombocytopenia EGD; HCC surveillance Long-term monitoring Biochemistries Risk stratification after 1 year of therapy Evaluate need for adjuvant therapy Transient elastography Approved: Ocaliva Off label: Fibrates, budesonide