Advances in Primary Biliary Cholangitis ... Primary Biliary Cholangitis (PBC)...

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  • New Management Strategies in Primary Biliary Cholangitis

    Cynthia Levy, MD, FAASLD Professor of Medicine

    Arthur Hertz Chair in Liver Diseases University of Miami

  • 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

  • Primary Biliary Cholangitis: 2 out of 3 needed

    Chronic unexplained cholestasis

    Positive anti-mitochondrial antibody or PBC-specific anti-nuclear antibody

    Non suppurative destructive cholangitis on histology

    Lindor K et al. Hepatology 2019

    AMA (+) in general population 1:1000

    Prevalence of PBC 0.4:1000

  • First Line Therapy: UDCA

    UDCA 13- 15

    mg/kg/day

    Improves TB, ALP,

    GGT, AST and ALT

    Improves cholesterol,

    IgM

    Delays histological progression

    Delays development of esophageal

    varices

    Improves survival free of

    liver transplantation

    Levy C and Lindor KD. In: Zakim and Boyer's Hepatology: A Textbook of Liver Disease. Elsevier Inc;2011:738-753.

    According to FOLD- PBC, of 3488 patients with PBC, only 70% had been prescribed

    UDCA.

  • Primary Biliary Cholangitis: Transplant-Free Survival

    Lammers WJ et al. Gastroenterology 2014

    5 years 15 years

    Chart1

    5-year 5-year

    10-year 10-year

    15-year 15-year

    10 years

    UDCA-treated

    Untreated

    90

    79

    78

    59

    66

    32

    Sheet1

    UDCA-treated Untreated

    5-year 90 79

    10-year 78 59

    15-year 66 32

  • APPROXIMATELY 40% OF PATIENTS WITH PBC WILL NOT HAVE COMPLETE BIOCHEMICAL RESPONSE TO UDCA

    EASL clinical practice guidelines J Hepatol 2017; AASLD practice guidance 2019

  • Risk Stratification

    Baseline 1-year after treatment is

    initiated

    Biochemistries; Modeling Liver stiffness

  • HIGH RISK FOR PROGRESSION Baseline factors

    Younger than 45

    Male gender

    Elevation total

    bilirubin, lower

    albumin

    Presence of gp-210,

    anti- centromere

    APRI Liver

    stiffness > 9.6 kPa

  • Binary definitions Time (months) Treatment failure Rochester1 6 ALP ≥2 ULN Barcelona2 12 Decrease in ALP ≤40% and ALP ≥1x ULN Paris-I3 12 ALP ≥3x ULN or AST ≥2x ULN or bilirubin >1 mg/dl Rotterdam4 12 Bilirubin ≥1x ULN and/or albumin 1.67x ULN Paris-II6 12 ALP ≥1.5x ULN or AST ≥1.5x ULN or bilirubin >1 mg/dl Ehime7 6 Decrease in GGT ≤70% and GGT ≥1 ULN

    Continuous scoring Time (months) Scoring parameters

    UK-PBC8 12 12 months: bilirubin, ALP and AST (or ALT); Baseline: albumin and platelets

    GLOBE9 12 12 months: bilirubin, ALP, albumin, and platelet count; Baseline: age

    EASL Clinical Practice Guidelines. J Hepatol 2017

  • GLOBE Score: Online Calculation

  • At a Minimum…

    • Look at serum ALP, TB, albumin after 1 year of therapy with UDCA

    • If ALP > 2x ULN or abnormal bilirubin  Consider incomplete response to UDCA

  • There are Options for Non-Responders!!!

    • Obeticholic Acid is FDA-Approved – In combination with UDCA for patients with PBC who have

    been treated with UDCA for > 1 year and have incomplete response

    – As monotherapy for patients with PBC who are intolerant to UDCA

  • FXR Agonist

    Modulates BA

    homeostasis

    Anti- inflammatory

    Anti-fibrotic

    Increases hepatic insulin

    sensitivity

    Decreases portal

    pressure

  • 46% of patients on OCA met the primary endpoint compared to 10% of pts on placebo

    Significant drop in ALP, AST, ALT, GGT, TB

    Significant reduction in inflammatory markers

    Reduction in HDL-cholesterol

    No change in liver stiffness scores

    Obeticholic Acid for PBC: POISE trial

    Nevens F, et al. N Engl J Med. 2016;375:631-643.

  • Cumulative Incidence of Complications of PBC

    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% • OLT from 4.5% to 1.2% • Liver-related deaths from 16.2% to

    5.7%

    Samur S, et al. Hepatology. 2017.

  • OCA Dosing Recommendations OCA Dose Disease Stage

    Non-cirrhotic or compensated cirrhosis (Child-Pugh A)

    Decompensated cirrhosis, Child B or C (including prior decompensation)

    Starting dose – 1st

    3 months 5 mg/day 5 mg/week

    Dose titration at 3 months

    10 mg/day 5 mg twice a week, at least 3 days apart

    May increase to 10 mg twice a week, at least 3 days apart

    Maximum dose 10 mg/day 10 mg twice a week

    DOSE TITRATION IS RECOMMENDED TO MINIMIZE ITCHING

  • Real World Effectiveness of OCA in PBC • 15 pts (24%) discontinued OCA

    • Adverse events – 16 (25%) itching, fatigue

    (12.7%), abdominal pain (9.5%)

    • 63 patients treated with OCA – Median age 56 years, median duration of OCA

    treatment 10.7 months – 55.6% with cirrhosis, 48% decompensated – 19% with overlap syndrome

    • 22.6% had drop in ALP to < 1.5x ULN

    • Mean change in ALP was -21.5% (p < 0.0001; similar rates in cirrhotics and non cirrhotics)

    Levy C et al. ILC 2018

  • Management of Moderate to Severe Itching During OCA Treatment

    • If on 10 mg/day, reduce dose to 5 mg/day • If on 5 mg/day and no contra-indication consider adding

    rifampin or cholestyramine* • If no improvement, consider alternating days: OCA 5 mg qod,

    or even a short drug holiday of a few days or a week, then resuming OCA

    * As is the case with UDCA, cholestyramine must be administered 1 hour before or > 3 hours after OCA

  • Management of Itching in PBC

    General: - Skin moisturizer - Wet, cooling, moist wraps - Avoid contact to exacerbating factors - Loose clothing - Trim fingernails - Anti-histamines at bedtime

    First-Line Agent: -Cholestyramine 4-16 g/day ***

    Second-Line Agents: - Rifampin 150-300 mg bid - Sertraline 75-100 mg/day - Naltrexone 12.5-50 mg/day

    Other Treatments - Fibrates - Butorphanol - Nasobiliary drainage - Phototherapy - Plasmapheresis - MARS

    Liver Transplantation

    Carrion AF et al. Clin Liver Dis 2018; Lindor KD et al. Hepatology 2019

  • Use of Fibrates in PBC

    • Available: Bezafibrate & Fenofibrate • PPAR agonists • Several ongoing clinical trials • Currently off-label use only

    - BA detoxification - BA secretion - BA synthesis - Fatty acid oxidation - Down-regulates NF-

    KB pathway

  •  100 patients with incomplete response to UDCA

     Randomized to BZF 400 mg/day or placebo, for 2 years

     Primary endpoint* at 2 years: 30% BZF vs. 0% Placebo

     Itch score, LSM and ELF improved in BZF group

    BEZURSO: Bezafibrate + UDCA vs. Placebo + UDCA

    0%

    10%

    20%

    30%

    40%

    50%

    60%

    70%

    normalization ALP

    67%

    2%

    BZF Placebo

    Corpechot C et al. N Engl J Med 2018

  • Change in ALP in 48 Patients Treated with Bezafibrate for a median of 38 months

    ALP decreased from 2.4x ULN to 1x ULN (p

  • Effect of Bezafibrate on Pruritus

    • 26/48 had pruritus

    • 16 resolved, 7 improved, 3 unchanged

    Reig et al. Am J Gastro 2017

  • o Open-label (n = 20) o ALP levels decreased

    significantly o Rebound in ALP levels occurred

    following fenofibrate discontinuation

    Fenofibrate + UDCA—Phase II Findings in PBC Patients with Incomplete Response to UDCA

    Levy C et al Aliment Pharmacol Ther. 2011

    Time interval (weeks) M

    ea n

    Se ru

    m A

    LP

    (U /L

    )

    Chart1

    0

    6

    12

    24

    36

    48

    9-12 f/u

    ALP

    405

    186

    168

    174

    171

    176

    328

    Sheet1

    ALP

    0 405

    6 186

    12 168

    24 174

    36 171

    48 176

    9-12 f/u 328

  • Safety concerns with Fibrates

    • Hepatotoxicity – Acute and chronic toxicity described – AIH-like picture possible

    • Rise in creatinine – Typically reversible and without decline in GFR

    • Rhabdomyolysis if in conjunction with a statin

    Livertox.com; Ahmad J et al. Dig Dis Sci 2017; Davidson MH et al. Am J Cardiol 2007; 99(supp):3C-18C

  • o Randomized, double-blind, placebo-controlled trial (NCT00746486) o 62 patients randomized and treated (ITT population) with 36 months of treatment

    with UDCA (12–16 mg/kg BW/day) with or without BUD (3 mg tid*)

    Budesonide add-on therapy in PBC patients: Phase 3 trial

    Hirschfield G, et al. ILC 2018, #2095 (GS-011)

    Improved liver histology†

    29.4 %