Improving Patient Outcomes in PBC

Associate Professor Simone StrasserSenior Staff Specialist,

AW Morrow Gastroenterology and Liver Centre and

Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, Sydney

President,

Gastroenterological Society of Australia

Disclosures

Dr Strasser has received honoraria for advisory boards or speaking from:

• Bayer Healthcare• Sirtex

• Gilead• BMS• MSD

• AbbVie• Norgine• Astellas

• Novartis• Eisai• Ipsen

• Pfizer

Outline

• Introduction

• What is the prognosis of untreated PBC?

• What is the role of UDCA?

• How should we treat UDCA non-responders?

• What is the future?

Primary Biliary Cholangitis

EASL CPG PBC. J Hepatol 2017;67:145–72

• Female predominant disease

• Mainly >40 yrs; not in children

• Estimated 1 in 1,000 women over the age of 40 living with PBC

• Cholestatic disorder with serologic reactivity to antimitochondrial antibodies (AMA) or specific antinuclear antibody (ANA)

• Histologic evidence of chronic non-suppurative, granulomatous, lymphocytic small bile duct cholangitis.

• In adults with cholestasis and no likelihood of systemic disease, an elevated ALP plus AMA at a titre >1:40 is diagnostic – liver biopsy not required for diagnosis

Overview of utility of investigations in PBC

EASL CPG PBC. J Hepatol 2017;67:145–72

Test Finding Notes

ALP Values associated with disease progression

AST/ALT May be suggestive of PBC with features of AIH

GGT Reflects cholestatic liver injury

IgM Elevated values associated with disease

AMA (>1/40) + Diagnostic in >90% of cases in correct clinical context

Specific ANA + Specific immunofluorescence patterns* present in 30%

Anti-gp210 + Specific immunoassays available

Anti-sp100 + Specific immunoassays available

Anti-centromere + Associated with portal hypertensive phenotype

Bilirubin Elevation at late stages frequently indicative of cirrhosis†

Platelets Indicative of cirrhosis

INR Indicative of cirrhosis

Albumin Indicative of cirrhosis

* Perinuclear rims, nuclear dot, centromere;† Except in patients with ductopenic non-cirrhotic variant

Correlations of liver stiffness measurement (LSM) with Histologic fibrosis stage

Clinical utility of FibroScan as a non-invasive diagnostic test for primary biliary cholangitis

J Gastroenterol Hepatol. 2019 Nov 14.

A combination of LSM ≥7.0 kPa and a noninvasive serum marker - M2BPGi ≥1.00 COI - could predict late-stage PBC (i.e., moderate to advanced disease progression) with a sensitivity of 0.58, specificity of 0.82, and accuracy of 0.74.

Mac-2 binding protein glycosylation isomer

Transient elastography useful for baseline assessment, and monitoring

Corpechot C et al. Noninvasive Elastography-Based Assessment of Liver Fibrosis Progression and Prognosis in Primary Biliary Cirrhosis HEPATOLOGY 2012;56:198-208)

Prognosis in PBC• 36-89% of asymptomatic pts develop symptomatic disease in 5-17 years

• Untreated, PBC is a slowly progressive cholestatic disease associated with the development of cirrhosis and liver failure (6-10 yrs after onset symptoms) that may require liver transplant

• Response to treatment significantly impacts long term outcomes

• UDCA improves liver biochemistry, delays histological progression, as well as the development

of portal hypertension and its complications. UDCA era since 1990.

• Symptoms associated with PBC impact on QoL and are often independent of disease severity:

• cholestatic pruritus, sicca complex, abdominal discomfort and fatigue

• restless legs, sleeplessness, depression and cognitive dysfunction

EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitisJournal of Hepatology 2017 vol. 67 j 145–172

Mediators

1. Lysophosphatidic acid (produced by autotaxin)2. Endogenous opioids3. Bile acids

Management of Pruritus

Beuers et al. Pruritus in Cholestasis: Facts and Fiction. HEPATOLOGY 2014;60:399-407; Lindor et al. AASLD Practic Guidance. Hepatology 2019;69(1);394-419

Fatigue in PBC

• Fatigue in 50% - 78% of PBC patients

• Serious disturbances in 20% of patients.

• Aetiology multifactorial – including autonomic dysfunction, cognitive defects,

impaired muscle recovery and sleep disturbance

• Fatigue unrelated to severity of PBC – not improved with UDCA, OCA or LT

• Antioxidants may have role - Bio-quinone Q10 (Co-Q10) improved fatigue and

itchiness in PBC patients in an open-label pilot study

Gao et al. Clin Rev Allergy Immunol. 2019 Nov 11. doi: 10.1007/s12016-019-08772-7. [Epub ahead of print]Lindor et al. AASLD Practic Guidance. Hepatology 2019;69(1);394-419

Hyperlipidaemia in PBC

Wah-Suarez MI, et al. Frontline Gastroenterology 2019;10:401–408

• Hypercholesterolaemia common – no

increased CV risk

• Increased cardioprotective Lp-X, HDL and adiponectin Decreased atherogenic LDL-C and lipoprotein(a).

• Treatment recommended :

• cardiovascular disease or diabetes

• primary hyperlipidaemia (ApoB-100 >120 mg/dL)

• cardiovascular risk factors (tobacco use, hypertension) and ApoB-100 >90 mg/dL

• Atorvastatin 10-20mg daily or Simvastatin 20-40mg for Intitialtreatment

Outline

• Introduction

• What is the prognosis of untreated PBC?

• What is the role of UDCA?

• How should we treat UDCA non-responders?

• What is the future?

On-Line calculator available:

https://www.mayoclinic.org/medical-professionals/model-end-stage-liver-disease/updated-natural-history-model-for-primary-biliary-cirrhosis

Not on effective therapy

The Mayo Model

Hepatology. 1989 Jul;10(1):1-7.

Indications for Liver

Transplantation in ANZ

PBC accounts for 5.5% of all adult LT in ANZ since

1985

Outline

• Introduction

• What is the prognosis of untreated PBC?

• What is the role of UDCA?

• How should we treat UDCA non-responders?

• What is the future?

EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitisJournal of Hepatology 2017 vol. 67 j 145–172

UDCA for ALL

Assess response

Consider2nd lineTherapy(up to 40%

NR to UDCA)

Saffioti F, Gurusamy KS, Eusebi LH, Tsochatzis E, Davidson BR, Thorburn D.Pharmacological interventions for primary biliary cholangitis.Cochrane Database of Systematic Reviews 2017, Issue 3.

Liver transplantation.

(n=5)

(n=6)

Mortality at maximal follow-up.Authors Conclusions:

Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis.

However, the follow-up periods in the trials were short and there is significant uncertainty in this issue.

Further well-designed randomised clinical trials are necessary.

(n=6)

Cochrane analysis of RCTs of UDCA versus no intervention

Excellent Long-Term Survival in Patients With Primary Biliary Cirrhosis and Biochemical Response to Ursodeoxycholic Acid

Patients without biochemical response to UDCA Patients with biochemical response to UDCA

p=0.15P < 0.001 P < 0.001

P < 0.001

Pares et al. GASTROENTEROLOGY 2006;130:715–720

192 patients with PBC treated with UDCA [15 mg/kg per day] for 1.5–14 years.Biochem Response: ALP decrease > 40% of BL or normal after 1 year of treatment.

Biochemical non-responders

should be targeted for new

therapies

Biochemical responders have

excellent long term survival

No need for additional therapies

J Hepatol 2011;55 (6) 1361-1367

• Outcome assessed after 1 year of UDCA in 165 patients with early-stage PBC (defined by absence of fibrotic septa or cirrhosis, normal bilirubin and albumin levels) followed for median 7 yrs (range, 1.6–20.3 years)

92%96%

Poor outcomes in UDCA non-

responders in early stage PBC:

85%

Excellent outcomes in

UDCA responders in early stage PBC

Paris II Response criteria

ALP ≤ 1.5 × ULN, AST ≤ 1.5 ×ULN, and normal bilirubin after 1 year of treatment with UDCA

Levels of alkaline phosphatase and bilirubin can predict outcomes (LT or death) of patients with PBC treated with UDCA

Lammers et al. Gastroenterology. 2014 Dec;147(6):1338-49.

n= 4845; 90% female; 88% AMA positive; 42% early stage disease; 85% treated with UDCA; median FU 7.3 years (IQR, 3.6–11.5 yrs)

Elevated ALP levels persist in up to 40% of UDCA-treated patients, and their mortality risk remains higher than that for the general population

Used in clnicaltrials to select pts for 2nd line therapy

Is response to UDCA the only predictor of outcome?

• Majority of patients are now treated with UDCA

• Older scoring systems based just on response to UDCA (Barcelona, Paris I, Rotterdam, Toronto, and Paris II criteria)

Nonresponders to UDCA and pts with advanced histologic fibrosis stage at baseline have inferior survival

1828 patients with baseline liver biopsyPoor correlations were observed between non‐invasive measures of fibrosis and histologic fibrosis stage

Perez et al. Aliment Pharmacol Ther. 2019 Nov;50(10):1127-1136

The GLOBE score predicts Liver Transplant-free survival

Lammers et al. Gastroenterology 2015;149:1804–1812

• International, multicentre meta-analysis of 4119 patients with PBC treated with UDCA (8 European and North American countries)

• Patients randomly assigned to derivation [60%] and validation cohorts [40%]

• Age, bilirubin, albumin, ALP, platelet count = independent predictors of LT or death

• Patients with a GLOBE score >0.30, (40% of cases), had a significantly diminished survival compared with a matched general population

<10th

10th-40th

40th-60th

60th-90th

>90th

Percentiles

The UK-PBC Risk Score predicts risk of developing ESLD

Carbone et al. The UK‐PBC risk scores: Derivation and validation of a scoring system for long‐term prediction of end‐stage liver disease in primary biliary cholangitis. HEPATOLOGY 2016;63:930-950

• UK-PBC Risk Score provides individualized estimates of the risk of developing ESLD within defined time points in the future.

• Based on derivation cohort of 1,916 UDCA-treated participants and validation cohort of 1,249 UDCA-treated participants.

• Best-fitting Cox model included five variables: B/L albumin, B/L platelet, bilirubin 12 mths, transaminases 12 mths, and ALP 12 mths

• Online calculator : http://www.uk-pbc.com/resources/tools/riskcalculator/

Outline

• Introduction

• What is the prognosis of untreated PBC?

• What is the role of UDCA?

• How should we treat UDCA non-responders?

• What is the future?

Treatments for UDCA Non-responders

Suraweera et al. Treatment of primary biliary cholangitis ursodeoxycholic acidnon-responders: A systematic review. Liver International. 2017;37:1877–1886.

Available in Australia• Fenofibrate

• Methotrexate

• Colchicine

• Budesonide

• Mycophenolate mofetil

• Azathioprine

• Chlorambucil, Penicillamine

• Available internationally • Obeticholic acid – only agent FDA approved for UDCA non-responders ; TGA Approved in Australia

Definition: Typically, a serum ALP greater than at least 1.5-2 (often 1.67) times the ULN, applied after 6-12 months of UDCA monotherapy

Studied in PBC but no consistent benefit, none recommended

Available in New Zealand• Bezafibrate

N Engl J Med 2016;375:631-43.

• 93% of the patients took UDCA at baseline and throughout• ALP ≥1.67 x ULN or Tbili abnormal but <2 xULN. (Toronto)• Primary composite end point: ALP level of less than 1.67

xULN, at least 15% reduction from baseline, and a total bili ≤ ULN at 12 months.

316 screened for participation, 217 randomised

OCA administered with UDCA (or as monotherapy) for 12 months in resulted in significant decreases from baseline in ALP and Tbili levels compared with placebo.

Pruritus in up to 72%

47% vs 10%p<0.001

ALP

Bilirubin

Kowdley K et al. HEPATOLOGY 2018;67:1890-1902

phase 2 study

ALP

Bilirubin

P< 0.05

P< 0.0001

The primary endpoint was the percent change inALP from baseline to end of study (mth 3)

Estimated Long-Term Survival using Globe PBC and UK-PBC Prognostic Models

Effect of OCA on liver biochemistries

P < 0.0001

Primary Endpoint

Changes in ALP over 6 years of OLE

Role of OCA in PBC

• Biochemical response is durable

• Longer term survival benefit unknown

• Significant tolerability concerns – pruritus – limits use in many patients

• Lack of response in some patients - ? What then

Corpechot et al. N Engl J Med 2018;378:2171-81.

• On UDCA 13 to 15 mg/kg/d• Met Paris criteria* for inclusion • Primary Outcome: % of patients with a

complete biochemical response at 24 months

* Paris Criteria: serum ALP or AST >1.5 times ULN or abnormal total bilirubin level after 6 months or more of treatment. J Hepatol 2011; 55: 1361-7.

P<0.001

Pruritus in 8%

5-, 10-, and 15-year estimated rates of events were calculated at baseline and after 12 months of study treatment in both groups. Asterisks indicates significant differences. Similar results were obtained after 24 months of treatment.

Corpechot et al. N Engl J Med 2018;378:2171-81. Supplementary Appendix

The Globe score predicts liver transplantation and all-cause mortality UK-PBC score predicts liver transplantation and liver-related mortality

Treatments for UDCA Non-responders

Suraweera et al. Treatment of primary biliary cholangitis ursodeoxycholic acidnon-responders: A systematic review. Liver International. 2017;37:1877–1886.

• Available in Australia• Fenofibrate

• Available internationally • Obeticholic acid – only agent FDA approved for UDCA non-responders

• Bezafibrate (available in New Zealand)

Definition: Typically, a serum ALP greater than at least 1.5-2 (often 1.67) times the ULN, applied after 6-12 months of UDCA monotherapy

Grigorian et al. Clinics and Research in Hepatology and Gastroenterology (2015) 39, 296—306

• Fenofibrate at doses of 100—200 mg daily appears to be effective adjunctive therapy in PBC patients who had no or incomplete response to UDCA.

• There is a critical need for larger scale randomised trials to determine its effect on liver-related morbidity and mortality (or progression towards end-stage disease).

Dohmen et al. 2004 9 subjectsWalker et al. 2009 16 subjectsLevy et al. 2010 20 subjectsLiberopoulos et al 2010 6 subjectsHan et al. 2012 22 subjectsPoupon et al. 2014 13 subjects; 18 subjects

Fenofibrate prescribing information (Australia)

Pack 145 mg [30] (AUSTR118634) PBS/RPBS (NP) (Rp 5)

Dig Dis Sci (2017) 62:3596–3604

Fenofibrate accounted for 7 of 1229 patients (0.6%) withDILI enrolled during the first 12 years of the DILINprospective study.

Latency:• Typically 5-8 weeks – or longer

Liver injury pattern:• cholestatic or mixed, 5• Hepatocellular, 2, may have

autoimmune features

Course:• Self limited with stopping, 5• Prolonged and progressive, 2,

LTx (1), Death (1)

DILI due to fenofibrate appears to be a rare event probably arising in fewerthan 1:10,000 exposed persons*

* Keech A et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849.

Outline

• Introduction

• What is the prognosis of untreated PBC?

• What is the role of UDCA?

• How should we treat UDCA non-responders?

• What is the future?

Entero-hepatic circulation of bile salts and targets for pharmaceutical intervention.

Jansen PLM. Expert Rev Gastroenterol Hepatol. 2018 Mar;12(3):277-285.

Effective biliary secretion is essential for adequate hepatic detoxification and is integral to digestive function

PBC reflects the consequences of immune and cellular injury to biliary epithelial cells, resulting in cholestasis and progressive liver fibrosis

Many novel therapies targeting nuclear and surface receptors involved in bile acid signalling are currently under evaluation for PBC, including agonists of FXR, PPAR, PXR and TGR5, among others, with promising results.

Targets for Therapies in PBC - Selected

Class Mechanism of action Drug names

UDCA Decrease bile viscosity, increase BS transport and bicarbonate production Ursofalk

FXR Agonist Reduces bile salt synthesis Obeticholic AcidEDP-305

CilofexorTropifexor

FGF19 Agonist Regulates bile acid synthesis NGM 282

PPAR-a Agonist Anticholestatic effects, reduce bile acid synthesis and bile acid–related hepatic inflammation

FenofibrateBezafibrate

PPAR-δ Agonist Hepatoprotective, antifibrotic, choleretic effects Seladelpar

PPAR-α and PPAR-δ Agonist

Elafibranor

PPAR : Peroxisome proliferator-activated receptor

Change in liver enzymes from baseline over time

Well tolerated, although some diarrhoeaHepatology Communications 2018;2:1037-1050

- Phase 2

Lindor et al. AASLD Practic Guidance. Hepatology 2019;69(1);394-419

Conclusions • Remains important to diagnose and treat early stage PBC

• UDCA (13-15 mg/kg/d) indicated in all patients and improves long term outcomes

• For patients that fail to respond to first line treatment with UDCA, second line treatments are associated with improved biochemical outcomes

• There remains an unmet need in UDCA non-responders

• Pruritis and fatigue remain significant issues

• Evidence that new therapies improve clinical endpoints is awaited