AUTOIMMUNE LIVER DISEASE: PROGRESS IN PBC & PSC

Maria A. Lagarde, MD

Gastroenterology and Transplant Hepatology

2019

DISCLOSURES

•none

OBJECTIVES

Treatment options for autoimmune hepatitis

Drugs in the pipeline for AIH

New treatment options for PBC beyond Ursodiol

New therapeutic targets for PBC

Treatment strategies for PSC

WHAT IS NEW FOR 2020: GENERAL PATHOPHYSIOLOGY AND

DEMOGRAPHICSOf all autoimmune liver diseases

CHANGES IN DEMOGRAPHICS

• Element exposure as possible pathogenesis mechanism

• Racial disparities in AIH

• PBC is on the rise!

Oral abs. #48 Dyson et Al.

BLACK PATIENTS AND AIH

Younger age median 38 vs 45 years(P < .007)

Higher IgG levels (mean 31.0 vs 27.5 mg/dL) (P <

.04)

Higher proportion of SLE (10%) > whites(2%) (P <

.001)

No difference in response to treatment (P.20) or

rate of relapse (P=0.3), yet

Increased risk of LT and liver-related death

(HR 2.4, 95% CI, 1.4–4.0; P < .001)

DeBoer YS, et Al. Clin.GastroHep 2019.

England and Netherlands

from 1971-2016

88 blacks vs 897 whites with AIH

PBC

Retrospective data from National (Nationwide) InpatientSample (NIS) 2005 to 2014. Total of 22,665 PBC discharges.

Trends in PBC‐related discharges, total charges, length of stay (LoS), and in‐hospital mortality

RESULTS

• PBC-related discharges ↑ from 3.24 (in 2005) to 3.68 per 100k (in 2014)

• Avg. annual ↑↑ of 1.4% (95% CI 0.4%-2.4%)

• ↑ severity of illness and risk of death

• Drop by 5.4% in-hospital mortality rate

Shahab et Al. Hepatol Commun 2019

Incidence/Prevalence

Environmental exposure

Better in-Hospital survival

Early diagnosis, longer survival

Failure of effective 1st line therapy

AUTOIMMUNE HEPATITIS IN

2020

AUTOIMMUNE HEPATITIS (AIH)

• Unresolving inflammation of the liver

• Unknown cause

• 1-2 cases per 100K PPY

• W:M 3.6:1

• All ages, but peak in the young (13-30)

• Variable presentation: commonly slow progression (acute/severe liver failure)

• Diagnosis: clinical, laboratory (abnormal globulins/autoantibodies) and histologic features

• First liver disease found to be manageable with Rx

AIH PREDNISONE + AZA 70 YRS OF EXPERIENCE

• Goal: Normal ALT/AST, GG and IgG

• Cont. treatment for 2 years after normalization

• Histological remission confirmation:

• ~45% of patients in biochemical remission, have positive Bx

• Failure:

• medication intolerance (10%)

• incomplete response (15%) treatment failure (9%)

Verling JM. Clin Gastro Hep 2015

Lammert Current Gast Rep 2016

Unmet needs

Tolerable steroid-free induction regimens

2nd line Rx in refractory or intolerant patients

Management of recurrent AIH (rAIH) post‐liver transplantation (LT)

MYCOPHENOLATE MMF

• Biochemical remission from 31%-73% (discontinuation 13% to 34%)

• Cirrhotics ↑ risk of infections, sepsis, death

• SE: diarrhea, abdominal pain

• Teratogenic!

Zachou. Aliment Pharmacol Ther. 2016

MMF AS A 1ST LINE AGENT?

Real-world observation prospective study (Zachou, 2016)

• 109 pts on Pred+MMF vs 22 pts on Pred+AZA

• 72% in MMF group achieved complete response on Rx w/higher prob of remission (P=0.03)

• Treatment withdrawal was feasible in 40/109 patients and 30 (75%) were still in remission after 24 (2-129) months.

CAMARO TRIAL:

• RCT on MMF vs AZA. Enrolling until Dec 2019. NCT02900443

Doycheva. Liver Inter 2019

LOWER STEROID DOSES. SAFE?

Retrospective cohort study with AIH (5 countries/9ctrs-

Europe)1978-2017

Patients divided to:

HD (n=281)

LD (n=170)

Primary outcome: normalization of

AST/ALT @6m

Pape. Clin Gastroenterol Hepatol 2019

AST/ALT AST/ALT

+GG

FUTURE THERAPIES

DRUG Stage Mx of Action outcome

JKB-122

Ph 2

(open

label)

Toll-like r4

(TLR4)

Agonist

Change in

ALT

VAY736

Ianalu-

mab

Ph 2&3

(RDB-

PCT)

MAB→

B-cell

activating

receptor

ALT

normal

IL-2

Ph 2

(open

label)

Treg inducer% of Tregs

@day 8

Treg Cells

(inf)

Ph 1&2

(open

label)

Down-

regulates

pro-inflamm.

state

Biochem.

Immun.

remission

LPS (gut

bacteria)

TLR411

2

2

3 3

3

4

4

Doycheva. Liver Inter 2019Manns. J Hepatol. 2015

PRIMARY BILIARY

CHOLANGITIS IN 2020

PRIMARY BILIARY

CHOLANGITIS

• Chronic cholestasis

• Inflammation and destruction of small interlobular bile ducts

• Mainly affects middle-aged females

• Clinical presentation: pruritus, fatigue and sicca symptoms

• Criteria 2/3:

• Unexplained elevation of ALP > 1.5 x ULN

• Positive AMA

• Non-suppurative destructive cholangitis on histology

UDCA STILL1ST LINE?

- USE in all patients who have elevated ALP

- Improves biochemistries

- Slows progression of fibrosis

- Delays appearance of EVs

- Lowers IgM and cholesterol

- Use of UDCA decreases death or the need for LT

90

78

66

79

59

32

0

10

20

30

40

50

60

70

80

90

100

5-year 10-year 15-year

UDCA-treated Untreated

Transplant-Free Survival

Lammers et Al Gastroenterology 2014

SECOND LINE THERAPY

40% of patients do not respond to UDCA

When to consider?

• Lack of Biochemical response at 1 year

GLOBE-PBC/UK-PBC risk stratification scores

AST to

Platelet

Ratio

Index

(APRI)

Lindor. Hepatology 2019

OBETACHOLIC ACID

• FXR agonist • Inhibits BA uptake/synthesis• TNF-alpha pathway• Increases BA secretion

• FDA Approved based on the NEJM POISE trial (Nevens, 2016)

• 216 pts failed/intolerant to UDCA 1ary EP: Normalization of ALP (<1.67 ULN, and n-Tbili)

• OCA 46/47% vs 10% UDCA

• Worsening PBC and death in CPT B-C

PEROXISOME PROLIFERATOR ACTIVATOR RECEPTOR (PPAR)

• PPAR 𝛂: reg. bile acid homeostasis, PPL secretion and inflammatory path.

• PPAR 𝛅: improves insulin res. and lipid metab. enhanced energy use, anti-inflammatory properties

• PPAR 𝛄: regulates adipogenesis, anti-inflammatory, anti-fibrotic properties

Fibrate In the liver Other

benefits

Fenofibrate-α Cholestasis markers TNF levels

TG

Bezafibrate-

pan

Cholestasis markers and

inflammation

Pruritus

stiffness

Seladelpar-δ Cholestasis markers and

inflammation

LDL

Elafibranor-α/δ fatty deposition and

inflammation

In the US, fenofibrate is approved for treatment of hyperlipidemia and bezafibrate is not available.

Corpechot NEJM 2018

BEZAFIBRATE

• 24-month DBPCT phase 3

• 100 patients inadequate response to UDCA

• UDCA + bezafibrate vs. UDCA + placebo

FROM THE GUIDANCE 2018

Fibrates can be considered as OFF-label use alternatives for patients with PBC and inadequate response to UDCA

Use of Fibrates is discouraged in patients with decompensated liver disease CPT B or C

FROM BASIC SCIENCE: • Hepatic mast cell (MCs) infiltration and

activation correlates with biliary damage and fibrosis in late stage PBC. • Activated MCs →H2-histamine receptors (H2HR)

signals → disease progression

• biliary HDC (histidine)→ perpetuate injury →autocrine mechanisms.

• Secretin and Secretin receptor: • excretion of bicarb/Cl- (by secretin) appears

protective from BAs

• Promotes cholangiocyte proliferation

Inhibition of MC activation or

biliary HDC/H2HR signaling

Potential therapeutic target

Mice (advanced PBC) treated

with Secretin and UDCA

amelioration of ductopenia

liver damage and fibrosis

vs. controls

PRIMARY SCLEROSING CHOLANGITIS

IN 2020

PSC

• Chronic, immune-mediated cholestasis

• Inflammation and fibrosis of IH/EH bile ducts

• Progressive to cirrhosis/portal HTN

• Median LT-free survival 12 yrs

• Males (70%) > females

• Diagnosis at 20-40 yrs (can present in childhood)

• 60-80% have IBD (occurs in 2-7% pts with IBD)

• Associated with AIH 7-10% (overlap)

• Other outcomes: bacterial cholangitis, bone disease, cholangiocarcinoma, higher risk for colon cancer

DIAGNOSIS

Liver biopsy is not necessary when Cholangiography is characteristic

Exceptions: Small duct PSC, AIH overlap

ERCP may be used 1st in patients who are symptomatic or require interventions

MRCP has replaced ERCP as the diagnostic modality of choice for asymptomatic individuals

May miss early PSCNo radiation, non-

invasive

TREATMENT OPTIONS

There is NO

treatment

UDCA

Maybe, but if at all

LOW dose <15mg/kg

This Year

Statins and AZA

Fecal microbiota transplantation

Cilofexor

STATINS AND AZA

Swedish population cohort PSC+IBD 2005-2014 (n=2914)

Drug exposure PLUS Risk or death, LT, EVB, and cancer

Findings

• Statin and AZA use ↓ Risk of • all-cause mortality (HR 0.68 / 0.66; 95%

CI) • Death or liver transplantation (HR, 0.50 /

0.65; 95%)

• Exposure to UDCA did not affect mortality (HR, 1.04; 95% CI)

FMT10 pts with PSC+IBD (9UC/1CD) and ALP1.5>ULN (mean 489U/L) open label single FMT. LFTs and microbiome up to 24 wks

• 1st outcome: safety

• 2nd outcome drop in ALP levels >50%

• stool microbiota and metabonomic dynamics

Findings

• NO adverse events, 3/10 patients had drop in ALP >50%

• Diversity increased in all patients

• Patients with higher engrafting OTUs (bacterial variety and restitution) had the higher ALP response

CILOFEXOR

Methods:

• DBRPCT comparing 2 doses of Cilofexor and PBO x 12 weeks

• 52 non-cirrhotics with large-duct PSC and ALP > 1.67 x ULN

Main Findings:

• ↓ALP irrespective of UDCA use

• ↓ALT, GGT, TIMP-1, C4 and BA’s

• Grade 2-3 pruritus less frequent with Cilofexor c/w PBO

Conclusion

• significant ↓ in liver biochemistry and markers of cholestasis w/o aggravating pruritus

TAKE HOME POINTS

AIH has effective therapy, but there is an unmet need for steroid spearing therapy

that is safe and effective

In PBC, UDCA and OCA are now first and second line therapy, with new

therapeutic targets rapidly approaching.

PPAR inh-fibrates are the most promising new therapies for PBC

PSC remains a diagnosis without treatment. Potential future therapies

(including Cilofexor) are still in early stages

THANK YOU!