NAFLD the new epidemic: New concepts for therapy

1

NAFLD – the new epidemic: New concepts

for therapy

Nicolas Goossens, MD, MSc, PD

Division of Gastroenterology & Hepatology

Geneva University Hospitals

Sanct Gallen 2019 Gastroenterology/Hepatology

December 5th 2019

Non-alcoholic fatty liver disease (NAFLD)

Normal liver

NAFLD

Exclusion:

HBV, HCV

Alcohol

Hemochromatosis

Auto-immune….

Factors linked to

progression

• Insulin resistance

• Overweight

• Metabolic syndrome

• Ethnicity

• Genetics

• Sex

• Food

• ….

Definition:

Steatosis in >5% of

hepatocytes

EASL, J Hepatology, 2016

2

Adapted from Drew, Nature 2017

Natural history of NAFLD

Simple

steatosis

Cirrhosis

NASH &

fibrosis


Simple

steatosis

Cirrhosis

NASH &

fibrosis


3

Hepatocellular

carcinoma

(HCC)


Simple

steatosis

Cirrhosis

NASH &

fibrosis


Dulai et al, Hepatology, 2017

NASH – the role of liver fibrosis

Systematic review of 1,495 NAFLD patients with 17,452 patient years of follow‐up.

No adjustment for confounders

0

10

20

30

40

50

F0 F1 F2 F3 F4

Mort

alit

y r

ate

(per

1,0

00 P

YF

)

Fibrosis stage

All-cause and liver-related mortality in NAFLD

All-cause

Liver-related

4

NASH is a reversible disease

Lassailly et al, Gastro 2015

1 year after bariatric surgery in 109 obese NASH subjects

33% 24%

Resolution

of NASH

Improvement of

fibrosis

Lifestyle interventions

Vilar-Gomez et al, Gastroenterology, 2015

Romero-Gomez et al, J Hep, 2017

N=293 patients with biopsy-proven NASH.

52 weeks of lifestyle interventions (low-fat hypocaloric diet, walk 200 mins/week,

behavioral sessions every week). 2nd liver biopsy at 52 weeks (n=261/293)

16% 18% 16% 45%

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Lifestyle interventions

Vilar-Gomez et al, Gastroenterology, 2015

Romero-Gomez et al, J Hep, 2017

N=293 patients with biopsy-proven NASH.

52 weeks of lifestyle interventions (low-fat hypocaloric diet, walk 200 mins/week,

behavioral sessions every week). 2nd liver biopsy at 52 weeks (n=261/293)

16% 18% 16% 45%

No clear role for metformin

Musso, Hepatology, 2010

AST/ALT

Steatosis

Fibrosis resolution

6

247 patients

83 Placebo 84 Vitamine E

(800 IU)

80 Pioglitazone (30mg)

Pioglitazone and Vitamine E in non-diabetic patients with NASH (22 months)

19%

[VALUE]

34%

0%

10%

20%

30%

40%

50%

P=0.001 P=0.04

Histological Improvement

31%

[VALUE]

44%

0%

10%

20%

30%

40%

50%

P=0.24 P=0.12

Fibrosis Improvement

Placebo

Vitamin E

Pioglitazone

Sanyal, NEJM, 2010

101 patients

51 Placebo 50 Pioglitazone

(45mg)

Pioglitazone in patients with (pre-) diabetes and NASH (18 months)

17%

58%

0%

10%

20%

30%

40%

50%

60%

70%

P<0.001

Improvement NAS ≥ 2 with

no worsening fibrosis

25%

39%

0%

10%

20%

30%

40%

50%

P=0.13

Fibrosis ≥ 1 Improvement

Placebo

Pioglitazone

Cusi, Ann Int Med, 2016

Pioglitazone

101 patients

51 Placebo 50 Pioglitazone

(45mg)

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Upcoming therapies in NAFLD

Drew, Nature, 2017

Intrahepatic drug targets in phase 2 and 3 clinical trials for NASH.

Friedman, Nat Med, 2018

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Intrahepatic drug targets in phase 2 and 3 clinical trials for NASH.

MGL-3196

Elafibranor

Elafibranor

Selonsertib

Obeticholic acid

Cenicriviroc

Friedman, Nat Med, 2018

Obeticholic acid

Positive results from REGENERATE: A phase 3 international, randomized, placebo-controlled study of obeticholic acid (FXR

agonist) treatment for NASH

INTERCEPT press release Feb 19th 2019

Oral presentation EASL ILC 2019, April 2019

11.9%

8.0%

17.6%

11.2%

23.1%

11.7%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

Fib improvement (no worseningNASH)

NASH resolution (no worseningfibrosis)

REGENERATE phase 3 study (OCA in stage 2-3 NASH – month 18 interim analysis)

Placebo, n=311

OCA 10mg, n=312

OCA 25mg, n=308

* *

* p < 0.05 compared to placebo

Pruritus - Placebo 19%, OCA 10mg 28%, OCA 25mg 51% (9% discont.)

Increase in LDL cholesterol peak at wk 4

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Phase 3 trials of selonsertib (ASK-1 inhibitor) in NASH with advanced fibrosis (STELLAR-3 and -4) did not meet week 48 primary

endpoint

GILEAD press release Feb 11th 2019 and April 25th 2019

13.2% 12.8% 12.1% 12.5%

9.3%

14.4%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

STELLAR 3 (F3) STELLAR 4 (F4)

Selonsertib in NASH phase 3 studies (F3 or F4 fibrosis)

Placebo

SEL 6mg

SEL 18mg

Fibrosis improvement without worsening of NASH

Ratziu et al, Gastroenterology 2016

Phase 2 trial of elafibranor (PPAR α/δ agonist) – 1 year

Resolution of NASH

(modified definition)

Detailed fibrosis improvement not

reported

Reduced liver fibrosis in subjects

with NASH resolution

276 non-cirrhotic NASH ≈40% T2D, 23% F3

12%

[VALUE]

19%

0%

5%

10%

15%

20%

Placebo, n=92

Elafibranor 80mg, n=93

Elafibranor 120mg, n=91

Phase 3 clinical trial interim results of first 1,000 enrolled patients after 72

weeks of therapy due end 2019

*

Fibrosis ?

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Friedman et al, Hepatology, 2018

Phase 2 trial of cenicriviroc (CCR2-CCR5 antagonist) – 1 y results

19%

16%

0%

5%

10%

15%

20%

25%

Improvement NAS ≥ 2 with

no worsening fibrosis Fibrosis ≥ 1 Improvement

Placebo, n=144

CVC, n=145

289 non-cirrhotic NASH w F1-3 ≈50% T2D, 38% F3

10%

20%

0%

5%

10%

15%

20%

25%

Phase 3 clinical trial results due in 2020

*

Oral presentation EASL ILC 2018, April 2018

Oral presentation AASLD 2018, November 2018

Phase 2 trial of MGL-3196/resmetirom (THR-beta agonist) – 36 week results

125 non-cirrhotic NASH w F1-3 ≈35% T2D, 45% F2-3

-8%

-37% -40%

-35%

-30%

-25%

-20%

-15%

-10%

-5%

0%

Relative fat reduction by

MRI-PDFF

*


Fibrosis ≥ 1 Improvement

23%

29%

0%

5%

10%

15%

20%

25%

30%

35%

Placebo, n=41

MGL-3196, n=84

Phase 3 clinical trial first results due in 2021

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Seghieri et al, Front Endocrino, 2018

Role of GLP-1 analogues in NASH

Armstrong et al, Lancet, 2016

Phase 2 trial of liraglutide (GLP-1 analogue) – 48 week results

52 NASH (40% F3, 12% F4) ≈30% T2D

9%

39%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

NASH resolution with no

worsening of fibrosis

*


Fibrosis progression

36%

9%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Placebo, n=26

Liraglutide, n=26

-5.3 kg in liraglutide group vs -0.6 kg in placebo group at 48 weeks (p<0.05)

Semaglutide phase 2 completion estimated in early 2020

*

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Duodenal mucosal resurfacing

Haidry et al, GIE, 2019


Bergman et al, AASLD 2019 (Boston)

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Conclusions

• The epidemiological burden of NASH is increasing

• Lifestyle interventions are effective but only in a minority of

patients

• There are challenges to drug development for NASH

• 1st phase 3 clinical trial results are encouraging

• The future: combination therapy?

• Place of endoscopic / non-pharmacological therapy?

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Thank you for your attention

NAFLD the new epidemic: New concepts for therapy

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