NAFLD:Clinical Trial Overview

Timothy MorganChief, Gastroenterology

VA Long Beach Healthcare SystemFebruary 29, 2020

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Disclosures

Timothy Morgan

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Category CompaniesGrants for Research Genfit, Gilead, Abbvie, MerckAdvisor or Consultant NoneSpeakers Bureau None

Overview• Pathophysiology of NAFLD

• Available now (not approved) Phase II/III• Diet/exercise ● Obeticholic acid• Bariatric surgery ● Cenicriviroc (CCR2/5 inhibitor)• Vitamin E ● Elafibranor (PPAR-α/ẟ agonist)• Pioglitazone (PPAR-γ agonist) ● NGM282 (FGF19 analogue)• Liraglutide (GLP-1 agonist) ● Pegbelfermin (FGF21)• Empagliflozin (SGLT-2 inhibitor) ● Resmetirom (THR-β agonist)

3

Blood

Absorption

Energyingestion

BrainFood availability

ChoiceSatiety

Bariatric surgeryFGF21GLP1Neuropeptides

WAT• Storage

Lipase-iSGLT1/2i

PPAR-γ

Carbohydrates,Fatty acids

BAT• Heat

TGR5FGF21GLP1

Muscle• Locomotion• Heat

ExerciseTestosteronePPARδ

Urine• Excretion

SGLT2i

Triglyceride• Storage as lipid droplets• Secretion as VLDL

Lipo

lysis

Oxidation

PPARαDGAT2i

Lipotoxic lipids

•ER stress• Inflammasome activation

• Inflammation•Apoptosis

Vitamin EASK1iPDEiCCR2/5iLeukotriene-iCaspase-i

Gut microbiomeCholesterolHypoxia/OSA

TLR4iProbioticsStatinsCPAP

“NASH”

HCC

Fibrogenesis

Galectin-3iFXRCCR2/5iRAAS-IIntegrin-i

Liver synthesis and

disposal of fatty acids

Diet controlRegular exercise FXR

GLP1FGF19THR-βSCD1iACCiMPC-IASBTiTestosterone

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HKi

Modified from: Qureshi Exp Op in Invest Drugs 2019 i=inhibitor

Blood

Absorption

Energyingestion

Bariatric surgeryFGF21GLP1Neuropeptides

WAT• Storage

Lipase-iSGLT1/2i

PPAR-γ

Carbohydrates,Fatty acids

BAT• Heat

TGR5FGF21GLP1

Muscle• Locomotion• Heat

ExerciseTestosteronePPARδ

Urine• Excretion

SGLT2i

FXRGLP1FGF19THR-βSCD1iACCiMPC-IASBTiTestosterone

Triglyceride• Storage as lipid droplets• Secretion as VLDL

Lipo

lysis

Oxidation

PPARαDGAT2i

Lipotoxic lipids

•ER stress• Inflammasome activation

• Inflammation•Apoptosis

Vitamin EASK1iPDEiCCR2/5iLeukotriene-iCaspase-i

Gut microbiomeCholesterolHypoxia/OSA

TLR4iProbioticsStatinsCPAP

“NASH”

HCC

Fibrogenesis

Galectin-3iFXRCCR2/5iRAAS-IIntegrin-i

HKi

Liver synthesis and

disposal of fatty acids

Diet controlRegular exercise

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BrainFood availability

ChoiceSatiety

Modified from: Qureshi Exp Op in Invest Drugs 2019

Measuring response in NASH clinical trials

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Fat in Liver ALT NASH resolution Fibrosis Clinical Outcomes

MRI PDFF Blood test Biopsy Biopsy

↓>30% Normal ALT↓>30%

“not NASH”↓≥2-point in NAS(ballooning, inflammation, fat)

↓≥1-point(? MRE)

Cirrhosis (Bx)HE, ascites, HCC

3-6 months“biomarkers” of likely response

1-2 yearsOutcomes likely to have clinical benefit

Many yearsClinical benefit

Phase IIa Phase IIa FDA definition of effective drug+ for several drugs in Phase II trials

FDA-definition of effective drug+ for several drugs in Phase II trials

Required by FDA post-marketingNot shown yetLong, large trials

Diet and Exercise

• Diet• 750 kcal less than daily needs• CHO 64%, fat 22%, protein 14%

• NASH on biopsy• 293 patients• 52 weeks • Outcome

• NASH resolution w/o ↑fibrosis25

19

1016

26

18

64

16

90

45

0

10

20

30

40

50

60

70

80

90

100

NASH resolution Fibrosis regression

Histologic Response at Week 52

Overall <5% 5-7% 7-10% >10%

293

Vilar-Gomez Gastroenterology 2015;149:367

203 34 25 29~1/3 of patients lost ≥5% weightNASH improved (>7% wt loss)Fibrosis improved (>10% wt loss)

7Weight Loss at Week 52 (%)

Bariatric Surgery• No randomized controlled trials• Several procedures

• Roux-en-Y gastric bypass (RYGB)• Laparoscopic sleeve gastrectomy

-2.8

-1

-2.3

-0.7

-3

-2.5

-2

-1.5

-1

-0.5

0

Histologic Outcomes after surgery

RYGB LSG

Meta-analysis of RYGB vs. LSG

• Improves metabolic and T2DM• NASH resolution related to wt loss• Fibrosis worsens in a few patients• Unknown mortality benefit (vs. NASH)

Baldwin Surg Obes Relat Dis 2019;15:2123; Laursen W J Hepatol 2019;11:138 8

NAS

Fibrosis

Pioglitazone vs. Vitamin E vs. Placebo (PIVENS)

• NASH on Bx• Exclude

• Cirrhosis• Diabetes

• 96 weeks• Outcome

• 2-point ↓ in NAS• NASH resolution

• rrr-alpha tocopherol (anti-oxidant)• 800 IU daily

• Pioglitazone (PPAR-γ agonist)• 30 mg daily

Treatment

PIVENS: Sanyal NEJM 2010; 362:18:16759

PIVENS: Histologic improvement at 96 weeks

19

34

43

0

10

20

30

40

50

60

Placebo Pioglitazone Vitamin E

2-point improvement in NASw/o worse fibrosis

21

47

36

0

10

20

30

40

50

60

Placebo Pioglitazone Vitamin E

Resolution of Definite NASH

P<0.001

P<0.05

P<0.001; NNT=4.4

P<0.04; NNT=6.6

PIVENS: Sanyal NEJM 2010; 362:18:167510

Pioglitazone

• Pioglitazone• 45 mg/d

• Pre-DM or T2DM• 18 months• Outcome

• 2-point ↓ in NAS• NASH resolution

19 21

6558

0

20

40

60

80

100

2-point reduction in NAS Resolution of NASH

Histologic Improvement at 18 months

Placebo Pioglitazone

P<0.01 P<0.01

Cusi Ann Int Med 2016;165:305-31611

Pioglitazone: Risks and BenefitsBenefits• Prevent DM (in pre-DM)• Decrease cardiac/stroke

• (PROactive, IRIS)

Risks• Weight gain• Edema• Heart failure (NY Class II-IV)• Osteoporosis, fractures• Bladder cancer

Weight Gain (30 mg/d x 96 weeks)

PIVENS: Sanyal NEJM 2010; 362:18:1675

4.7 kg

0.8 kg

0.2 kg

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Obeticholic Acid (OCA)• FXR agonist• REGENERATE

• Placebo• OCA 10 mg/d• OCA 25 mg/day

• Fibrosis F2 or F3 (Kleiner)• F1 with DM, BMI≥30 or ALT>1.5 ULN

• 18 months• Outcome (biopsy)

• ↓ fibrosis ≥1 stage, or• NASH resolution

without worse fibrosis

Improvement in fibrosis with no worsening of NASH

REGENERATE Younossi Lancet 2019;394:2184

NNT: ~9

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Obeticholic Acid: REGENERATE

• Pruritus• Placebo: 19% (<1% d/c’ed)• 10 mg: 28% (<1% d/c’ed)• 25 mg: 51% (9% d/c’ed)• Most d/c were protocol mandated

• No hepatoxicity• No difference in cardiac events• ~23% of patients discontinued

treatment (same across groups)

• Cholesterol• ↑ LDL• ↓ HDL

• Statin use

• ~95% of OCA used statins• LDL controlled with statins

Placebo(311)

OCA 10 mg(312)

OCA 25 mg(308)

Entry 144 (46) 142 (46) 127 (41)

New 66 (21) 155 (50) 159 (52)

End of Tx 210 (68) 297 (95) 286 (93)

REGENERATE Younossi Lancet 2019;394:2184

Black Box: Hepatic decompensation and failure has occurred in PBC with CTP B or C.

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Liraglutide: LEAN Trial

• NASH, ±T2DM• Liraglutide: 1.8 mg SQ daily (22)• Placebo: SQ daily (23)• 48 weeks• Outcome (Bx)

• Resolution of NASH

• Adverse Events• No difference overall• More GI with liraglutide

9

3639

9

0

10

20

30

40

50

NASH resolution Fibrosis worsening

Histology at 48 weeks

Placebo Liraglutide

Weight Change over 48 weeks

23 2322

22

Armstrong Lancet 2016;387:679 16

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Cenicriviroc (CCR2/CCR5 inhibitor): CENTAUR• Inhibits inflammatory signaling

and immune cell infiltration• NASH (NAS≥4), Fibrosis 1-3• Primary: ≥2-point improvement

in NAS, no worsening in fibrosis11.1

16.7

19.9

15.2

0

5

10

15

20

25

1 year 2 years

Placebo CVC

Arm A

Arm B

Year 1

Placebo

Year 2

CVC CVC

CVCPlacebo

PlaceboPlacebo

Bx Bx Bx

Ratziu Gastroenterology 2020, Friedman Hepatology 2018

P=0.09; OR: 2.03

Fibrosis improvement ≥1 stageAND no worsening NASH

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Elafibranor (PPAR-α/PPAR-ẟ agonist): GOLDEN 505

• PPAR-α: ↓triglycerides, ↑HDL

• PPAR-ẟ: ↑ insulin sensitivity• 12 months• Outcome

• Protocol: “0” on steatosis, inflammation or ballooning

• Modified: “0” on ballooning, “0 or 1” on inflammation, overall not NASH, no fibrosis progression

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12

9

23

13 13

2119 19

0

5

10

15

20

25

Protocol Definition Modified Definition NAS≥4

NASH Resolution at 12 months

Placebo Elafibranor 80 mg Elafibranor 120 mg

Ratziu 2016;150:1147

P<0.05 P<0.015

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Empagliflozin (SGLT-2 inhibitor): E-LIFT trial

• ↓renal glucose reabsorption• T2DM and NAFLD (clinical Dx)• Randomization

• SOC for T2DM• SOC + empagliflozin 10 mg/day

• 20 weeks, 25/group• Outcome

• MRI-PDFF (primary)• ALT (secondary)

-0.9

-3.7-4.9

-14.6-16

-14

-12

-10

-8

-6

-4

-2

0

Change at Week 20 vs. baselineSOC + Placebo SOC + empagliflozin

Kuchay Diabetes Care 2018;41:1801

MRI PDFFLiver Fat

ALT

P<0.0001

P<0.005

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NGM282 (FGF19 analogue)

• FGF19: inhibits CYP7A1 (bile synth), • NGM282: non-tumorgenic

recombinant FGF19 (SQ daily)• 12 week

• Placebo vs. 3 mg/day vs. 6 mg/day• Outcome:

• Change in MRI-PDFF (liver fat)• ALT

• Histology• non-blinded• 1 mg vs. 3 mg

• Adverse eventsDiarrhea: 22% v. 41% v. 36%

-0.9

-9.7

-11.9

-14

-12

-10

-8

-6

-4

-2

0

Placebo 3 mg 6 mg

P<.0001

P<.0001

Harrison Lancet 2018;391:1174; Harrison Hepatology 2019

-1.9*

-0.1

-2.2*

-0.5*

-2.5

-2

-1.5

-1

-0.5

0NAS score Fibrosis score

Histology Score at W12

1 mg 3 mg

* p<0.05 vs baseline

Liver fat at W12

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FGF21 (pegbelfermin)

• FGF21 improves:• Glucose and lipid• Non-mitogenic

• Pegbelfermin: long-acting, SQ• NASH, Fibrosis 1-3, >10% PDFF• 16 weeks

• Placebo (n=26)• 10 mg/daily (n=25)• 20 mg once a week (n=24)

• Outcome• Reduction in hepatic fat (PDFF)

-1.3

-5.2

-6.8

-8

-7

-6

-5

-4

-3

-2

-1

0

Change in % fat fraction (absolute) at W16

Placebo 20 mg Weekly 10 mg daily

Sanyal Lancet 2018;392;2705

p<0.0005

p<0.01

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Resmetirom (THR-β agonist)• Thyroid hormone receptor-β in

liver (not systemic)• NASH (NAS≥4), fibrosis 1-3• 36 weeks

• Sub-group with 36 week extension

• Outcome• Reduction in fat (PDFF) at Week 12• Reduction in fat (PDFF) at Week 36• Fibrosis regression (≥1 stage) W36• NASH resolution at Week 36

• Week 36: ↓LDL, ↑HDL, ↓TG

-2.3

-8.5-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Fat (%) absolute

Placebo All doses

Harrison Lancet 2019;394:2012

6

27

0

5

10

15

20

25

30

35

NASH resolution

Placebo All doses

12

32

0

5

10

15

20

25

30

35

↓Fibrosis ≥1-pt

Placebo All doses

Changes at Week 36

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Summary• No FDA-approved treatment for NASH• Multiple Phase II/III trials • Multiple mechanisms• Modest improvement in NASH or fibrosis• Available Phase II/III

• Diet/exercise ● Obeticholic acid• Bariatric surgery ● Cenicriviroc• Vitamin E ● Elafibranor• Pioglitazone ● NGM282 • Liraglutide ● Pegbelfermin• Empagliflozin ● Resmetirom

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