The Hong Kong Association for the Study of Liver D 11/25/18 The - - PDF document

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NAFLD Therapeutics: How Will We Treat NASH 5-Years from Now?

Prof Quentin M. Anstee PhD, FRCP

Professor of Experimental Hepatology & Honorary Consultant Hepatologist, Institute of Cellular Medicine, Newcastle University, UK. Hong Kong Association for the Study of Liver Disease, Hong Kong, November 2018

Disclosure Slide

Research Grant Funding Abbvie, Allergan/Tobira, Astra Zenica, GlaxoSmithKline, Novartis Pharma AG, Pfizer Ltd., Vertex. Active Research Collaborations (including research supported through the EU IMI2 LITMUS Consortium*) Abbvie, Antaros Medical*, Allergan/Tobira, AstraZenica, Boehringer Ingelheim International GMBH*, Ellegaard Gottingen Minipigs AS*, Eli Lilly & Company Ltd.*, Exalenz Bioscience Ltd.*, Genfit SA*, GlaxoSmithKline, HistoIndex, Intercept Pharma Europe Ltd.*, iXscient Ltd.*, Nordic Bioscience*, Novartis Pharma AG*, Novo Nordisk A/S*, One Way Liver Genomics SL*, Perspectum Diagnostics*, Pfizer Ltd.*, Sanofi-Aventis Deutschland GMBH*, SomaLogic Inc.*, Takeda Pharmaceuticals International SA*. Consultancy Abbott Laboratories, Acuitas Medical, Allergan/Tobira, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genfit SA, Gilead, Grunthal, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel Pharma, Raptor Pharma, Servier, Viking Pharma. Speaker Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Genfit SA, Gilead, Integritas.

This lecture contains discussion of off-label/investigative use of commercial products, medical devices, biologic or pharmaceutical agents. The lecture is for academic purposes only and does not constitute any form of medical advice regarding use of these compounds in routine clinical practice or any form of financial advice/recommendation regarding the companies or the products discussed.

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Risk of Death or Transplantation

Early fibrosis

F1 F2 F3 F4

Advanced fibrosis & Cirrhosis Steatosis Steatosis + Lobular Inflammation NASH +/- Portal Inflammation

“Dynamic” Steatotic/Steatohepatitic phase “Non-Linear” Fibrotic phase

NAFLD Natural History

Steatohepatitis (NASH) is the biological driver of disease progression and fibrogenesis. The presence of advanced stage of fibrosis (F3-4) is the strongest predictor of long-term mortality.

Mortality Increases with Fibrosis Stage in NAFLD

Cardiovascular Disease Non-Liver Malignancy Liver Disease Hepatocellular Carcinoma Liver Transplantation Infections Other 18% /Unknown 8% 38% 19% 8% 1%

8% <1%

26%

Liver-Related Mortality

Angulo et al., Gastroenterology 2015

Systematic review and meta-analysis of 5 studies 1,495 NAFLD patients with 17,452 patient-years follow-up.

Dulai et al, Hepatology 2017;

All-Cause Mortality

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1. Target Obesity

– Lifestyle: Diet and Physical exercise – Bariatric Surgery

2. Target the Metabolic Syndrome – reduce CVD risk whilst selecting medication with additional ‘liver directed’ benefits

– Insulin resistance/Type 2 diabetes mellitus – Hypertension – Dyslipidaemia

3. Target the liver disease – ameliorate steatohepatitis and prevent progression to fibrosis and cirrhosis 4. Minimise down-stream complications such as HCC Targeting NAFLD: Four Principles of Treatment Lifestyle Changes: Current Evidence

• Weight reduction through diet and exercise

should be recommended because if sustained it improves: – Cardiovascular risk profile Hallsworth 2011 & 2015 – Steatosis Hallsworth 2011 & 2015; Houghton 2017; Sullivan 2012; Wong

2013; Promrat, 2010; Vilar-Gomez 2015

– Steatohepatitis (7-9% weight loss) Promrat 2010;

Vilar-Gomez 2015

– Fibrosis (>10% weight loss) Vilar-Gomez 2015

• NAFLD patients lack confidence to exercise

and may not be ready to make and sustain the necessary lifestyle changes Frith, 2010; Centis, 2013

Weight Loss Improves NAS (NASH)

Promrat, Hepatology 2010

Weight Loss Improves Fibrosis Stage

Vilar-Gomez, Gastroenterology 2015

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Bariatric Surgery

N = 82 cases with confirmed NASH and f/u Biopsy at 1-Year

PHARMACOLOGICAL THERAPY FOR NAFLD…?

Currently there are no licenced pharmacological treatments specifically for NAFLD Targeting the Liver Disease -

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Targeting Insulin Resistance & Oxidative Stress with Currently Available Agents

Compound Mechanism of Action Trial Name Company Primary Endpoint(s) Metformin Multiple Multiple Studies Investigator Led

Various

Pioglitazone PPARγ agonist PIVENS* Multiple Studies Investigator Led

Reduction in NAS ≥2 without fibrosis worsening

Liraglutide GLP-1 analogue LEAN*

(NCT01237119)

Novo Nordisc† / IL

Resolution of NASH without fibrosis worsening

Com Compou

• und

Me Mechanism sm of Ac Action

• n

Tr Trial Name Com Company Pr Primary Endpoint(s) Vitamin E Anti-oxidant PIVENS* TONIC* Investigator Led

Improvement in NAS ≥2 without fibrosis worsening

Targeting Insulin Resistance Targeting Oxidative Stress

*Phase IIb.

Currently Available Pharmacological Compounds

† Note Disclosures

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• Both agents improved steatosis & inflammation scores
• Only Vitamin E reduced ballooning
• Neither Vitamin E or Pioglitazone reduced fibrosis

P = 0.001* OR 3.14 P = 0.04 OR 2.13

Pioglitazone & Vitamin E for NASH: The Phase 2b PIVENS Study

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 83) Pioglitazone 30mg/day (N = 80) Vitamin E 800 IU/day (N = 84)

W0 W96

End of Treatment Liver Biopsy

T -24

Inclusion Liver Biopsy

W48 W24 W72

247 non-diabetic adults with biopsy proven NASH 96 Weeks

Primary Endpoint = 2-point NAS reduction (inc. reduced ballooning) with no worsening of fibrosis

Inclusion: NAS ≥ 4, F ≤3 * Significance: P < 0.025

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 51) Pioglitazone 45 mg/day (N = 50)

W0 W78

End of Treatment Liver Biopsy

T -24

Inclusion Liver Biopsy

W24 W12 W36

78 Weeks 101 pre-diabetic/diabetic adults with biopsy proven NASH

Pioglitazone for NASH: Further evidence

Cusi et al, Ann Int Med 2016

• Pioglitazone produced a significantly higher resolution of

NASH but no improvement in fibrosis.

Inclusion: “Confirmed NASH” ?NAS ≥3, F ≤3 + 500 kcal/day deficient diet

Primary Endpoint = 2-point NAS reduction (inc. reduced ballooning) with no worsening of fibrosis

10 20 30 40 50 60

Placebo Pioglitazone % Reaching Primary End-Point

P < 0.001

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• Vitamin E

– Increased all cause mortality risk at >400 IU/day

Miller, 2005; Bjelakovic, 2007

– Increased haemorrhagic stroke risk (although reduced embolic stroke risk)

Schwarts, 2010

– Increased Prostate carcinoma risk

Lippman, 2009; Klein, 2011

• Pioglitazone

– Oedema and Weight gain

Basu, 2006; Sanyal, 2010

– Increased risk of Osteoporosis

Schwartz, 2006

– Increased Bladder Cancer risk (HR 1.63) in some, but not all studies

Toccori, 2016; Lewis, 2015

Safety & Tolerability Issues

Use of these agents should be personalised for selected patients with histologically confirmed NASH after careful consideration of risk/benefit ratio

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 22) Liraglutide 1.8mg/day (N = 23)

W0 W48

End of Treatment Liver Biopsy

T -24

Inclusion Liver Biopsy

W24 W12 W36

48 Weeks 45 diabetic and non-diabetic adults with biopsy proven NASH

Primary Endpoint = resolution of NASH (loss of ballooning) with no worsening of fibrosis

Liraglutide for NASH: The Phase 2b LEAN Study

Armstrong et al, Lancet 2015

• Liraglutide improved NASH with no worsening of fibrosis.
• Unclear if effects were entirely independent of weight loss.
• Unusually rapid disease progression observed in Placebo arm.

Inclusion: “Definite NASH” ?NAS ≥3, F ≤3

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Hypertension Dyslipidaemia* T2DM

Control Obesity Reduce CVD Risk Targeting NASH Reduce HCC Risk

Promrat et al, 2010 Thoma et al, 2012 Vilar-Gomez et al, 2015 Lassailly et al, 2015 Zhang et al, 2012 Chen et al, 2013 El-Serg et al, 2009 Singh et al, 2013 Sanyal et al, 2010 Lavine et al, 2011 Musso et al, 2010 Cusi et al, 2016 Armstrong et al, 2012 Ratziu et al, 2010 Musso et al, 2010

Recommendations with Currently Available Treatments

45 year old with type 2 diabetes and NASH with stage 3 fibrosis comes in to discuss therapeutic options…

Treat Metabolic Syndrome Lifestyle Change “Liver Directed” Rx

• Vitamin E
• Pioglitazone
• (Liraglutide)
• Metformin
• Simvastatin

Potential effects for “HCC Chemoprevention”

• Diet
• Exercise
• Bariatric Sx

* NAFLD does not increase Statin DILI risk

Bays 2014; Bril 2017

Pharmacotherapy: What’s on the Horizon…?

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Targeting Pathophysiological Processes

Steatohepatitis Cirrhosis Normal Liver Steatosis Targets related to Insulin Resistance and/or Lipid Metabolism Targets related to Lipotoxicity & Oxidative Stress Targets related to Inflammation and Immune activation Targets related to Cell Death (Apoptosis and Necrosis) Targets related to Fibrogenesis & Collagen Turnover

PPARα/∂: Elafibranor PPARα/∂/γ: IVA337 PPARα/γ: Saroglitazar THR-β: MGL-3196 mTOT: MSDC-0602K FXR: OCA, GS-9674, LJN-452, LMB-763 TGR5: INT-767, INT-777 ASBT: Volixibat FGF19: NGM282 AMPKi: PXL770 Vitamin E PPARγ: Pioglitazone GLP-1: Liraglutide Semaglutide MPCi: PXL065 SGLT1/2: LIK066 GLP-1/GR: MEDI0382 KHKi: PF-06835919 ACCi: GS-0976, PF-05221304 DGAT2i: PF-06865571 SCD1: Aramchol FGF21: BMS-986036 CCR2/5: Cenicriviroc AOC3: BI 1467335 TLR4: JKB-121 Anti-LPS: IMM-124E ASK1: Selonsertib Caspases: Emricasan LOXL2: Simtuzumab Galectin: GR-MD-02

Modified from Perrazo & Dufour, Liver International 2017

FXR

Obeticholic Acid (FXR)

Apoptosis

Selonsirtib (ASK1)

Pathophysiology & Therapeutic Targets

PPARs

Elafibranor (PPAR α/δ) Cenicriviroc (CCR2/CCR5)

Fibrosis

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Com Compou

• und

Me Mechanism sm of Action Tr Trial Name Com Company Pr Primary Endpoint(s) Obeticholic Acid

(INT-747, Ocaliva)

FXR agonist (bile acid derived)[1] REGENERATE

(NCT02548351)

Intercept†

Co-primary endpoints: (i) Improvement in Fibrosis by ≥1-stage without worsening of NASH; (ii) Resolution of NASH without worsening

• f Fibrosis

Elafibranor

(GFT-505)

PPAR α/δ agonist[2] RESOLVE-IT

(NCT02704403)

Genfit†

Resolution of NASH (no ballooning, no/minimal lobular inflammation) without worsening of fibrosis

Cenicriviroc

(TAK-652/TBR-652)

CCR2/CCR5 antagonist[3] AURORA

(NCT03028740)

Allergan†

Improvement in Fibrosis by ≥1-stage without worsening of NASH

Selonsertib

(GS-4997)

ASK1 inhibitor[4] STELLAR-3

(NCT03053050)

STELLAR-4

(NCT03053063)

Gilead†

Improvement in Fibrosis by ≥1-stage without worsening of NASH

Sources: ClinicalTrials.gov and the UK NIHR Innovation Observatory

Supporting Phase 2 Trial Publications

• 1. Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.
• 2. Ratziu V, et al. Gastroenterology. 2016;150:1147-1159.
• 3. Friedman S, et al. Hepatology. 2017; in press.
• 4. Loomba et al. Hepatology. 2017, in press.

Compounds Currently in Phase 3 Clinical Trials

† Note Disclosures

Modified from Perrazo & Dufour, Liver International 2017

FGF19 FXR Bile Acids

FXR Agonists

Pathophysiology & Therapeutic Targets

Fibrosis

Activation of Inflammatory Cytokines

Inflammation

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Enterohepatic Bile Acid Circulation & FXR/FGF19 Agonists

• BAs are secreted into the bile and

reabsorbed in the terminal ileum.

• Hepatic FXR activation by BAs:

– ↓ BA synthesis (CYP7A1), – ↓ Lipogenesis (SREB1c/ChREBP), – ↓ Gluconeogenesis, – ↑ Insulin sensitivity.

• Ileal FXR activation ↑FGF-15/19

production that acts via FGFR4:

– ↓ BA synthesis (CYP7A1) – ↑ Hepatic glycogen storage – ↑ FA oxidation.

Figure: Arab et al, Hepatology 2016, in press.

• Intestinal TGR5 activation by BAs

promote GLP-1 release that promotes insulin release from pancreatic b-cells.

• Muscle and adipose tissue TGR5

activation increases thermogenesis and energy expenditure.

Figure: Arab et al, Hepatology 2016, in press.

Exploitable drug targets: FXR agonists (OCA, GS-9674, LJN-452, LMB-763) TGR5 agonist (INT-767, INT-777) ASBT inhibitors (SHP-626) FGF-19 agonists (NMG-282)

Enterohepatic Bile Acid Circulation & FXR/FGF19 Agonists

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Relevance of FXR Agonists in NAFLD Therapy

↑ Insulin Sensitivity ↓ Gluconeogenesis ↓ Bile acid synthesis ↓ Lipogenesis ↑ Fatty Acid oxidation

Obeticholic Acid (OCA) for NASH: The Phase 2b FLINT Study

Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 142) Obeticholic Acid 25 mg/day (N = 141)

W0 W72

End of Treatment Liver Biopsy

T -12

Inclusion Liver Biopsy

W36 W18 W44

72 Weeks 283 diabetic and non-diabetic adults with biopsy proven NASH

Primary Endpoint = improvement of NAS ≥ 2 points with no worsening of fibrosis

5 10 15 20 25 30 35 40 45

Placebo Obeticholic Acid % Reaching Primary End-Point

P = 0.0002

Reduced NAS Reduced Fibrosis Obeticholic Acid 45% (50/110) 35% (36/102) Placebo 21% (23/109) 19% (19/98)

Inclusion: NAS ≥ 4, F ≤3

• Trial terminated early by DSMB due to clear effect
• Apparent beneficial effects for NASH & Fibrosis

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• 0.4
• 0.3
• 0.2
• 0.1

0.1 0.2 0.3 0.4 0.5 0.6 0.7

Total Cholesterol HDL LDL Triglycerides

Obeticholic Acid Placebo Mean Change from Baseline (OCA vs Placebo)

Obeticholic Acid (OCA) for NASH: The Phase 2b FLINT Study

P = 0.0009 P = 0.01 P < 0.0001 P = 0.88

mmol/L

Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.

FXR-Related Targets Currently in Phase 2/3 Trials

Com Compou

• und

Me Mechanism sm of Action Tr Trial Name Com Company Pr Primary Endpoint(s) Obeticholic Acid

(INT-747, Ocaliva)

FXR agonist (bile acid derived) FLINT

(NCT01265498)

REGENERATE*

(NCT02548351)

Intercept†

Co-primary endpoints: (i) Improvement in Fibrosis by ≥1-stage without worsening of NASH; (ii) Resolution of NASH without worsening of Fibrosis

GS-9674

(PX-104)

FXR agonist (bile acid) GS-US-402-1852

(NCT02854605)

Gilead†

Safety and tolerability

LMB-763 FXR agonist (synthetic) CLMB763X2201

(NCT02913105)

Novartis†

Change in Transaminase levels at 12 weeks.

Tropifexor LJN-452 FXR agonist (synthetic) FLIGHT-FXR

(NCT02855164)

Novartis†

Safety and tolerability

NGM-282 FGF-19 agonist 15-0105

(NCT02443116)

NGMBio†

Change in hepatic fat by MRI at 12 weeks.

Volixibat

(SHP-626)

ASBT inhibitor SHP626-201

(NCT02787304)

Shire

Improvement in NAS ≥2 without fibrosis worsening at 48 weeks. Combination therapies also being studied

*Phase III † Note Disclosures

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FGF19 Agonist (MGM-282) for NASH

Harrison et al, AASLD 2018 Harrison et al, AASLD 2018

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NGM-282 1mg for 12 weeks NGM-282 3mg for 12 weeks

Harrison et al, AASLD 2018 Harrison et al, AASLD 2018

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PPARs as Therapeutic Targets for NAFLD

γ β/δ α

Targets: PPAR γ (Glitazones), PPAR α/∂ (Elafibranor), PPAR α/γ (Saroglitazar) and PPAR α/∂/γ (IVA337)

é Fatty acid β-oxidation ê Hepatic Steatosis ê Gluconeogenesis ê Inflammatory genes controlled by NF-κB é Insulin Sensitivity ê Hepatic Steatosis ê Inflammation ê Stellate cell activation é Adipose FA Uptake

✓ ✗ ✓

é Body weight é Oedema ê Bone strength

Metabolically active tissues (especially Liver) Adipose tissue Skeletal muscle, fat, intestine, liver and the heart

ê Inflammation (M2 polarisation) ê Plasma TG levels é Plasma HDL levels é Insulin Sensitivity é FA transport & oxidation ê Hepatic steatosis

✓

PPAR Related Targets Currently in Phase 2/3 Trials

Com Compou

• und

Me Mechanism sm of Action Tr Trial Name Com Company Pr Primary Endpoint(s) Pioglitazone PPAR γ agonist PIVENS

(NCT00063622)

Investigator Led

Reduction in NAS ≥2 without fibrosis worsening

Elafibranor

(GFT-505)

PPAR α/δ agonist GOLDEN-505

(NCT01694849)

RESOLVE-IT*

(NCT02704403)

Genfit†

Resolution of NASH (no ballooning, no/minimal lobular inflammation) without worsening of fibrosis

IVA-337 PPAR α/∂/γ agonist NATIVE

(NCT03008070)

Inventiva† Saroglitazar PPAR α/γ agonist EVIDENCES II

(NCT03061721)

Zydus

Percentage change from baseline in serum ALT and AST levels at week 16 *Phase III

† Note Disclosures

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5 10 15 20 25

Placebo Elafibranor 80mg Elafibranor 120mg % Reaching Primary End-Point

Elafibranor (ELA) for NASH: The Phase 2b GOLDEN-505 Study

Ratziu et al, Gastroenterology, 2016

274 diabetic and non-diabetic adults with biopsy proven NASH

Per Protocol Primary Endpoint = resolution of NASH (score 0 for >1 NAS component [S, B, I]) with no worsening of fibrosis Results of Per Protocol Endpoint

NS NS

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 92) Elafibranor 80mg/day (N = 93) Elafibranor 120mg/day (N = 89)

W0 W52

End of Treatment Liver Biopsy

T -39

Inclusion Liver Biopsy

W26 W13 W39

52 Weeks

Inclusion: NAS ≥ 3, F ≤3

274 diabetic and non-diabetic adults with biopsy proven NASH

Post Hoc Modified Primary Endpoint = resolution of NASH (loss of ballooning and 0-1 for inflammation) with no worsening of fibrosis

SCREENING PERIOD FOLLOW-UP PERIOD

Placebo (N = 92) Elafibranor 80mg/day (N = 93) Elafibranor 120mg/day (N = 89)

W0 W52

End of Treatment Liver Biopsy

T -39

Inclusion Liver Biopsy

W26 W13 W39

52 Weeks

Inclusion: NAS ≥ 3, F ≤3

2 4 6 8 10 12 14 16 18 20

Placebo Elafibranor 80mg Elafibranor 120mg % Reaching Modified Primary End-Point

Results of Post Hoc Modified Endpoint

NS P = 0.045 OR 2.31

Baseline Histology [N] Placebo ELA 120mg OR P-Value NAS ≥ 3 [N = 274] 12% 19% 2·31 0·045 NAS ≥ 4 [N = 234] 9% 19% 3·52 0·013

Elafibranor (ELA) for NASH: The Phase 2b GOLDEN-505 Study

Ratziu et al, Gastroenterology, 2016

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Modified from Perrazo & Dufour, Liver International 2017

Pathophysiology & Therapeutic Targets

FGF21 Metabolic Homeostasis Fatty Acids Triglyceride

Lipid Metabolism, Lipotoxicity & Oxidative Stress in NAFLD

­ Insulin ­ Glucose

NASH ROS

Dicarboxylic Acid

Insulin Resistance De Novo Lipogenesis Mitochondrial β-Oxidation Peroxisomal β -Oxidation Microsomal ω-Oxidation

ACC

CPT1

Triglyceride Steatosis VLDL

­ Lipotoxic Intermediates

Phosphatidic acid Lysophospahtidic acid Lysophosphatidyl choline Ceramides Diacylglycerols

ER Stress Mitochondrial Dysfunction Apoptosis & Necrosis ­ Circulating Fatty Acids Adipose Lipolysis

SREBP1 ChREBP

­ Hepatocyte Free Fatty Acid Flux

­ Acetyl-CoA ­ Mal-CoA

FAS SCD1 DGAT2

Exploitable drug targets: KHKi (PF-06835919) ACCi (GS-0976, PF-05221304) SCD1i (Aramchol) DGAT2i (PF-06865571)

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Other Compounds with Targets Related to Lipid Metabolism

Com Compou

• und

Me Mechanism sm of Action Tr Trial Name Com Company Pr Primary Endpoint(s) Aramchol SCD1 Aramchol_005

(NCT02279524)

Galmed†

Percentage change in the liver triglycerides concentration measured by NMRS.

BMS-986036 FGF21 NCT02413372 BMS†

Change in hepatic fat fraction (%) by MRI. Safety.

GS-0976 ACC inhibitor GS-US-426-3989

(NCT02856555)

GS-US-384-3914

(NCT02781584)

Gilead†

Safety and Efficacy alone or in combination with other compounds.

PF-05221304 ACC inhibitor C1171002

(NCT03248882)

Pfizer†

Safety and tolerability

PF-06835919 KHK inhibitor Pfizer†

Safety and tolerability

PF-06865571 DGAT2 inhibitor Pfizer†

Safety and tolerability

† Note Disclosures

Ratziu et al, AASLD 2018

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Acetyl CoA Carboxylase (ACC) Inhibition (GS-0976)

Lawitz et al, EASL 2017

12-weeks treatment with GS-0976 led to significant reductions in de novo lipogenesis, MRI-PDFF and MRE-Liver Stiffness relative to Baseline levels. Open-Label Phase IIa Study

Preliminary efficacy and safety of acetyl-CoA carboxylase (ACC) inhibitor GS-0976 in patients with compensated cirrhosis due to NASH

• In this 12-week, proof-of-

concept study in patients with compensated NASH cirrhosis, GS-0976 was safe and associated with significant reductions in hepatic DNL, MRI-PDFF, and serum ALT

*Small bowel obstruction; †Hypertriglyceridemia (n=1) and fatigue (n=1); ‡Grade 3 neutropenia (n=1), hyperglycemia (n=2), hyponatremia (n=1), and hypertriglyceridemia (n=1)

Changes from baseline to Week 12 Adverse events and laboratory abnormalities Median relative % change from BL to Week 12 GS-0976 20 mg, N=10 ALT –28.8 (–34.6, –14.8), p=0.004 AST –12.3 (–22.6, –2.3) Bilirubin –8.3 (–25.0, 8.3) GGT –8.3 (–20.0, 13.2) ELF –3.0 (–6.2, 3.1) TIMP-1 –1.7 (–9.7, 16.1) PIIINP –9.2 (–40.5, 18.8) Hyaluronic acid –19.1 (–35.0, 41.2)

Pts, n (%) GS-0976 20 mg, N=10 Completed Tx 10 (100) TEAEs 8 (80) Grade 3 1* Grade 4 Death Tx-related AE 4 (40) Grade ≥2 2 (20)† TE lab abnormalities Grade 3 4 (40)‡ Grade 4

10 6 4 2

MRE-stiffness (kPa)

No effect of GS-0976 on MRE-stiffness

↓32% p=0.01

15 10 5

MRI-PDFF (%) BL

Decreases in liver fat by MRI-PDFF

p=0.01 p=0.004

Wk 12 Wk 4

8

BL Wk 12 Wk 4

50 30 20 10 40

BL Wk 12 Contribution to plasma palmitate (%)

↓39% p=0.56

Inhibition of hepatic de novo lipogenesis

Harrison S, et al. EASL 2018, Paris. #FRI-487

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Thyroid Hormone Receptor (THRβ) Agonist (MGL-3196)

• Epidemiological studies link NAFLD with high rates of clinical and subclinical

hypothyroidism.

• Evidence that NAFLD patients exhibit decreased thyroid hormone response gene

expression in the liver.

• Patients with hypothyroidism exhibit:

– Increased TG and Cholesterol levels. – Insulin resistance

• THRβ agonists potentially have beneficial effects including:

– Decreased TG, LDL-Cholesterol, non-LDL-Cholesterol, Apolipoprotein B – Decrease PCSK9, so increased reverse cholesterol metabolism

MGL-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36-week serial liver biopsy study

Mechanism of action: The importance of liver THR-β in NASH

Thyroid gland T4 T3 TSH Liver T4→T3 Nuclear thyroid hormone receptor α or β

T4, prohormone T3, active hormone TSH, thyroid stimulating hormone

In humans THR-β agonism: ↓ Lowers LDL-cholesterol ↓ Lowers triglycerides ↓ Lowers liver fat, potentially reducing lipotoxicity, NASH No thyrotoxicosis (THR-α effect)

MRI-PDFF Liver biopsy D1 W2 W4 W8 W12 W24 W36 Screening Pharmacokinetic assessment MRI-PDFF MRI-PDFF Liver biopsy

N=125

• In vivo preclinical and clinical data support use of MGL-3196

– High specificity hepatic uptake – Avoids activity at the systemic THR-α receptor – Well tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increases

2:1 randomization

Placebo MGL-3196 80 mg/day (Possible dose adjustment +20 mg at Week 4)

Primary endpoint: relative ↓ MRI-PDFF fat Secondary: # achieving ≥30% ↓ MRI-PDFF fat, NASH/fibrosis biomarkers and lipids, LMS Secondary: Histology, MRI-PDFF, NASH/fibrosis biomarkers and lipids

Key Inclusion/exclusion: § NASH: NAS ≥4 + F1–3 § MRI-PDFF: ≥10% liver fat

Baseline Placebo (n=41) MGL-3196 (n=84) NAS, mean (SD) 4.8 (1.1) 4.9 (1.0) Fib n (%) 0–1 21 (51.2) 48 (57.1) n (%) 2–3 20 (48.8) 36 (42.8) Diabetic, n (%) 13 (31.7) 35 (41.7) MRI-PDFF, mean (SD) 19.8 (6.7) 20.7 (7.0)

All baseline demographics comparable between groups Harrison S, et al. EASL 2018, Paris. #GS-009

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32 51 65 61 18 47

10 20 30 40 50 60 70 p=0.09 p=0.006 p=0.02 p=0.02 % of biopsies <5% Weight loss

6 27 39 25 37

5 10 15 20 25 30 35 40 45 p=0.02 p=0.001 p=0.03 p=0.003 % of biopsies no fibrosis worsening

NASH Liver Biopsy Endpoints at Week 36

2-pt reduction in NAS in placebo patients was correlated with body weight loss

MRI Responder; ≥ 30% fat reduction on Week 12 MRI-PDFF High Exp,, n=44; 2-pt NAS reduction; MGL-3196, n=73, placebo n=34; NASH Resolution, prespecified endpoint: at least 2-pt reduction in NAS; ballooning=0, inflammation=0, 1, <9.5% weight loss;

Placebo MGL-3196 (all) MGL-3196 (high exp) MGL-3196, MRI responder In MGL-3196 treated patients with NASH resolution, 50% had fibrosis resolution (F=0)

2-Point NAS Reduction

with at least a 1-pt reduction in ballooning or inflammation (% of liver biopsies)

NASH Resolution

ballooning=0, inflammation =0, 1 with at least 2-point reduction in NAS (% of liver biopsies)

Harrison et al, AASLD 2018

12 32 47 10 20 30 40 50 All F3 p=0.03 p=0.05 % biopsies

Placebo MGL-3196

Change in Fibrosis Score on Liver Biopsy at Week 36

n Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen n SHG score was generated and aligned with the pathologist baseline score (baseline, r=0.76), (left panel), blinded to treatment code n Using SHG, MGL-3196 treated compared with placebo showed a statistically significant ≥1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo

≥1 pt reduction in fibrosis

• n liver biopsy (SHG)

Pathologist Score SHG (qfibrosis)

3 2 1 SHG Score

1A 1B 2 3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Harrison et al, AASLD 2018

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Modified from Perrazo & Dufour, Liver International 2017

Gut Microbiome Oxidative Stress

Pathophysiology & Therapeutic Targets

Fibrosis Inflammation Apoptosis

Selonsirtib (ASK1)

Activation of Inflammatory Cytokines

Cenicriviroc (CCR2/CCR5)

CCR2/CCR5 Signaling in Inflammation & Fibrogenesis

Ceniciviroc (CVC) is a CCR2/CCR5 Antagonist

Kupffer Cells

Bacterial Endotoxin

CCR5 CCR2 CCR5 CCR2 CCR5 CCR2 Inflammatory Monocytes Inflammatory Macrophages RECRUITMENT MATURATION

PAMPs DAMPs

Secondary Inflammatory Injury

TNFa IL-1b TGFb PDGF CCL2 (MCP-1)

Oxidative Stress Lipotoxicity ER Stress

Necrosis & Apoptosis

Quiescent Stellate Cell Activated Stellate Cell Fibrosis Deposition ACTIVATION & PROLIFERATION CCR5 CCR2

CCR2/5 blockade potentially interferes with inflammatory signaling by Kupffer cells & Monocyte/Macrophage recruitment CCR2/5 blockade potentially disrupts signaling that activates stellate cells Chemokine receptors type 2 (CCR2) and type 5 (CCR5) are expressed on cells that promote inflammation & fibrogenesis.

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289 diabetic and non-diabetic adults with biopsy proven NASH

Primary Endpoint = improvement of NAS ≥ 2 points (with ≥1 point reduction in Inflammation or Ballooning) and no worsening of fibrosis

Ceniciviroc (CVC) for NASH: The Phase 2b CENTAUR Study

2 4 6 8 10 12 14 16 18 20

Placebo Ceniciviroc % Reaching Primary End-Point

NS

Results of Primary Endpoint Analysis at Year 1

SCREENING PERIOD YEAR 2 CONTINUATION STUDY

Placebo (N = 144) Ceniciviroc 150 mg/day (N = 145)

W0 W52

End of Treatment Liver Biopsy

T -24

Inclusion Liver Biopsy

W26 W13 W39

52 Weeks

Inclusion: NAS ≥ 4, F 1-3

Friedman et al, Hepatology 2017

• Year 1: No clear benefit for histological NASH but significant

anti-fibrotic effect

• Year 2 data indicates the anti-fibrotic effect was maintained but

without a statistically significant additive effect

SCREENING PERIOD YEAR 2 CONTINUATION STUDY

Placebo (N = 144)

W0 W52

End of Treatment Liver Biopsy

T -24

Inclusion Liver Biopsy

W26 W13 W39

52 Weeks 289 diabetic and non-diabetic adults with biopsy proven NASH

Key Secondary Endpoint = improvement in Fibrosis by ≥ 1 point with no worsening of steatohepatitis

Inclusion: NAS ≥ 4, F 1-3

Ceniciviroc (CVC) for NASH: The Phase 2b CENTAUR Study

2 4 6 8 10 12 14 16 18 20

Placebo Ceniciviroc % Reaching Key Secondary End-Point

P = 0.023 OR 2.20

Results of Secondary Endpoint Analysis at Year 1

Ceniciviroc 150 mg/day (N = 145)

Friedman et al, Hepatology 2017

• Year 1: No clear benefit for histological NASH but significant

anti-fibrotic effect

• Year 2 data indicates the anti-fibrotic effect was maintained but

without a statistically significant additive effect

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ASK1 Inhibition in NASH (Selonsertib)

• Apoptosis signal-regulating kinase 1

(ASK1), aka MAP3K5.

• ASK1 pathway is activated in NASH

and correlates with fibrosis stage

• In rodent models, ASK1 inhibition

improves steatosis, inflammation and fibrosis

• Selonsertib (SEL, formerly

GS-4997) is a selective, potent, small molecule inhibitor of ASK1

ASK1, apoptosis signal-regulating kinase 1. Trx, thioredoxin. Xiang, et al. J Hepatol 2016;64:1365–77; Zhao, et al. Gut 2014;63:1159–72; Huntzicker, et al. AASLD 2015 (#2149); Budas, et al. AASLD 2016 (#1588). ↑ Cytokine secretion ↑ Inflammation ↑ Activation ↑ Collagen production ↑ Apoptosis/necrosis ↑ Mitochondrial ROS ASK1

P

JNK p38 ASK1

P P

Oxidative Stress & ER Stress

Trx Trx

Oxidized

ROS

Hepatocyte Stellate Cell Macrophage

Selonsertib

Figure courtesy of Gilead 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

SEL 18mg ± SIM SEL 6mg ± SIM SIM % Reaching Primary End-Point

Worse No Change Improved

Selonsertib (SEL) for NASH: Phase 2a GS-US-384-1497 Study

Adult patients with biopsy proven NASH + Fibrosis

Primary Endpoint ≥ 1 stage improvement of fibrosis Results of Change in Fibrosis by ≥ 1 Stage

SCREENING PERIOD FOLLOW-UP PERIOD

SIM (N = 10) SEL 18mg ± SIM (N = 32) SEL 6mg ± SIM (N = 30)

W0 W24

End of Treatment Liver Biopsy

T -39

Inclusion Liver Biopsy

W12 W6 W18

24 Weeks

Inclusion: NAS ≥ 3, F 2-3

Loomba et al, Hepatology 2017

No Placebo Arm (Simtuzumab: “no effect on histology or pharmacokinetics”)

43%

N = 30 N = 27 N = 10

50% 7% 30% 56% 15% 20% 40% 40%

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Combination Therapy

Activation of Inflammatory Cytokines

Cenicriviroc (CCR2/CCR5)

Combination Therapy #1: Tropifexor (Novartis) + Cenicriviroc (Allergan)

Fibrosis FGF19 FXR Bile Acids

Tropifexor (FXR Agonist)

Gut Microbiome Inflammation

Modified from Perrazo & Dufour, Liver International 2017

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TANDEM Study

A 48-week, Phase 2b, multicenter, randomized, double-blind study

Stringer et al, AASLD 2018

Apoptosis

Activation of Inflammatory Cytokines

Selonsirtib (ASK1i)

Combination Therapy #2: FXR ± ASK1i ± ACCi (Gilead)

Oxidative Stress Metabolic Homeostasis Fatty Acids Triglyceride

GS0976 (ACCi)

Gut Microbiome FGF19 FXR Bile Acids

GS9674 (FXR Agonist)

Fibrosis Inflammation

Modified from Perrazo & Dufour, Liver International 2017

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Proof-of-concept study of an apoptosis-signal regulating kinase (ASK1) inhibitor (selonsertib) in combination with an acetyl-CoA carboxylase inhibitor (GS-0976) or a farnesoid X receptor agonist (GS-9674) in NASH

• Inclusion:

– Clinical diagnosis of NAFLD – MRI-PDFF ≥10% and MRE ≥2.88 kPa, or biopsy consistent with NASH and F2–F3 – Noncirrhotic (FibroTest™ <0.75, historical imaging and liver biopsy)

Lawitz E, et al. EASL 2018, Paris. #PS-105 *p<0.05 and †p=0.11 for comparison of baseline vs Week 12 using Wilcoxon signed-rank test

• *p<0.05, †p=0.083, and ‡p=0.064 for comparison of baseline vs Week 12
• using Wilcoxon signed-rank test
• 12-week therapy with SEL + ACC or FXR was safe and well tolerated
• Combination regimens demonstrated beneficial effects on:

– Hepatic DNL and steatosis – Liver biochemistry – Markers of fibrosis, including reduced lumican synthesis in SEL + ACC arm

• Phase 2, 48-week study with histological assessment ongoing to

better characterize efficacy and safety of combinations vs monotherapies in advanced fibrosis due to NASH

• Significant reductions in MRI-PDFF in patients treated

with ACC

• Reductions in MRE-stiffness and TIMP-1 in patients

treated with ACC monotherapy MRI-PDFF responses

• 6 0
• 4 0
• 2 0

2 0 M R I-P D F F , M e d ia n R e la tive C h a n g e (% ) a t W e e k 1 2

7.1% –15.6%* –9.4%

n=47 n=26

–42.7%* –32.0%*

≥30% relative reduction 10% (1/10) 70% (7/10) 0% (0/10) 50% (10/20) 15% (3/20) SEL ACC FXR Lawitz E, et al. EASL 2018, Paris. #PS-105

Proof-of-concept study of an apoptosis-signal regulating kinase (ASK1) inhibitor (selonsertib) in combination with an acetyl-CoA carboxylase inhibitor (GS-0976) or a farnesoid X receptor agonist (GS-9674) in NASH

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Activation of Inflammatory Cytokines

Combination Therapy #2: FXR (Novartis) ± ACCi ± KHKi ± DGAT2i (Pfizer)

Oxidative Stress Metabolic Homeostasis Fatty Acids Triglyceride

PF-05221304 (ACCi) PF-06865571 (DGAT2i) PF-06835919 (KHKi)

Gut Microbiome FGF19 FXR Bile Acids

Tropifexor (FXR Agonist)

Fibrosis Inflammation

Modified from Perrazo & Dufour, Liver International 2017

• In the absence of regulator approved drug therapy, at present the treatment of

NAFLD/NASH should focus on:

– Weight loss via calorific restriction diets (and exercise), or bariatric surgery – Reducing CVD risk-profile (statins “safe”) – Consider use of agents with trial evidence of a beneficial effect on NASH:

• Pioglitazone, or possibly Liraglutide, in patients with T2DM.
• Vitamin E may be used in selected non-diabetic patients.
• Individualised decision making balancing known risks vs. benefits required for all.
• NAFLD clinical practice guidelines published by AASLD (2017) and EASL-EASD-EASO

(2016).

• The drug-development pipeline for NAFLD/NASH is burgeoning. A number of

promising compounds to treat NAFLD are entering Phase 2/3 clinical trials.

• Results of clinical trials must be awaited before any firm recommendations can be

made in terms of efficacy or side-effect profiles for these new agents.

Conclusions

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Acknowledgements

Prof Chris Day, Prof Ann Daly, Dr Olivier Govare, Dr Jeremy Palmer, Dr Marie Boyle, Dr Tim Hardy, Dr Yang-Lin Liu, Ms Emma Scott. Prof Helen Reeves, Prof Fiona Oakley, Prof Derek Mann, Prof Jelena Mann, Dr Dina Tiniakos, Dr Stuart McPherson, Dr Kate Hallsworth, Ms Laura Haigh.

FP7, Horizon 2020 & IMI2

Elucidating Pathways of Steatohepatitis

EPoS

quentin.anstee@newcastle.ac.uk

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