Pharmacological therapies for NASH

S. Francque, MD, PhDProfessor of Medecine

Antwerp University

Chairman, Department of Gastroenterology Hepatology

University Hospital Antwerp

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Disclosures

consultancy and/or speaker for Gilead, MSD, BMS, Roche, Bayer, Aktelion, Janssen,

Intercept, Genfit, Inventiva, GSK, BoehringerIngelheim, Galmed, Genentech, Galapagos, Aligos, Enyo, Novartis, Novo Nordisk, Astra

Zeneca, Promethera, Echosens.

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Steatosis

Primary

• Alcohol

• Drugs

• Hepatitis C

• …

Non-Alcoholic Fatty Liver DiseaseNAFLD

Secondary

Visceral obesity, hyperinsulinism, diabetes, dyslipidaemia, metabolic

syndrome

“Metabolic steatosis”

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Furtherdevelopments?

Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019

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CV and renal

Adapted from Francque et al. J Hep 2016

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Causes of NASH• Metabolic syndrome vs. lean NASH

• Genetic factors– PNPLA3

– TM6SF2

– MBOAT7

– …

• Specific genetic factors– LAL-deficiency

• Lipodystrophy– Lipohypertrophy

• HIV

• HAART (“Crix belly”)

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Haas, Francque & Staels. Ann Rev Physiol 2016

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Vanni et al, Dig Liv Dis 2010Targher et al, NEJM 2010Ekstedt et al, Hepatology 2006Anstee et al, Nature Reviews 2013Ballestri et al, WJG 2014Yki-Järvinen, Lancet 2014

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Schuppan et al. J Hep 2018

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Metabolic drivers

Damage/inflammation

Fibrogenesis

Repair & fibrinolysis

• Design Phase 3– Accelerated/conditional approval (FDA Subpart H)

• Accelerated/Conditional approval on surrogate endpoint• Final approval on clinically meaningful benefit

– So need hard clinical endpoints

• For NASH Phase 3– Surrogate = liver biopsy

• Resolution of NASH (i.e. ballooning = 0) without worsening of fibrosis• Improvement in fibrosis without worsening of NASH

– Hard clinical endpoints• Liver related (histology of cirrhosis or any decompensation/complication)

When will we have a drug approved?

StartInterim analysis

Conditional approval

Clinical endpoints

Approval

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Primary endpoint: histology

Treatment IndicationNASH

±

Some degree of activity?

(NAS ≥ 4?, A3?)

+

Some degree of fibrosis

F ≥ 2

or

F1 + risk factors (NAS ≥ 5, DM2, obesity,…)

In patients who have otherwise been optimised cardiometabolically

Sanyal et al. Hepatology 2015EASL-EASD-EASO Practice Guideline. J Hep 2016Chalasani et al. AASLD Practice Guidance. Hepatology 2017Francque et al. Acta Gastroenterol Belg 2018

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• What are the endpoints?

– Resolution of NASH?

• Reduction in NASH activity (NAS or A)?

– Regression of fibrosis (1 stage, 2 stages,…)?

• Stable disease?

– Prevention of evolution towards cirrhosis and decompensated cirrhosis…?

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Currently available drugs

• Not licensed for NASH

• Tested– Specifically for NASH

– In RCT

– With histological end-points

• TZD: Pioglitazone

• Vit E

• GLP-1: liraglutide

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PPARs

Tailleux et al. BBA 2012

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• HIV viral protein (Vpr)

– Repressor of PPAR gamma in adipose tissue

– Repressor of PPAR alpha in liver

• HIV negative regulatory factor (Nef)

– Downregulation of PPAR gamma

• NNRTI

– Downregulation of PPAR gamma

• Other HAART drugs

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Shrivastav S et al, Mol Endocrinol 2008Shrivastav S et al, Mol Endocrinol 2013Otake K et al, AIDS 2004

• PPAR alpha activation by fenofibrate

– Reduced HIV-1 replication

• PPAR gamma

– Reduced HIV replication in HIV-infected macrophages

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Skolnik P et al, Journal of Acquired Immune Deficiency Syndromes 2002Hayes M et al, The Journal of Biological Chemistry 2002

Furtherdevelopments?

Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019

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Bril & Cusi. Diabetes Care 2017

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Bril & Cusi. Diabetes Care 2017

GLP-1

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1Armstrong et al. Lancet 2016

• Approved for treatment of T2DM and obesity• RCT of liraglutide in NASH• Larger phase 2 semaglutide currently enrolling

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Furtherdevelopments?

Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019

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What to expect in the nearfuture?

• Compounds in phase 3

– Based on Phase 2

• with positive results on histological endpoints

– Elafibranor: PPAR alpha-delta dual agonist

– Obeticholic acid: steroid FXR agonist

– Selonsertib: ASK-1 inhibitor

– Cenicriviroc: dual CCR2-CCR5 antagonist

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Francque et al. J Hep 2015

PPARα expression and NASH severity

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Phase 2 Elafibranor 52 w(GOLDEN-505)

Ratziu, Francque et al. Gastroenterology 2016

Resolution of NASH without worsening of

fibrosis

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• Significant improvement in lipid profile• Significant improvement in glycaemic control• No changes in body weight• Good safety profile

Ratziu, Francque et al, Gastroenterology 2016

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PanPPAR Lanifibranor

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Wettstein, Francque et al. Hepatology Reports 2017

Furtherdevelopments?

Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019

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Lefere, Tacke et al. ILC

2019

FXR and TGR5

Schaap, Trauner, Jansen. Nat Rev Gastroenterology Hepatology 2013

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FXR

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Chavez-Talavera et al. Gastroenterology 2017

OCA Phase 2 (FLINT)

• Pruritus

• Increase in LDL and decrease in HDL

– Role of particle size: no increase small dense LDL1

– Corrected by adding a statin1

• No improvement in HOMA-IR

• Recent deaths in cirrhotic patients

– Because of inappropriate dosing

– Temporarily increased safety measures in REGENERATE: ceased

– No F4 at inclusion in REGENERATE

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1Pockros et al. Liver Meeting 2018. N°1672

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Cenicriviroc (CVC)• Oral, dual C-C chemokine receptor type 2

(CCR2) and type 5 (CCR5) antagonist with nanomolar potency

• Anti-inflammatory and antifibrotic activity observed in animal models

• Once-daily dose of 150 mg tablet

– Long plasma half-life (30–40 hours)

• Favorable safety and tolerability profile

– 600+ subjects treated in completed studies to date2-3

– Well tolerated in cirrhotic subjects with mild to moderate hepatic impairment3

1. Jalbert et al. Presented at CROI 2014; 2 Thompson et al. AIDS 2016; 3. Lefebvre et al. Clin Trans Sci 9 (2016) 139-148

MOA, mechanism of actionHepatic Stellate Cell

activation

CCR2CCR5

CCR

2CCR

5

Kupffer Cell

activation

Fat accumulation drives liver injury

CCR

2CCR

5

Monocyte/macrophage

recruitment

CVC

MOABlock overactive inflammatory signaling

Disrupt signaling to activate stellate cells

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Friedman, Francque et al. Hepatology 2017

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Ratziu, Francque et al. ILC 2018, GS-002

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CVC Phase 2 (CENTAUR trial)

• No significant effect on steatohepatitis

• Decrease in systemic markers of inflammation

• Generally well tolerated, good safety profile

• No effect on

– Body weight

– Lipid profile

– Glycaemic control

Ratziu, Francque et al. ILC 2018, GS-002

Friedman, Francque et al. Hepatology 2017

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Rationale for ASK1 Inhibition in NASH

• ASK1 pathway activated in NASH and correlates with fibrosis stage

• In rodent models, ASK1 inhibition improves steatosis, inflammation and fibrosis

• GS-4997 (selonsertib) is a selective, potent (EC50

10.8 nM), small molecule inhibitor of ASK1

Xiang, et al. J Hepatol 2016;64:1365–77Zhao, et al. Gut 2014;63:1159–72Huntzicker, et al. AASLD 2015 (#2149)Budas, et al. AASLD 2016 (#1588).

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Oxidative

stress

Hepatocyte

dysfunction Macrophage

activation/recruitment

Fibrogenesis

ASK1

P

JNKp38

ASK1

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Impact on fibrosis

4337

3

30 30

720 20 20

0

20

40

60

80

18 mg ± SIM 6 mg ± SIM SIM

Pati

ents

, %

Fibrosis

Improvement

Fibrosis

Improvement without

NASH Worsening*

Progression to

Cirrhosis

13/30 8/27 2/10 11/30 8/27 2/10 1/30 2/27 2/10n=

Loomba et al. Hepatology 2018

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Impact on steatohepatitis

23

0

194

20

00

20

40

60

80

100

18 mg ± SIM 6 mg ± SIM

5/27 2/10 0/31 1/277/31 0/10n=

Pati

ents

, %

≥2-Point Reductionin NAS NASH Resolution

Loomba et al. Hepatology 2018

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• Stellar 4

– Negative on primary endpoint

• Stellar 3

– Ongoing

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When will we have a drug approved?

• Phase 3 studies enrolling

– Completion of recruitment for surrogate endpoint analysis cohort (Subpart H) Treatment period 48w-72w for first part

– Selonsertib F4 Q1 2019 -> negative

– OCA Q1 2019 -> positive on fibrosis

– Elafibranor 2H 2019, Selonsertib F3 Q3 2019, CVC enrolling + OCA and Elafibranor continue to enroll

– So, 2020-2021?

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Furtherdevelopments?

Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019

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• Entering Phase 3

– Aramchol

– MGL 3916

• Trends

– Non-invasive tests (ALT, MRI PDFF, MRE…)

• Still histological benefit needed for Phase 3

– Shorter term trials (12 w)

– Combinations

• CVC + Tropifexor

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Summary

• Pathophysiology is complex

• Role of adipose tissue

• Part of a systemic disease

• Concern in HIV

– Evolving with newer therapies

• Numerous targets for pharmacological treatment

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Summary

• OCA first to announce efficacy in Phase 3

– Fibrosis endpoint on histology

• Several other molecules in Phase 3

– Conditional/accelerated approval 2020-2021

– Long term follow-up for hard clinical endpoints

• Large pipeline

– Including combination treatments

• Refine/tailor treatment in the future

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June 12, 2018 – 1st International NASH DaySAVE THE DATE !

2nd International NASH Day June 12, 2019

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