Pharmacological therapies for NASH
Transcript of Pharmacological therapies for NASH
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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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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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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• 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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• 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
21Noordwijk 2019
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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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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Furtherdevelopments?
Haas, Francque & Staels. Ann Rev Physiol 2016Francque & Vonghia. Advances in Therapy 2019
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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
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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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).
50
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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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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