The Intersection of CVD and NAFLD/NASH Identifying and ......The Intersection of CVD and NAFLD/NASH...
Transcript of The Intersection of CVD and NAFLD/NASH Identifying and ......The Intersection of CVD and NAFLD/NASH...
The Intersection of CVD and NAFLD/NASH Identifying and Managing Cardiovascular Risk
Seth Baum, MD, FACC, FAHA, FASPCImmediate Past President
American Society for Preventive CardiologyExcel Medical Clinical Trials, LLCFounder, Chief Medical Officer
Clinical Affiliate Professor of Biomedical ScienceCharles E. Schmidt College of Medicine
Relationships with Industry
◼ Consultant/Ad Board/Speaker/Research— Amgen— Sanofi/Regeneron— Akcea— BI/Lilly— Merck— Cymabay— The Medicines Company— Esperion— Novartis— AstraZeneca— Madrigal— NovoNordisk— NGM
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All patients with NASH have high CV risk
BL
ALT 59
AST 42
GGT 30
ApoB 85
HDL 34
LDL-C 82
Non-HDL-C 119
TG 167
hsCRP 1.8
What is the most likely cause of Mr. Jones’s mortality?
◼ Mr. Jones is a 59 yo white male— Medical history: Obesity, Diabetes, Hypertension,
Retinopathy, Psoriasis— Conmeds: Anti-hypertensives, Pravastatin, Fish
Oil, ASA, Anti-diabetics
◼ ASCVD risk score 27.5%— Diabetic with 3 risk factors: target LDL-C<70 mg/dL
◼ MRI-PDFF (% fat fraction)— Baseline: 15.2%
◼ Liver Biopsy: — Baseline NAS=4; Steatosis=1; Inflammation=2;
Ballooning=1; Fibrosis 1B
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Non-Alcoholic Fatty Liver Disease (NAFLD) Ranges from Simple Steatosis (NAFL) to NASH, a Progressive Form of Liver Disease
OUTCOME
NAFLD results from accumulation of excess fat within the liver (steatosis) unrelated to alcohol use
Some patients with NAFLD have NASH (nonalcoholic steatohepatitis)
25 – 30% of all adults in Western countries have NAFLD
NASH afflicts 3 – 12% of the U.S. population. In certain populations such as diabetics fat in the liver is virtually always NASH.
NAFLD leads to an increased risk of morbidity and mortality from:— Cardiovascular disease (leading cause
of death for NAFLD patients)— Liver-related events
11% of advanced NASH patients progress to cirrhosis over a 15 year period
Harmful Steatosis
Normal Liver
Lobular inflammation
Ballooning degeneration
Fat Accumulation
NAFLD Spectrum
SimpleSteatosis
Nonalcoholic Fatty Liver (NAFL)
NASH Fibrosis
NASH Cirrhosis
NASH
DISEASE
INCIDENCE
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The Spectrum of NAFLD/NASH
F3
F4
F2
F1B
F1
F0
NAFLD with dyslipidemia, diabetics, metabolic syndrome
2.0 million
3.5 million
15 million
6.3 million
3.4 million
1.3 million
NASH/NAFLD Spectrum1
PatientNumbers (US)
1 Estes et al; Hepatology, Vol. 67, No. 1, 20185
Complex Putative Connections Between NAFLD and CV Disease
6Stahl, E.P. et al. J Am Coll Cardiol 2019;73(8):948-963
NAFLD has Multiple Independent Cardiovascular Associations:
◼ Early LV Dysfunction and Impaired LV Energy Metabolism in Young Patients
◼ Coronary Artery, Carotid Artery and Peripheral Vascular Disease in Patients with Types 1 & 2 Diabetes
◼ Ischemic Heart Disease in Male Workers
◼ More Severe CAD in Unselected Patients Referred for Coronary Angiography
◼ Reduced Myocardial Perfusion in Patients with Type 2 DM
◼ Coronary Artery Disease in Children On Autopsy
7Targher, G, et al. N Engl J Med 2010;363:1341-50
Lipoprotein Subclasses
5 10 20 40 60 80 1000
Diameter (nm)
1.20
1.10
1.06
1.02
1.006
0.95
Den
sity
(g/m
l)
HDL2
HDL3
ChylomicronRemnants
VLDL
IDL
Chylo-microns
Lp(a)
LDL
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Dyslipidemia in NASH
Patients with NAFLD have a pro-atherogenic lipid/lipoprotein profile: — Increased apolipoprotein B— Increased TG— Low HDL-C— Higher concentration of small/dense LDL Most patients with NASH are either diabetic or insulin resistant and have “diabetic dyslipidemia.”— In diabetes, levels of small/dense LDL particles and the total number of LDL particles are increased. Thus, the
relatively “normal” LDL-C observed in many can hide a major atherogenic burden
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Retention of apo-B lipoprotein is critical to the early stages of atheroma formation. Apo-B lipoprotein particles enter the intima and are retained.
Apo B Lipoprotein Retention & Ensuing Inflammatory Response, Central to Atheroma Formation
Tabas et al. Circulation. 2007;116(16):1832–1844. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540.
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
VSMCs in media
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VSMC = vascular smooth muscle cell; LPs = lipoproteins.
Retained lipoprotein particles are likely modified (eg: oxidized and aggregated).
Apo B Lipoprotein Retention & Ensuing Inflammatory Response, Central to Atheroma Formation
Tabas et al. Circulation. 2007;116(16):1832–1844. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540.
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
VSMCs in media
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
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VSMC = vascular smooth muscle cell; LPs = lipoproteins.
Monocytes are attracted to the artery, which they enter and turn into macrophages.
Apo B Lipoprotein Retention & Ensuing Inflammatory Response, Central to Atheroma Formation
Tabas et al. Circulation. 2007;116(16):1832–1844. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540.
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
VSMCs in media
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
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VSMC = vascular smooth muscle cell; LPs = lipoproteins.
Macrophages ingest lipids and become foam cells.
Apo B Lipoprotein Retention & Ensuing Inflammatory Response, Central to Atheroma Formation
Tabas et al. Circulation. 2007;116(16):1832–1844. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540.
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
VSMCs in media
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
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VSMC = vascular smooth muscle cell; LPs = lipoproteins.
Other immune cells enter and are activated. Inflammatory cytokines, chemokines, proteases, and free radicals cause further tissue damage. The process of retention and responses to retention eventually lead to atheroma formation.
Apo B Lipoprotein Retention & Ensuing Inflammatory Response, Central to Atheroma Formation
Tabas et al. Circulation. 2007;116(16):1832–1844. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ, Tabas I. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540.
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
VSMCs in media
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
Diffuse intimal thickening
Apo B-LPs In plasma
Endothelium
Expanded intima, rich in retentive proteoglycans
Monocyte
Intima smooth muscle cells
Foam cell
Macrophage
T-cell
Fibrous cap
Mast cell
VSMCs in media
Retained lipoproteins
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VSMC = vascular smooth muscle cell; LPs = lipoproteins.
Fatty Liver is an Independent Predictor of CIMT
◼ IMT is increased in patients with NAFLD after controlling for metabolic risk factors
— Degree of IMT independently associates with histologic severity of NASH
◼ IMT predicts CVD Events Carotid-Artery Intimal Medial Thickness in Patients with NAFLD
Targher, G. et al. N Engl J Med 2010;363:1341-50 15
Coronary Artery Calcification is Increased in NAFLD
Proportion of Patients who developed CAC over 4 years according to baseline NAFLD
Kim, D. et al. PLOS One 2017;12(7) doi.org/10.1371/journal.pone.0180118 16
CAC is our Best Predictor of CV Events MESA CAC >300 Yields HR=9.67 for Future Coronary Events
*Myocardial infarction and death from CHD.†Each unit increase in log2(CAC+1) represents a doubling of the CAC score.Detrano R, et al. N Engl J Med. 2008;358:1336-1345.
Major Coronary Event* Any Coronary EventCAC Score n/N at
RiskHazard Ratio
(95% CI) P Valuen/N at
RiskHazard Ratio
(95% CI) P Value
0 8/3409 1.00 15/3409 1.00
1-100 25/1728 3.89 (1.72-8.79)
<.001 39/1728 3.61 (1.96-6.65)
<.001
101-300 24/752 7.08 (3.05-16.47)
<.001 41/752 7.73(4.13-14.47)
<.001
>300 32/833 6.84 (2.93-15.99)
<.001 67/833 9.67 (5.20-17.98)
<.001
Log2(CAC+1)†
1.20 (1.12-1.29)
<.001 1.26 (1.19-1.33)
<.001
Risk of Coronary Events Associated With Increasing CAC After Adjustment for Standard Risk Factors
Multi-Ethnic Study of Atherosclerosis (MESA) followed 6814 persons for new cardiovascular events for a median of 3.9 years
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Heart Scans From 3 Individuals Classified as the Same Risk According to FRS
Normal coronary arteries with little to no plaque build-up
Coronary arteries with beginning calcification and early plaque build-up
Coronary arteries with extensive calcification and plaque build-up
Added Value of CAC over Risk Scores
FRS=Framingham Risk Score. Images courtesy of Roger Blumenthal, MD. 18
Fatty Liver Associates with Overall CVD Mortality
Pisto P et al. BMJ Open 2014;4:e004973. doi:10.1136/bmjopen-2014-004973
Patients with more severe liver fat accumulation based on quantitative ultrasound had increased CV mortality
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Cardiovascular Death is Increased in NAFLD/NASH
◼ Highly cited longitudinal study in 619 patients with NAFLD used to demonstrate that NASH with advanced fibrosis stage is most predictive of liver related events
◼ Both stage of NASH and fibrosis predicted overall mortality◼ 38% died from CV disease. Overall, 32% of Americans die from CVD
Angulo, P. Gastroenterology 2015;149:389-397
The Angulo Study
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So, What will Mr. Jones Die From?
◼ Cardiovascular Disease!
— Identify and Aggressively Manage his Risk— Reduce weight— Control DM— Control BP— Lower LDL-C— Lower apoB— Check Lp(a)— Strongly Consider Assessing for subclinical CVD
— Consider evaluation for subclinical disease
—We Must Also Find a Way to Directly Treat His NASH
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Current CV Recommendations for NASH Patients are Limited
We need to do much more than this!
• Assiduous Assessment of CVD Risk is imperative
• Aggressive modification of CVD risk factors is mandatory in all patients with NAFLD
• We need to DIRECTLY treat NASH
Franque, S.M. et al. J Hepatol 2016;65:425-443
AND
AND
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The Madrigal Clinical Trial Program
Compound Indication Pre-Clinical Phase 1 Phase 2 Phase 3 Upcoming Catalysts
Resmetirom(MGL-3196)Thyroid Hormone Receptor-β (THR-β) Agonist
Treatment of Nonalcoholic
Steatohepatitis (NASH)With Fibrosis Stage 2-3
Phase 3 MAESTRO-NASH Initiated
Treatment of NASH
Phase 3 MAESTRO-NAFLD-1, safety and lipid lowering in NAFLD/NASH patients
MGL-3745THR-β Agonist
NASH andHyperlipidemia
Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429]
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Mechanism of Action: The Importance of Liver THR-β in NASH
Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially reducing
lipotoxicity, NASH
No thyrotoxicosis (THR-α effect)
In humans, thyroid hormone receptor-β (THR-β) agonism:
Sinha and Yen Cell Biosci (2016) 6:46 DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 1341-1357, DOI: 10.1080/15548627.2015.1061849
Resmetirom (MGL-3196) THR-β selective molecule, once a day oral, with proven safety and efficacy in more than 300
subjects and patients treated— No exposure outside the liver or activity at the systemic THR-α receptor
Pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly)
— Reduction of liver fat through breakdown of fatty acids— Stimulation of mitochondrial biogenesis, normalization of liver function
Thyroid Gland
Liver T4 T3
T3
Nucle
ar T
HR-α
, THR
-β
Thyroid Hormone Pathway
T4T4
T4, prohormoneT3, active hormone
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 24
Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled
Extension Study
Screening
MRI-PDFFLiver Biopsy
MRI-PDFFLiver BiopsyMRI-PDFF MRI-PDFFPK
Comparator/Arms 2:1 Resmetirom to placebo
125 patients enrolled in USA, 18 sites
Resmetirom or placebo, oral, once daily; dose 80 mg (+/-20 mg dose adjustment possible at Week 4 )
Inclusion/Exclusion NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3
≥10% liver fat on MRI-PDFF
Includes diabetics, statin therapy, representative NASH population
Endpoints
1o - Percent relative change from baseline in hepatic fat fraction by MRI-PDFF at 12 weeks
Changes in lipids at 30 and/or 36 weeks was a secondary endpoint
D1 W2 W4 W12 W36 W12 W36ExD136 Week Main Study
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 25
◼ Decreases inflammation on biopsy◼ Continued, sustained decreases in elevated liver
enzymes, many reaching normal levels (60% with ALT <30 by 36 weeks)
◼ Reduces reverse T3, a marker of inflammation
◼ Decreases ballooned hepatocytes on biopsy◼ Stimulates mitochondrial biogenesis reducing
hepatocyte dysfunction and death◼ Reduces GGT and CK-18 markers of oxidative
damage/ballooning
◼ Reduces steatosis on biopsy◼ At Phase 3 doses (80 or 100 mg/qd) clears more liver fat
on MRI-PDFF than other agents, average 55% reduction◼ About 90% of patients should clear ≥30% liver fat
— ≥30% hepatic fat reduction predicts higher rates of NASH resolution & decreased fibrosis on biopsy
Resmetirom: Phase 2 NASH, Non-invasive and Liver Biopsy Results
Steatosis
Ballooning
Lobular InflammationResmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429]
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Resmetirom: Sustained Robust Lipid/Lipoprotein Lowering in NASH Phase 2 Study
Significant sustained lowering effect in multiple atherogenic lipids
Lipids (% Change from Baseline)
Resmetirom compared with placebo; all analyses and cutoffs were prespecified; based on mITT; placebo n=39; Resmetirom n=79 (LOCF)
◼Resmetirom is the only NASH therapeutic in advanced development that lowers LDL-C, consistent with regulatory approval; and also reduces NASH, an independent CV risk factor
◼Resmetirom also lowers remnant cholesterol, small dense LDL particles, large VLDL and chylomicrons, all of which are associated with increased CV disease
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 27
Resmetirom: Dose Response on Lipid Markers in Phase 2
Higher doses (>60 mg) which are used in the Phase 3 MAESTRO-NASH study showed greater decreases in lipid markers in the Phase 2 NASH study
Lipids, placebo corrected, lipids are <0.0001 relative to placebo; *p<0.05; **p<0.01, 60 mg vs 80 mg
**
*
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 28
Safety
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AEs, mostly mild, a few moderate, balance between groups. Increase in resmetirom treated relative to placebo in loose stools, typically a single episode, only at the beginning of therapy, GI AEs not increased in Phase 1 or NASH extension study
No lab abnormalities or other AEs were increased in resmetirom compared with placebo patients
7 SAEs, distributed between placebo and drug-treated, all single occurrences, none related
AEs
Safety Biomarkers
No effects on TSH, bone mineral density, heart rate, QTc, other CV biomarkers or diabetes biomarkers
Small (<3%, not statistically significant) reduction in diastolic BP at Week 36 in resmetirom patients, consistent with reduced liver fat
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429]
Resmetirom Phase 3 Development Path Across the Spectrum of NAFLD/NASH
F3
F4Phase 3 MAESTRO-NASH study: NASH Resolution (primary), LDL-C, fibrosis (key secondary); Phase 4 (post-approval): cirrhosis and MACE
F2
F1B
F1
F0
NAFLD with dyslipidemia, diabetics, metabolic syndrome
CV Benefits
Fatty liverLDL-CApoBTriglyceridesLp(a) Phase 3 MAESTRO-NAFLD-1
study in presumptive NASH:Safety, lipids, noninvasive biomarkers(no liver biopsy requirement)Phase 4 (post-approval): MACE
2.0 million
3.5 million
15 million
6.3 million
3.4 million
1.3 million
NASH/NAFLD Spectrum1
PatientNumbers (US)
1 Estes et al; Hepatology, Vol. 67, No. 1, 2018Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 30
Phase 3: Resmetirom MAESTRO-NASH Trial: Recruiting
Inclusion/Exclusion
NASH on liver biopsy: NAS≥4, high risk F1, F2/3
Comparator/Arms
Resmetirom 80 or 100 mg or Placebo, once daily
Primary Endpoint
Phase 3: Liver biopsy at 52 weeks - resolution of NASH associated with a ≥2 pt reduction in NAS and no worsening of fibrosis
Phase 4: reduction in liver related events or progression to cirrhosis
Key Secondary Endpoints
LDL-C lowering
≥1 pt reduction in fibrosis with no worsening of NAS
Other Secondary and Exploratory Endpoints
Additional NASH biopsy endpoints
Imaging MRI-PDFF
Fibrosis biomarkers
Design
Stage
Drug MGL-3196 (resmetirom)
Blinded 1:1:1
Phase 3/4
Number of Patients
Centers
Treatment Duration
Phase 3: 900 Phase 4: up to 2000
~150, USA; EU
52 Weeks; 4.5 years
Study Overview Study Details
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 31
Phase 3: MAESTRO-NAFLD-1 in Planning Phase
Inclusion/Exclusion
NASH/NAFLD (presumptive NASH, not NAFL)
Eligibility: fibroscan, NASH on biopsy
Excludes advanced patients F2/F3 NAS≥4 who qualify for MAESTRO-NASH
Comparator/Arms
Resmetirom 80, 100 mg or Placebo, once daily; open label 100 mg arm in up to 100 patients
Key Endpoints
Safety
LDL cholesterol
ApoB, TGs, Lp(a),
MRI-PDFF (fatty liver)
Fibrosis biomarkers, fibroscan
Design
Stage
Drug Resmetirom
1:1:1:1
Phase 3
Number of Patients
Centers
Treatment Duration
700
50, USA
12 months
Study Overview Study Details
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429]
32
Patient Profile - All patients with NASH have high CV risk
◼ 59 yo white male— Medical history: Obesity, Diabetes, Hypertension,
Retinopathy, Psoriasis— Conmeds: Anti-hypertensives, Pravastatin, Fish Oil,
ASA, Anti-diabetics
◼ ASCVD risk score 27.5%— Diabetic with 3 risk factors: target LDL-C<70 mg/dL
◼ Randomized to MGL-3196, dose increased to 100 mg at Week 4 based on low exposure at 80 mg determined at Week 2
◼ MRI-PDFF (% fat fraction)— Baseline: 15.2% — Week 12: 5.1% — Week 36: 3.0% (80.3% PDFF reduction)
◼ Liver Biopsy: — Baseline NAS=4; Steatosis=1; Inflammation=2;
Ballooning=1; Fibrosis 1B— NASH resolution at Week 36, : NAS=1 (steatosis=0;
lobular inflammation=1; ballooning=0), F=0
BL Week 36 % change
ALT 59 28 -52.5AST 42 23 -45.2GGT 30 20 -33.3SHBG 34.2 67.2 96.5ApoB 85 55 -35.3ApoCIII 11.6 8 -31.0HDL 34 47 38.2LDL-C 82 58 -29.3Non-HDL-C 119 80 -32.8TGs 167 87 -47.9hsCRP 1.8 0.8 -55.6Adiponectin 3.5 5.5 57.1
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 33
Potential Indications for Resmetirom in NASH
◼ Resmetirom is a thyroid hormone receptor beta agonist:
— To resolve and reduce NASH and liver fibrosis in adults with NASH and advanced liver fibrosis
— To reduce histologic (and clinical) progression to cirrhosis and reduce decompensated cirrhosis events in adults with NASH
— As adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with NASH and hyperlipidemia to reduce low-density lipoprotein cholesterol LDL-C.
— As adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), to reduce ApoB and TG levels in adults with NASH and hyperlipidemia [key secondary endpoint]
— To reduce the risk of myocardial infarction, stroke, and coronary revascularization and [cardiovascular mortality] in adults with NASH and established or at high risk for cardiovascular disease.
Resmetirom is an investigational therapy and has not been approved by the FDA (or any other regulatory authority). Resmetirom is only available for use in a clinical trial setting (ClinicalTrials.gov NCT03900429] 34