The Intersection of CVD and NAFLD/NASH Identifying and ......The Intersection of CVD and NAFLD/NASH Identifying and Managing Cardiovascular Risk Seth Baum, MD, FACC, FAHA, FASPC Immediate

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

2

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

3

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

4

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

8

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

9

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

10

VSMC = vascular smooth muscle cell; LPs = lipoproteins.

Retained lipoprotein particles are likely modified (eg: oxidized and aggregated).



Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell



Apo B-LPs In plasma

VSMCs in media


Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media


11


Monocytes are attracted to the artery, which they enter and turn into macrophages.



Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell



Apo B-LPs In plasma

VSMCs in media


Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media


12


Macrophages ingest lipids and become foam cells.



Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell



Apo B-LPs In plasma

VSMCs in media


Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media


13


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.



Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell



Apo B-LPs In plasma

VSMCs in media


Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media



Apo B-LPs In plasma

Endothelium


Monocyte


Foam cell

Macrophage

T-cell

Fibrous cap

Mast cell

VSMCs in media


14


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

17

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

19

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

20

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

21

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

22

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]

23

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


◼ 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]

26

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: 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

**

*


Safety

29

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 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


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


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


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.


Documents

The Intersection of CVD and NAFLD/NASH Identifying and ......The Intersection of CVD and NAFLD/NASH Identifying and Managing Cardiovascular Risk Seth Baum, MD, FACC, FAHA, FASPC Immediate