Building Evidence for the Next Treatment Paradigm:

Curing Atherosclerosis

Jennifer G Robinson MD MPHProfessor, Epidemiology & Medicine,

Director, Prevention Intervention CenterUniversity of Iowa

Iowa City. Iowa USA

Samuel Gidding MD

Disclosures

Jennifer G Robinson MD MPH has received in the past year:

Received research grants to Institution from Acasti, Amarin, Amgen, Astra-Zeneca, Esai, Esperion, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, Takeda

Consultant for Amgen, Medicines Company, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi

Gidding MD has received in the past year:

None

Why CURE atherosclerosis?

Can it be done?

Now is the time!

Why cure atherosclerosis• CVD remains the leading cause of death & major cause of

morbidity in US & globally• In 2015, 42% US population (100 million) have CVD• Eliminating major CVD would increase life expectancy by almost

7 years

• CVD #1 cause of healthcare expenditures• Total CVD costs expected to double by 2035 as population ages

• Curing atherosclerosis eliminates CVD• Within a generation – save $1.1 trillion/year

Mozaffarian D, et al. Circulation 2016; 133: e38-e360; Danaei G, et al. PLoS Med. PLoS Med. 2009;6:e1000058.; Heidenreich P, Trogdeon J, Khavjou O, et al. Circulation. 2011;123:933-944; Soni A. AHRQ statistical brief #331;www.meps.ahrq.gov/mepsweb/data_files/publications/st331/stat331.pdf; AHA technical report. Projections of cardiovascular disease prevalance and costs:2015-2035; Nov 2016.

Global CVD prevalence Age-standardized 2016

Benjamin E, et al. Circulation 2019; https://www.ahajournals.org/doi/abs/10.1161/CIR.0000000000000659

Lifestyle only partially attenuates genetic risk

Khera, A.V., et al., New England Journal of Medicine, 2016. 375(24): p. 2349-2358.

High burden of CVD events before age 65

Sniderman, A.D., et al., JAMA Cardiology, 2016. 1(4): p. 492-494.

A, Average primary annual incidence rates of coronary heart disease, heart failure, stroke, or intermittent claudication. B, Numbers of US residents without clinical atherosclerotic cardiovascular disease represented in the 2005-2010 National Health and Nutrition Examination Survey. C, Percentage of the expected total of 930 621 annual primary events in men and 702 105 in women by age group.

ASCVD EVENTS

MI/Unstable

angina

Ischemic stroke/TIA

Critical leg

ischemia

Intermittent

claudication

CV death

Illustration Adapted from Libby P. Circulation. 2001;104:365-372; Robinson JG, Gidding SS. JACC. 2014;63(25, Part A):2779-2785; Robinson JG, Heistad DD, Fox KAA. Atherosclerosis, 2015. 243(2): p. 593-597.

Atherosclerosis progression with age

Start LDL-C lowering early to regress disease

“CURE”

LDL-C lowering started late

Large burden of atherosclerosisSTABILIZATION

Better paradigm: Treat the Disease = Atherosclerosisvs. Current paradigm: Prevent end-stage manifestations

Would you wait to treat hypertension until ESRD develops?

Apo B lipoproteins fundamental causal factor in atherosclerosis development & progression

Evidence from RCTs

Greater relative risk reductionStatins in Low Risk (eg younger) Individuals

But, CVD events still occur in low risk persons

*1 mmol/L (39 mg/dl) LDL-C reduction was the average in the primary prevention RCTs excluding JUPITERCTT Collaborators. Lancet 2012; 380: 581-590.

Loss of Function PCSK9 Mutations: Moderately Lower Lifelong LDL-C Levels Associated with Substantial Reduction in Incident CHD

Cohen JC. N Engl J Med 2006;354:1264-72.

30

20

10

0

PCSK9142x or PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

00 50 100 150 200 250 300

No Nonsense Mutation(N=3278) 50th Percentile

Plasma LDL Cholesterol in Black Subjects (mg/dL)

Freq

uenc

y(%

)

PCSK9142x or PCSK9679X

(N=85)

Cor

onar

y H

eart

Dis

ease

(%)

LOF PCSK9 mutations

88% lower risk of CHD

28 percent reduction in frequency

Despite same risk factor levels as those with functional PCSK9:

• Age 54 years• Male 31% • BMI 29.5• HDL-C 55 mg/dl• Hypertension

37%• Diabetes 13%• Smoking 27%

Cohen JC. N Engl J Med 2006;354:1264-72.

Implications of Cholesterol Genetics• Genetic variation largely determines LDL-C

• Low frequency large effect genes

• High frequency small effect genes

• Rare individuals have balancing genes

• Provides the rationale for benefit of lifelong low LDL-C and harm of lifelong high LDL-C

• 50% risk reduction/mmolL LDL-c reduction

• Consistent with clinical trial data suggesting greater effect with longer LDL lowering interventions

PCSK9 genetic risk scores and individual PCSK9 polymorphismsAssociation of LDL-C level and CHD risk

From Brian Ference with permission

PCSK9 LOF: Proprotein convertase subtilisin/kexin type 9 loss-of-function mutationRobinson JG et al. Submitted; Adapted from Robinson JG, Gidding SS. JACC. 2014;63(25, Part A):2779-2785

New paradigm: Curing atherosclerosisResetting the (vascular aging) clock with intermittent treatment“Induction-maintenance” model of treatment/prevention for ASCVD

LDL-C/non-HDL-C - Necessary & Sufficient to cause atherosclerosis

Low LDL-C/non-HDL-C →Very low ASCVD risk

Homozygous familial hypercholesterolemia, untreated→ 100% ASCVD risk before age 30

Navar-Boggin Am et al. Circulation 2015; 131: 451-458; Macciaiolo M, et al. Lancet 2012; 379: 1330; Goldstein JK, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2863-2913.

125 150 175 200Average non-HDL-C prior to age 55 years

Inflammation alone is insufficient for atherosclerosis development

• South American Tsimane• Lifestyle - hunting, gathering,

fishing, and farming along an Amazon River tributary

• Mean age 58

• Mean LDL-C 91 mg/dl

• Low rates hypertension, obesity

• 51% hs-CRP >3.0 mg/L

• 85% CAC = 0

• Age >75 years 65% CAC=0

Kaplan H, et al. Lancet 2018; 389:1730-39; https://www.telesurenglish.net/news/Bolivias-Indigenous-Tsimane-Have-Worlds-Healthiest-Heart-20170317-0019.html

Atherogenesis: Response to retention of ApoBlipoproteins

Robinson JG et al. J AM Heart Assoc 2018; in press

Regressing earlier stages of plaque after dramatically lowering apoB lipoproteins

Robinson JG et al. J AM Heart Assoc 2018; in press

Risk factors exacerbate/accelerate atherosclerosis

Borén, J. and K.J. Williams, Current Opinion in Lipidology, 2016. 27(5): p. 473-483;

Why cure atherosclerosis

• Short term intensive treatment to regress atherosclerosis• Return artery to normal

• Normalize vascular function

• Avoid lifetime therapy• Intermittent less intensive therapy (every 10 years?) to maintain normal

vessel

• Address disparities

• Prevent hypertension?

Evidence that curing atherosclerosis is possible

Aggressive LDL-C lowering – Animal models

• LDL-C<30 mg/dl

• Complete regression early atherosclerosis

• Partially regress fibrotic, mature, advanced plaque

• More regression with functional HDL

Williams, K.J., et al. Nat Clin Pract Cardiovasc Med, 2008. 5: p. 91-102; Björkegren, J.L.M., et al.,. PLoS Genet, 2014. 10(2): p. e1004201; Miller, J.D., et al. Arterioscl Thromb Vasc Biol, 2013. 33: p. 459-465; Benzuly, K., et al. Circulation, 1994. 89: p. 1810-1818.

Tot Chol to 11-55 mg/dlat 30, 40, or 50 weeks

Earlylesions

Advanced lesions

Mature lesions

Similar findings for very low LDL-C levels in advanced human plaque• LDL-C reduction → Atheroma regression

• Changes in plaque composition

• Plaque stabilization

Nicholls, S.J., et al., JAMA, 2016. 316(22): p. 2373-2384; Kataoka, Y., et al., Curr Opin Endocrinol Diab Obes 2017. 24(2): p. 122-132; Williams KJ, et al. Nat Clin Pract Cardiovasc Med. 2008;5:91-102

OCT & Statin therapy (TCFA Thin cap atheroma volume)

Additional CVD Reduction from High Intensity Statins or PCSK-9i added to statins

Individual level meta-analysis adjusted for sex, age, smoking, diabetes, SBP, HDL-C

-56

-49

-44-42

-36

-29

<50 50-74 75-99 100-124 125-149 150-174 >175

Relative reduction CVD Risk by Achieved LDL-C level (mg/dl)

REF

Boekholdt SM, et al. JACC 2014; 64:485-494; Sabatine, M.S., et al., NEJM 2017; online ahead of print 10.1056/NEJMoa1615664.

FOURIER. Evolocumab vs placebo in very high risk patients treated with moderate-high intensity atorvastatin

Aggressive LDL-C lowering can normalize arterial function

• Humans • Statins modestly lower blood pressure in younger individuals

• Animal models• Endothelial dysfunction from prolonged hypercholesterolemia-

induced atherosclerosis is a result of abnormal nitric oxide responses

• Nitric oxide responses completely normalize with aggressive LDL-C lowering

Golomb BA, et al. Arch Intern Med. 2008;168:721-727; Miller, J.D., et al. Arterioscl Thromb Vasc Biol, 2013. 33: p. 459-465; Benzuly, K., et al. Circulation, 1994. 89: p. 1810-1818; .

Legacy effects in statin RCTsAll-cause mortality ASCOT: Atorvastatin vs placebo 3.3 y; 8 y FU Cardiovascular events WOSCOPS:

Pravastatin vs placebo for 5 y; 15 y FU

Ford I, et al Circulation 2016; 133: 1073-1080; Sever P, et al. Eur Heart J 2011; 32: 2525-2531

The Pathologic Determinants of Atherosclerosis in Youth (PDAY) study

1a

1b

Figure 1 Dark blood T2 weighted MRI Images of abdominal Aorta at two different locations.

Small arrows indicate normal vessel wall as barely seen thin structure.

Large arrow indicate diffused thicken vessel wall implying early atherosclerosis.

15-24 25-34

n=385

n=107

0-2 2-4 4-6 6-8 8-10 10+

Desirable

Undesirable

n=341

n=185

Risk Factor

Non-HDL cholesterol

n=398

n=94

n=421

n=105

HDL cholesterol

n=416

n=76

Normotensive

Hypertensive

n=433

n=93

Hypertension

n=436

n=56

Non-obese

Obese

n=448

n=78

Obesity

Age group, y

Desirable

Undesirable

Age (y)

15-19 20-24 25-29 30-34

Surf

ace

Are

a In

volv

ed

(%

)

0

2

4

6

8

10

0 22

1 42

2 26

3 7

4+ 2

Risk FactorsNo. %

Right Coronary Artery Raised Lesions by Ageand Number of Risk Factors, Men

PDAY Risk Score CalculationStep 1. Calculate Score

Step 2: Look up probability

Prevalence of Raised Lesions in RCA by Risk Score

00-02 02-04 04-06 06-08 08-10 10 +

Risk Score N Raised Lesions

<05 348

06 – 10 314

11 - 15 320

16 + 384

Date of download: 3/13/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Risk Scores Predict Atherosclerotic Lesions in Young People

Arch Intern Med. 2005;165(8):883-890. doi:10.1001/archinte.165.8.883

Observed and estimated probability of target lesions by risk score in the coronary arteries for men (A) and women (C) and in the

abdominal aorta for men (B) and women (D). Probabilities are for groups of 3 integer values of the risk score, with the highest

category for each sex constructed to have at least 50 cases.

Figure Legend:

Gidding et al., Arch Intern Med 2006

PDAY Baseline Risk Score & 15 Year ChangeEffects on Odds Ratios for Coronary Calcification

Odds Ratios for Presence of Any CAC/point increase in PDAY score and c-statistic for likelihood of CAC presence at year 25by CARDIA Exam Year

Exam Year Presence of any CAC

(Odds Ratio)

c-statistic

0 1.29 (1.25, 1.33) 0.7315 1.26 (1.22, 1.29) 0.74010 1.20 (1.17, 1.23) 0.73115 1.17 (1.15, 1.19) 0.72320 1.16 (1.14, 1.18) 0.73025 1.12 (1.11, 1.14) 0.705

PDAY risk scores & atheroma probability

>40-60% probability

atheroma

>60% probability

atheromaMen Women Men

PDAY score 18-23 PDAY score >27 PDAY score >24Age 36-45 Age 41-45+obesity Age 36-45+obesityAge 30-35+obesity Age 36-40+obesity

+ non-HDL 130-189

(or hypertension or

HDL-C<40+smoking)

Age 30-35+

obesity+non-HDL-C

160-189 (or

hypertension)Age 20-

29+obesity+

non-HDL-C 130-

189 (or

hypertension)

Age 20-29+obesity+

Non-HDL-C 160-

189+hypertensionCARDIA

PDAY risk score & probability of coronary artery calcium

McMahan CA, et al. 2005;165(8):883-890. Gidding SS, et al. Circulation. 2016;133(2):139-146

FH as a model

Difference in mean carotid IMT and 95% confidence interval between FH children and unaffected siblings plotted versus age, adjusted for family relations

3/5/2020 44

Ultimate Modifier of FH – Early Lifelong Treatment

Prevalence Map of Raised Lesions of Right Coronary Artery by Age and Non-HDL Cholesterol

Non-HDL-C < 160mg/dL Non-HDL-C> 160 mg/dLAge

15-24

25-34

0-2 2-4 4-6 6-8 8-10 10+

n=531 n=159

n=523 n=277

Trials needed to determine if atherosclerosis can be cured• Why?

• CVD remains the leading cause of death & major cause of morbidity in US & globally

• In 2015, 42% US population (100 million) have CVD• Eliminating major CVD would increase life expectancy by almost 7 years

• CVD #1 cause of healthcare expenditures• Total CVD costs expected to double by 2035 as population ages

• Curing atherosclerosis could eliminate burden of ASCVD within a generation

• Within a generation – save $1.1 trillion/year

Mozaffarian D, et al. Circulation 2016; 133: e38-e360; Danaei G, et al. PLoS Med. PLoS Med. 2009;6:e1000058.; Heidenreich P, Trogdeon J, Khavjou O, et al. Circulation. 2011;123:933-944; Soni A. AHRQ statistical brief #331;www.meps.ahrq.gov/mepsweb/data_files/publications/st331/stat331.pdf; AHA technical report. Projections of cardiovascular disease prevalance and costs:2015-2035; Nov 2016.

Trial design for subclinical atherosclerosis in youth

DO-IT trial design

Subclinical Atherosclerosis ResearchStudy Design

FH Patients get a Subclinical Athero Measure

Test Positive Test Negative

Randomize by treatment intensity

Outcomes Chosen by AgeChange in Subclinical Athero Measure/Events/Cost/Safety are Outcomes

High intensity High intensity Lower intensityLower intensity

New paradigm: Curing atherosclerosis in adults

Robinson JG, Gidding SS. Curing Atherosclerosis Should Be the Next Major Cardiovascular Prevention Goal. JACC. 2014;63(25, Part A):2779-2785

Avoid lifelong treatment• Intermittent treatment as

needed • Minimal safety concerns• Recapitulate benefits of

lifetime low LDL-C • Low cost for lifetime

benefit

Necessary point: Lifestyle does not negate increased genetic risk of being human

Khera AV et al. N Engl J Med 2016;375:2349-2358.

10-Year Coronary Event Rates, According to Lifestyle and Genetic Risk

in 3 Prospective Cohorts

CURE ATHERO(CURing Early ATHEROsclerosis)

CCC: University of Iowa – Jennifer G Robinson MD MPH (PI)DCRI - Pamela Douglas MD (Co-I)

DCC: DCRI – Michael Pencina PhD (PI), Eric Peterson MD (Co-I)Clinical sites: University of Iowa, Duke University (Neha Pagidipati MD)CTA reading center: Mt Sinai – Zahi Fayad PhD (PI)

CURE ATHERO Study population• Healthy, men & women ages 25-55 years

• Overweight or obese with increased risk factor levels

• Significant burden uncalcified plaque (eg earlier stage atheroma)

• >40% probability of atheroma based on PDAY score*>25

• >80% power if randomize 130 subjects

• Subgroup & predictive analyses if randomize >800 subjects

* adapted for age up to 55 years

CURE ATHERO Randomized Interventions

• 3 years

• Usual care/control

• Intensive LDL-C reduction to 20-40 mg/dl• Statin

• PCSK9 inhibitor

• Ezetimibe

CURE ATHERO main objectives1. Characterize response to plan future imaging & CV outcomes trials

• Primary outcome• Percent regression low attenuation plaque volume (LAPV) from baseline

after 3 years by CTA

2. EMR prediction algorithm for accelerated atherosclerosis

CURE ATHERO• A pilot study: Identify “sweet spot” for atheroma regression &

stabilization• Clinical characteristics & CTA• Ancillary studies planned

• Genetics• Biomarkers & -omics• Imaging

• CTA perivascular fat attenuation index (PFAI) – inflammation• PET CT/MR - inflammation• 3D ultrasound – non-coronary arteries

• Address evidence gap: Epidemiology of atherosclerosis progression obese younger adults with risk factors

• Usual care group• Planned ancillary study: Screened but not randomized

Genetics for Risk Prediction

• Enhance screening efficiency

• Genetic risk scores• Minimal additional information over known risk factor levels

• Will likely be of most value for predicting more extreme manifestation in setting of more extreme exposure/environment

• Early onset – Susceptibility genes

• Late onset – Resilience genes

• Disease severity

Predicting premature CHD

https://www.nature.com/articles/gim201838

Genetics for Predicting Treatment ResponseGenetic risk score predicts CVD risk & risk reduction from statin treatment in middle-aged

individuals without clinical CVD and in those with clinical burden of CHD

Mega JL, et al. Lancet 2015; 385: 2264-2271

PCSK9 LOF: Proprotein convertase subtilisin/kexin type 9 loss-of-function mutationRobinson JG et al. Submitted; Adapted from Robinson JG, Gidding SS. JACC. 2014;63(25, Part A):2779-2785

New paradigm: Curing atherosclerosisResetting the vascular aging clock with intermittent treatment

CURE ATHERO 1st trial

CV outcomes trial needed to establish “Induction/maintenance” model to prevent ASCVD

CVOT could be a feasible next step:Intensive LDL-C RRR 80%ASCVD event rate 0.2%/year or 1%/5 years5-year treatment periodN=8000 Power >99%

Shorter term imaging & CV outcomes trials are needed before genetic revolution can occur

HERE NOW: GENES AS DRUGS

https://www.apnews.com/4997bb7aa36c45449b488e19ac83e86dhttps://www.sciencemag.org/news/2019/08/untold-story-circle-trust-behind-world-s-first-gene-edited-babieshttps://www.bloomberg.com/news/articles/2019-09-11/chinese-scientists-edit-dna-in-attempt-to-cure-man-s-cancer-hiv

GV leads $58.5M round for Verve, a startup looking to pit gene

editing against heart attacks by Amirah Al Idrus | May 7, 2019 6:00am

Verve Therapeutics is launching with $58.5 million and longtime cardiologist and geneticist Sekar Kathiresan at its helm. (Verve Therapeutics)

• 7 protective human LOF genes• Animal studies• Multiple gene editing approaches• Delivery vehicles TBD • https://www.vervetx.com/about-us/

Verve Therapeutics

https://www.vervetx.com/approach/

Our Ethical CommitmentAs we advance in our mission to develop therapies for adults at risk of heart disease, Verve will work in a manner that is consistent with the ethical and scientific frameworks set forth by leading professional societies, regulators, and biomedical ethicists.All of the therapeutics to be developed by Verve involve making edits in adult (somatic) cells, which are not passed down to offspring. We will not edit embryos, sperm cells, or egg cells.Safety is paramount for Verve. We will be implementing a rigorous safety protocol with the best available technology for detecting off-target effects. Verve has one of the world-leading experts on gene editing safety on our team, and our clinical development plan will proceed responsibly and transparently

Genes as drugs

• CRISPR-based technologies can add/remove snps or gene cassettes

• Requires gene target with high impact on disease development • HIV

• Sickle cell anemia, cystic fibrosis, Tay-Sachs disease, etc.

• Apo B lipoproteins?

• Goal: Gene delivery to cells of target organ only• Limit off-target adverse effects

• Ethics: Alter somatic cell genes only• Does not affect germ-line (reproductive cells)

https://www.sciencenews.org/article/crispr-gene-editor-first-human-clinical-trials

• Important recent development: Reannealing DNA without errors

https://www.technologyreview.com/s/614599/the-newest-gene-editor-radically-improves-on-crispr/

Gene-edited babies

• Congenital deafness• Embryo editing• In vitro fertilization

https://science.sciencemag.org/content/366/6465/562/tab-pdf

https://unsplash.com/photos/-IMlv9Jlb24; https://www.brainfacts.org/in-the-lab/tools-and-techniques/2019/crispr-explained-071519

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