Capital Region Right Care Initiative University of Best Practices

Monday June 11, 2018

Practical News from the World of Molecular Cardiology: Novel Risk Markers and

Therapies for Cardiovascular Prevention

Eveline Stock, MD Crystal Zhou, PharmD Akin Oni-Orisan, PharmD, PhD

CVD has declined in recent decades

2

Deaths attributable to CVD in US (1910-2015)

Benjamin et al, Circulation 2018

What is the role of prevention in our field?

• A big component of that is cardiovascular disease prevention

• Are we “hitting a wall” in terms of treating cardiovascular disease? • Small incremental benefits from additional new interventional treatments in

terms of minimizing morbidity and mortality for heart disease …What’s Next?

“An ounce of prevention is worth a pound of cure “ Benjamin Franklin

• Great strides in — exercise, quitting smoking, diet management, cholesterol control, blood sugar control, blood pressure control, sleep medicine

• We are educating and empowering a New Generation for awareness and active role in their own future cardiovascular health

• Role of practitioners – Accountability and implementing best practices

What are the“Big areas” of prevention for Atherosclerotic cardiovascular diseases?

What are the“Big areas” of prevention for Atherosclerotic cardiovascular diseases?

•Undiagnosed conditions: Growing burden • Lots of overlap • Risk factors are similar • A lot still needs to be done, starting with education and early

detection

•Defining people at risk – WHO should be targeted for treatment based on risk, will be a big component of the cardiology of the future

Molecular Targets for Atheroprotection • First element: Atherogenic Lipoproteins

LDL, VLDL, Lp(a) • Pathogenesis of atherosclerosis – Risk marker • Therapeutic target

• Second element: Inflammation

• Pathogenesis of atherosclerosis – Risk marker – hs-CRP • Novel markers – cytokines (HDL associated) • New therapeutic targets –

• IL-1 (CANTOS trial – Canakinumab) • IL-6 (methotrexate)

• Third Element : Efflux

• Pathogenesis of atherosclerosis • Risk marker - Emerging measurements – Prebeta1 HDL

First Element: Atherogenic Lipoproteins

Elevation of LDL

Secondary • Hypothyroidism • Early nephrosis • Cholestasis • Multiple myeloma

Genetic:

• Familial hypercholesterolemia • Ligand-defective apoB100 • PCSK-9 gain of function • Phytosterolemia • LAL-Deficiency - Cholesterol Ester Storage Disease (CESD)

60 yo F - ↑LDL Poor statin response

Phytosterolemia

• Rare? autosomal recessive disorder (< 1,000,000). • Gene Defect: ABCG5 and ABCG8 (ATP-binding cassette transporter family) • Expressed intestine and liver – f(x) to limit absorption and promote

excretion of plant sterols (sitosterol, campesterol) • Symptoms :

• high blood cholesterol • tendon xanthomas • premature atherosclerosis • arthritis • enlarged spleen • premature heart disease

Sitosterolemia Treatment

Effect of ezetimibe on NPC1L1-mediated internalization of cholesterol

Enzyme replacement therapy

Emerging lipid-lowering targets for ASCVD

Canadian Journal of Cardiology 33 (2017) 872-882 FIRST ELEMENT: Atherogenic Lipoproteins

Case example: Apolipoprotein(a) Antisense Oligonucleotides Lipoprotein spectrum

FIRST ELEMENT: Atherogenic Lipoproteins

Case example: Apolipoprotein(a) Antisense Oligonucleotides Lowering Lp(a)

• There are currently no treatments that selectively target Lp(a) • Therapies that lower Lp(a)

• Extended release niacin • Lipoprotein apheresis • Mipomersen (apo B antisense) • PCSK9 inhibitors • Estrogen

FIRST ELEMENT: Atherogenic Lipoproteins

Patient Case

71 year-old male • Past Medical History Coronary artery disease (s/p 4vCABG 1998) Peripheral vascular disease (s/p PCI to right leg 2014) Hypertension Hyperlipidemia

• Family History Mother has CAD, stroke, and aortic aneurysm Brother has CAD and hyperlipidemia

Patient Case Ref. Range 4/15/2016 10:24 8/11/2016 10:11

Cholesterol, Total Latest Ref Range: 125 - 200 mg/dL 178 113 (L)

Triglycerides, serum

Latest Ref Range: <150 mg/dL 168 (H) 95

Cholesterol, HDL Latest Ref Range: > OR = 40 mg/dL 56 71

LDL Cholesterol Latest Ref Range: <130 mg/dL (calc) 88 23

Chol HDL Ratio Latest Ref Range: < OR = 5.0 (calc) 3.2 1.6

Non HDL Cholesterol

Latest Units: mg/dL (calc) 122 42

Lipoprotein (a) Latest Ref Range: <75 nmol/L 543 (H) 237 (H)

LDl/HDL Ratio (External Lab) Latest Units: (calc) 1.6 0.3

2/19/2018 08:38

127

140

67

38

1.9

60

192 (H)

0.6

Case example: Apolipoprotein(a) Antisense Oligonucleotides ISIS 681257

• ISIS 681257 is an investigational antisense oligonucleotide against apo(a)

• Phase 1 studies demonstrate a selective reduction in Lp(a) by up to ~80% at the highest dose

• Current status: a phase 2 study is underway with an expected completion date of November 2018

FIRST ELEMENT: Atherogenic Lipoproteins

Lipid therapies for ASCVD

• LDL • RNA-induced silencing complex (RISC) inhibitor • Adenosine triphosphate citrate lyase (ATP-ACL) inhibitor • Acetyl CoA carboxylase (ACC) inhibitors • Microsomal triglyceride transfer protein inhibitor • Antisense oligonucleotide for apo B • PCSK9 inhibitors

• Lp(a) • Antisense oligonucleotide for apo (a)

• TG • Apolipoprotein C-III inhibitors • Selective PPAR alpha modulator • Angiopoietin-like protein 3

FIRST ELEMENT: Atherogenic Lipoproteins

Second Element: Inflammation

Ridker et al. Circ Res. 2016; 118:145-156

56 yo M Newly ↑LDL and ↑ hs-CRP

Emerging anti-inflammatory targets for ASCVD

European Heart Journal (2014) 35, 1782–1791 SECOND ELEMENT: Inflammation

Dose-dependent effects of canakinumab at 4 months for CRP, IL-6, and fibrinogen among 556 diabetic patients at high risk for vascular disease

Ridker et al. Circ Res. 2016; 118:145-156

Case example: Interleukin-1 antagonists CANTOS trial: introduction & methods

• Canakinumab is a IL-1b antibody indicated for several rare IL-1b over-expression disorders

• ~10,000 patients with prior heart and hs-CRP levels ≥2 mg/L were randomized to receive one of four treatment groups

• Canakinumab (50 mg, 150 mg, or 300 mg administered SQ every 3 months) or placebo

SECOND ELEMENT: Inflammation

Case example: Interleukin-1 antagonists CANTOS trial: CRP and lipoprotein results

N Engl J Med 2017; 377:1119-1131 SECOND ELEMENT: Inflammation

Case example: Interleukin-1 antagonists CANTOS trial: cardiovascular outcomes results

4.5

4.11

3.86 3.9

3.4

3.6

3.8

4

4.2

4.4

4.6

Placebo 50 mg 100 mg 300 mg

Rate

per

100

Per

son-

Year

s

Dose of Canakinumab

Primary end point (median follow-up of 3.7 years)

HR=0.85 P=0.021

N Engl J Med 2017; 377:1119-1131 SECOND ELEMENT: Inflammation

Anti-inflammatory therapies for ASCVD

• IL-1 • Canakinumab • Anakinra

• TNF and/or IL-6 • Low-dose methotrexate • Etanercept • Tocilizumab

• Multiple targets • Colchicine

• Alternative inflammatory pathways • Lp-PLA2

• P-Selectin • sPLA2

• Ox-LDL

SECOND ELEMENT: Inflammation

Third Element: Cholesterol Efflux

Anti-Atherogenic Properties of HDL

Reverse Cholesterol Transport

Prebeta 1 -HDL

369,000x

Association of Prebeta-1 HDL with Coronary Heart Disease and MI

Odds ratios and their 95% confidence intervals are shown for tertiles of prebeta-1 HDL, as percent total apo A-I.

“Wounded” HDL Inflammatory disorders SAA proteins Clusterin ( Apo J) Diabetes-Glycation

Oxidative stress Schiff base adducts, MDA, others Nitration ( Myeloperoxidase) Proteolysis-Chymase, Serine Proteases, MMPs

Amyloidogenic fragments

Determinants of HDL Function: HDL-Associated Molecules

Cytokine expression in whole plasma and HDL fraction Normolipidemic CAD (n=52) vs control subjects (n=69)

HDL: The Changing Landscape Total HDL cholesterol levels do not reflect risk in many individuals HDL can vary many-folds in its ability to promote efflux The level of prebeta-1 HDL is an independent indicator of the rate of efflux Prebeta-1 HDL is an independent indicator of risk of MI Inflammation is a key factor in the initiation and progression of CAD; HDL are

anti-inflammatory but mechanism is unknown We have detected at least 20 unique molecular species of HDL in human plasma Determinants of function: Emerging roles for HDL associates molecules such as

miRNA and cytokines - Emerging biomarkers of risk – HDL as mediators of inflammatory response - Targeted delivery for novel therapies

Emerging cholesterol efflux targets for ASCVD

Nature Medicine 18, 1344–1346 (2012) THIRD ELEMENT: Cholesterol Efflux

Case example: Cholesteryl ester transfer protein inhibitors Dalcetrapib failure

THIRD ELEMENT: Cholesterol Efflux N Engl J Med 2012;367:2089-99.

Case example: Cholesteryl ester transfer protein inhibitors Anacetrapib failure

Increased HDL by 43 mg/dl

Reduced non-HDL by 17 mg/dl

THIRD ELEMENT: Cholesterol Efflux N Engl J Med 2017; 377:1217-1227

Cholesterol efflux therapies for ASCVD

• HDL-related • HDL mimetics • Apolipoprotein A-I synthetic peptides • Pre-beta HDL mimic

• Upregulation of macrophage cholesterol efflux • LXR agonists • miR-33 inhibitors

THIRD ELEMENT: Cholesterol Efflux

Summary of emerging therapies for ASCVD

• There are a variety of therapies across three therapeutic strategies that show great potential to reduce ASCVD

• Lipid-lowering drug targets are furthest along • Inflammation

• The CANTOS trial shows proof-of-concept the cardioprotective effects of anti-inflammation

• Low-dose methotrexate (currently in late clinical trials) • Cholesterol efflux strategies are in early stages

• The field should focus on promoting reverse cholesterol transport rather than simply increasing HDL cholesterol levels

PCSK9 Inhibitors

https://www.inquisitr.com/2376070/us-food-and-drug-association-approves-repatha-for-high-cholesterol/. Accessed June 8th, 2018.

PCSK9 Inhibitors

Adverse Drug Reactions • >10%: Respiratory: Nasopharyngitis (6% to 11%) • 1% to 10%: Cardiovascular: Hypertension (3%); Central nervous

system: Dizziness (4%), fatigue (2%); Dermatologic: Skin rash (1%); Gastrointestinal: Gastroenteritis (3% to 6%), nausea (2%); Genitourinary: Urinary tract infection (5%); Hematologic & Oncologic: Bruise (1%); Infection: Influenza (8% to 9%); Local: Injection site reaction (including erythema, pain, bruising: 6%); Neuromuscular & Skeletal: Myalgia (4%); Respiratory: Upper respiratory tract infection (9%), cough (1% to 5%), sinusitis (4%)

• <1%, postmarketing, and/or case reports: Antibody development, decreased LDL cholesterol (<25 mg/dL), hypersensitivity, urticaria

Repatha (evolocumab) [prescribing information]. Thousand Oaks, CA: Amgen; December 2017.

FOURIER Trial-Primary Endpoint

Primary efficacy end point: composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization

ODYSSEY Trial-Primary Endpoint

Clinic Workflow

PCSK-9 inhibitor is prescribed

PA Team is notified

PA process begins Denial #1

Denial #2 or Peer-to-

Peer

Medication approved!!

Clinic Workflow

Confirm approval with pharmacy

Call patient to provide

counseling

Patient starts PCSK-9 inhibitor

Lab check after 6-8 weeks (3-4 doses)

Support Services

• Live nurses • Training videos • Co-pay cards • Needle disposal kits • Medication reminders

UCSF PCSK9 Inhibitor Population

• N~195 • 45% statin use • Prescribing department

o54% Cardiology or endocrine oOthers: neurology, heart transplant, vascular surgery, nephrology, general

medicine, dermatology, hepatology, ophthalmology, rheumatology, stroke, urology

• Initial chart screen of 10 patients o70% fill rate (4 alirocumab, 3 evolocumab)

Patient Case

58 year-old Caucasian male • Past Medical History Familial hypercholesterolemia Coronary artery disease (calcium score 998 with most prominent

involvement of the LAD) Hypertension Anxiety

• Family History Father passed away from MI at age 37; had HTN Mother has CAD and T2DM

Patient Case Ref. Range 2/23/2018 08:58 4/23/2018 16:30

Cholesterol, Total Latest Ref Range: <200 mg/dL 169 181

Triglycerides, serum

Latest Ref Range: <200 mg/dL 75 221 (H)

Cholesterol, HDL Latest Ref Range: >39 mg/dL 77 70

LDL Cholesterol Latest Ref Range: <130 mg/dL 77 67

Chol HDL Ratio Latest Ref Range: <6.0 2.2 2.6

Non HDL Cholesterol

Latest Ref Range: <160 mg/dL 92 111

Lipoprotein (a) Latest Ref Range: <75 nmol/L 242 (H)

Hemoglobin A1c Latest Ref Range: 4.3 - 5.6 PERCENT

5.8 (H)

Patient Case

Step 1 • PA submitted • Denied

Step 2 • Appeal letter #1 submitted • Denied, patient did not have LDL >100 or LDL >70 AND ASCVD

Step 3 • Appeal letter #2 submitted • Peer to peer medication approved!

Large spherical

(alpha) HDL

Preβ -1 HDL

A-I

A-I

A-I

Free Cholesterol

CETP Chylos VLDL IDL LDL

De novo synthesis of apo A-I

Liver

Removal and degradation

LCAT

ABCA1 Transporter

Peripheral Cell

PLTP

liver and intestine

SR-BI

PreBeta-1 HDL Metabolism

Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels

Prospective Cardiovascular Münster Study

* Bar represents 5% of subjects in which 25% of CHD events occurred. Assmann G, Schulte H. Am J Cardiol 1992;70:733–737. Copyright ©1992, with permission from Excerpta Medica Inc.

24 31

116

245

0

50

100

150

200

250

≤ 5.0 > 5.0

*

LDL-C/HDL-C ratio

Inci

denc

e pe

r 1,

000

(in

6 ye

ars)

TG < 200 mg/dL TG ≥ 200 mg/dL