Professor of Medicine University of California San Diego May 24, - - PowerPoint PPT Presentation

Lp(a): Phase 2 Data and NHLBI Recommendations “The imminent danger of Lp(a): Time to Face the Challenge” EAS satellite meeting Maastricht, The Netherlands Sotirios Tsimikas, MD Director of Vascular Medicine Professor of Medicine University of California San Diego May 24, 2019

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Faculty Disclosure

I I have received a research grant(s)/ in kind support

A From current sponsor(s) NO. B From any institution NO

II

I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) NO B From any institution NO

III I have been a consultant/strategic advisor etc

A For current sponsor(s) NO B For any institution (Boston Heart Dx) YES

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation NO B Not related to presentation (UCSD) YES

Declaration of financial interests For the last 3 years and the subsequent 12 months:

Disclosures

Co-inventor and receives royalties from patents owned by the University of California San Diego on oxidation-specific antibodies Dual appointment at UCSD and Ionis Pharmaceuticals Co-Founder Oxitope, Inc and Kleanthi Diagnostics

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Association of Lp(a) with CVD risk in Patients

• n Statins from 7 Landmark Trials
• 29 069 patients8064 [28%] women; 5751

events, 95,576 person-years at risk

• AFCAPS, CARDS, 4D, JUPITER, LIPID,

MIRACL, and 4S trials.

• Comparison of groups with lipoprotein(a)

levels of <15 mg/dL, 15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL.

• Multivariable adjustment included age, sex,

previous CVD, diabetes, smoking, systolic blood pressure, LDL cholesterol corrected for lipoprotein(a) cholesterol, and HDL cholesterol.

• Associations were independent of

established risk factors.

• In an interaction analysis, the association of

high lipoprotein(a) with CVD risk was stronger in patients allocated a statin than in patients allocated placebo

Willeit et al. Lancet 2018;392:1311-20

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Predictive value of on-statin vs. on-placebo Lp(a) with CVD risk from 7 Landmark Trials

In an interaction analysis, the association of high lipoprotein(a) with CVD risk was stronger in patients allocated a statin than in patients allocated placebo

Willeit et al. Lancet 2018;392:1311-20

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Predictive value of on-statin vs. on-placebo Lp(a) with CVD risk from 7 Landmark Trials

In an interaction analysis, the association of high lipoprotein(a) with CVD risk was stronger in patients allocated a statin than in patients allocated placebo

Willeit et al. Lancet 2018;392:1311-20

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“When LDL-attributable risk is reduced with statin treatment, lipoprotein(a)- associated risk becomes an even stronger predictor of residual risk. This observation is especially evident at lipoprotein(a) concentrations exceeding 50 mg/dL.”

Antisense Oligonucleotides Targeting Lp(a)

Antisense Oligonucleotide

Tsimikas JACC 2017;69:692-711

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Antisense

Single-Strand Multiple Mechanisms

DNA

Phosphorothioate (PS) 2’-MOE, 2’-OMe, cEt, LNA

siRNA

Double-strand RISC Mechanism

RNA

Phosphodiester 2’-OMe, 2’-F Aliphatic substituents

Aptamer

Structured

DNA or RNA

Mixed modifications Pegylation

(REG1 anticoagulation system)

Distinct Chemical Classes of RNA-Based Technologies & Therapeutics

Aptamer Target Protein Sense Strand Antisense Strand Antisense Strand

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Antisense Oligonucleotide RNA Target

The Antisense Drug-Receptor Interaction

~15-20 base pairs required for specificity and binding Natural DNA and RNA do not make good drugs due to insufficient stability and distribution in animals This can be addressed with appropriate chemical modification

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Isis Pharmaceuticals Confidential

RNaseH1 and siRNA Antisense Mechanisms

◼ siRNA Mechanism ◼ RNase H1 Mechanism

Antisense Strand mRNA-Antisense Duplex RNase H1

DNA mRNA

Nucleus Cytoplasm Cell Membrane Cell Membrane Cytoplasm Nucleus Antisense Strand RNase H like nuclease DNA mRNA RISC Sense Strand siRNA Duplex

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Examples of Chemical Modifications Used in RNA Therapeutic Agents

2ʹ-O-methoxyethyl (MOE)

O B O O B O O B O O O B O O O P O O O P O B O O P O O P O O P O Me O O Me O O Me O O Me O O Me X = S, O

• X
• X
• X
• X
• X

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Significant Advances in Medicinal Chemistry of Antisense Improve Potency and Tolerability

LICA

LIC A

Gen 2.5

LIC A

Gen 2/2+

cEt Gapmer Design GalNac Design

MOE Gapmer Design

LIC A

1st Gen

P-S

1X ↑10X ↑10X ↑10X =1000X

Side effect profile Potency

(600-1200/wk) 100-300/wk 10-40/wk 10-40/wk 1-3/wk

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Genetic architecture of the LPA gene

Schmidt et al J Lipid Res 2016;57:1339-59

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IONIS-APO(a)Rx Targets a unique splice site of Kringle-IV2 exon 24/25 junction present in 1 copy of all apo(a) mRNA

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Graham et al J Lipid Res 2016;57:340-51

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IONIS-APO(a)Rx ASO to Lower Plasma Lp(a)

Targets a unique splice site of exon 24/25 present in 1 copy of all apo(a) mRNA, corresponding to a Kringle-IV2 repeat

2‘ Methoxyethyl Phosphorothioate Oligonucleotide (2’ MOE Gapmer)

S S O O C H3 O O C H3 O B O O B O O B O O B O O O P O O O P S O O P S O O P 5' 3' H H

Chimera / Gapmer

affinity stability tolerability RNase H1 Substrate

It does not bind to or reduce hepatic expression or plasma levels of plasminogen

C T T G T T C T G C T C C G T T G G T C

MOE MOE Deoxy

MOE Deoxy

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Screening Process for ASOs

In Vivo

IND Toxicology/PK Monkey Study (Tolerability) Transgenic Mouse Rodent PK/Tox Microwalk DRCs (Multiple Rounds) Select Lead Sites For Microwalk DRC (Multiple Rounds)

38 ASOs 6 ASOs 1 ASO In Vitro 2280 ASOs

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Pre-Clinical Proof-of-Concept Studies with ASO Therapy for Lp(a)

Reduction in Lp(a) levels with ASO to apoB and apo(a)

Merki E et al Circulation 2008;118:743–53 Merki et al. JACC 2011;57:1611–2

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Relationship of Plasma ISIS-APO(a)Rx Trough Concentrations and Mean Percent Change in Lp(a), OxPL-apoB and OxPL-apo(a) - 300 mg 18 Terminal elimination half- life of ASO = ~23 days

Tsimikas et al Lancet 2015;386:1472-1483

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IONIS-APO(a)Rx Phase 2 trial- Effect on Lp(a) and OxPL Patients with Lp(a) >50 mg/dL

Placebo Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL) Viney et al Lancet 2016;388:2239-53

Lp(a) OxPL-apoB OxPL-apo(a)

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Reduction in Lp(a), OxPL-apoB and OxPL-apo(a) is strongly associated with reduced transendothelial monocyte migration

First In vivo demonstration of anti-inflammatory effect of Lp(a)-OxPL lowering

Placebo Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL)

Transendothelial monocyte migration

Viney et al Lancet 2016;388:2239-53 With van Capelleveen and Stroes

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Traditional Lipid Profile TC = LDL-C + VLDL-C+ HDL- C HDL-C 51 mg/dL “LDL-C” 112 mg/dL VLDL-C 26 mg/dL Total Cholesterol 188 mg/dL LDL-Ccorr 56 mg/dL Lp(a)-C 56 mg/dL HDL-C 51 mg/dL VLDL-C 26 mg/dL Total Cholesterol 188 mg/dL Total Cholesterol 162 mg/dL ApoB-100 95 mg/dL ApoB-100 95 mg/dL ApoB-100 79 mg/dL HDL-C 48 mg/dL Corrected Lipid Profile for Lp(a)-C TC = LDL-C + Lp(a)-C + VLDL-C + HDL-C Corrected Lipid Profile Post IONIS-Apo(a)Rx LDL-Ccorr 72 mg/dL Lp(a)-C 17 mg/dL VLDL-C 25 mg/dL

Additional Net Reduction of Atherogenic LDL- ApoB-100 with ASO to Apo(a)

Viney et al J Clin Lipidol 2018;12:702-10

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Hepatocyte Targeting Antisense via Asialoglycoprotein Receptor Enhances Drug Delivery to the Liver 10-15x

LICA - ligand conjugated antisense

Prakash et al Nucleic Acids Res 2014;42:8796-807

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Dose-Dependent Effect of Optimized ASO to Apo(a) in Reducing Plasma Lp(a)

IONIS-APO(a)-LRx has ~30x Improved Potency vs. IONIS-APO(a)Rx in Humans ED50 4 mg vs 122 mg, 30-fold more potent

Viney et al Lancet 2016;388:2239-53

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IONIS-APO(a)-LRx Produced Dose-dependent, Significant Reductions in Lp(a) in Phase 1 Study in Subjects with Lp(a) >30 mg/dL

Up to 97% Reduction in Lp(a), with Mean Reduction of 85% Up to 99% Reduction in Lp(a), with Mean Reduction of 92%

Single Ascending Dose Multiple Ascending Dose

Lp(a) (nmol/L) Mean % Change from Baseline (+/- SEM) Study Day

20 mg Placebo 80 mg 10 mg 40 mg 120 mg

Lp(a) (nmol/L) Mean % Change From Baseline (+/- SEM) Study Day

20 mg Placebo 10 mg 40 mg

Mean Lp(a) reductions: 10 mg = ↓ 68% 20 mg = ↓ 80% 40 mg = ↓ 92%

Viney et al, Lancet 2016;388:2239-53

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Safety and efficacy of AKCEA-APO(a)-LRx to lower lipoprotein(a) levels in patients with established cardiovascular disease: A phase 2 dose-ranging trial

University of California San Diego (ST, JLW); Akcea Therapeutics (E K-P, JG, LO’D), University of Cologne (IG-B); Montreal Heart Institute, (J-CT); Excel Medical Clinical Trials, (SJB); Charité-Universitätsmedizin Berlin and University Medicine Greifswald (E S-T); Oregon Health & Science University (MDS); Academic Medical Center (ESS); University of Kansas Medical Center, (P.M.M.); Herlev and Gentofte Hospital, Copenhagen University Hospital and University of Copenhagen (BGN); Ionis Pharmaceuticals, Inc. (NJV, ST)

Sotirios Tsimikas, Ewa Karwatowska-Prokopczuk, Ioanna Gouni-Berthold, Jean-Claude Tardif, Seth J. Baum, Elizabeth Steinhagen-Thiessen, Michael D. Shapiro, Erik S. Stroes, Patrick M. Moriarty, Børge G. Nordestgaard, Jonathan Guerriero, Nicholas J. Viney, Louis O'Dea, Joseph L. Witztum on behalf of the AKCEA-APO(a)-LRx Study Investigators

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Study Design and Endpoints - AKCEA-APO(a)-LRx Trial

QW = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; R = randomization; SC = subcutaneous.

*Cohorts (SC administration): 20 mg or placebo Q4W 40 mg or placebo Q4W 60 mg or placebo Q4W 20 mg or placebo Q2W 20 mg or placebo QW Treatment duration: 6-12 months

Five cohorts*, N per cohort=54, randomized 5:1 (45 active, 9 placebo)

≤4 weeks Screening 16 weeks follow up R The primary endpoint was the mean percent change in Lp(a) from baseline to week 25–27 depending on dose regimen Secondary endpoints included:

• Mean percent change in OxPL-apoB, OxPL-apo(a), LDL-

C, apoB and the percentage of patients reaching Lp(a) <50 mg/dL (<125 nmol/L)

Tsimikas et al AHA 2018

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Principal Investigators and Sites

Principal Investigator Investigator Site Name Patients enrolled, n Ioanna Gouni-Berthold Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne 29 Jean-Claude Tardif Montreal Heart Institute, University of Montreal 29 Seth Baum Excel Medical Clinical Trials, LLC 19 Elizabeth Steinhagen-Thiessen Charite - University Hospital Berlin - Campus Virchow - Hospital 19 Michael Shapiro Oregon Health & Science University 17 Erik Stroes Academic Medical Center 16 Patrick Moriarty University of Kansas Medical Center 15 Bǿrge Nordestgaard Copenhagen University Hospital 15 Daniel Gaudet ECOGENE-21 13 Marina Cuchel Perelman School of Medicine at The University Perelman School of Medicine at The University of Pennsylvania Translational Medicine & Human Genetics 12 David Maron/Abha Khandelwal Stanford University Medical Center 11 Ib Christian Klausen Regionshospitalet Viborg, Hospitalsenhed Midt 10 Robert Rosenson Cardiometabolics Unit, Icahn School of Medicine at Mount Sinai 10 Anthony DeMaria UC-San Diego 9 Samuel Butman Verde Falley Medical Center Cardiovascular Research 9 Tsimikas et al AHA 2018

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Principal investigators and Sites

Principal investigator Investigator Site Name Patients enrolled, n Howard Weintraub New York University School of Medicine 8 Ruth McPherson University of Ottawa Heart Institute 8 Michael Koren Jacksonville Center for Clinical Research 6 Jean Bergeron Clinique des maladies lipidiques de Québec 6 Christie Ballantyne Center for Cardiovascular Disease Prevention Baylor College of Medicine and DeBakey Heart & Vascular Center 5 Anthony DeFranco Aurora St. Luke's Medical Center 5 Karen Aspry Miriam Hospital 5 Haitham Ahmed Cleveland Clinic 2 Rolf Andersen LGHealth / Penn Medicine Research Institute 2 Linda Hemphill Massachusetts General Hospital 1 Prediman Krishan Shah Cedars Sinai Medical Center 1 Michael Miller University of Maryland Medical Center 1 Russell Strader UCH-MHS 1 Merle Myerson Bassett Medical Center – Bassett Research Institute 1 George Thanassoulis Research Institute of the McGill University Health Centre 1 Tsimikas et al AHA 2018

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Objectives, Patient Population and Key Inclusion/Exclusion Criteria

• This was a multicenter, international, randomized,

blinded, placebo-controlled, dose-ranging Phase 2b study

• The patient population included:
• Subjects with pre-existing cardiovascular disease (CAD, MI, PAD, stroke/TIA)

and baseline Lp(a) ≥60 mg/dL (~≥150 nmol/L) (normal levels: <30 mg/dL or <75 nmol/L)

• Key exclusion criteria included:
• Revascularization or lipoprotein apheresis within 3 months of screening
• Acute coronary syndrome, major cardiac surgery, or stroke/TIA within 6

months of screening

• NYHA class IV
• Uncontrolled hypertension (>160/100 mm/Hg)
• Use of oral anticoagulants

Tsimikas et al AHA 2018

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Laboratory measurements

OxPL-apoB, oxidized phospholipids on apolipoprotein B-10 OxPL-apo(a), oxidized phospholipids on apolipoprotein(a)

• Lp(a) molar concentrations (nmol/L) were measured with

an isoform-independent assay at the Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington

• Lp(a) mass (mg/dL) was estimated by dividing molar

concentration by 2.5 (nmol/L ÷ 2.5 = mg/dL)

• OxPL-apoB and OxPL-apo(a) levels were measured with

established assays at the University of California San Diego

• All safety lab measurements were measured at Medpace

Reference Laboratories

Tsimikas et al AHA 2018

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Baseline patient demographic characteristics

PCSK9 = proprotein convertase subtilisin/kexin type 9; QW = once a week; Q2W = every 2 weeks; Q4W = every 4 weeks; SD = standard deviation.

20 mg/Q4W N=48 40 mg/Q4W N=48 20 mg/Q2W N=48 60 mg/Q4W N=47 20 mg/QW N=48 Pooled Rx N=239 Pooled placebo N=47 Age, years, mean (SD) 60 (9.6) 61.3 (10.6) 57.9 (11.5) 62.2 (9.7) 58.9 (8.0) 60.1 (10.0) 59.9 (10.5) Sex, male, n (%) 29 (60.4) 36 (75.0) 31 (64.6) 33 (70.2) 28 (58.3) 157 (65.7) 32 (68.1) Anti-Platelet Rx, n (%) 47 (97.9) 47 (97.9) 47 (97.9) 47 (100) 48 (100.0) 236 (98.7) 43 (91.5) Lipid-Lowering Rx, n (%) Statin Ezetimibe PCSK9 inhibitor 42 (87.5) 25 (52.1) 8 (16.7) 44 (91.7) 25 (52.1) 11 (22.9) 43 (89.6) 23 (47.9) 9 (18.8) 44 (93.6) 19 (40.4) 10 (21.3) 44 (91.7) 23 (47.9) 13 (27.1) 217 (90.8) 115 (48.1) 51 (21.3) 39 (83.0) 23 (48.9) 10 (21.3) Previous history, n (%) Coronary artery disease Carotid artery disease Peripheral artery disease 44 (91.7) 13 (27.1) 9 (18.8) 45 (93.8) 12 (25.0) 10 (20.8) 45 (93.8) 10 (20.8) 4 (8.3) 46 (97.9) 11 (23.4) 1 (2.1) 44 (91.7) 14 (29.2) 5 (10.4) 224 (93.7) 60 (25.1) 29 (12.1) 45 (95.7) 9 (19.1) 4 (8.5) MI, n (%) 25 (52.1) 25 (52.1) 31 (64.6) 20 (42.6) 27 (56.3) 128 (53.6) 27 (57.4) Stroke/TIA, n (%) 6 (12.5) 6 (12.5) 7 (14.6) 4 (8.6) 5 (10.4) 28 (11.7) 8 (17.0) Hypertension, n (%) 28 (58.3) 35 (72.9) 34 (70.8) 31 (66.0) 25 (52.1) 153 (64.0) 30 (63.8) Type 2 Diabetes, n (%) 7 (14.6) 8 (16.7) 5 (10.4) 4 (8.5) 6 (12.5) 30 (12.6) 10 (21.3)

AKCEA-APO(a)-LRx dose/regimen Tsimikas et al AHA 2018

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Baseline laboratory variables

20 mg/Q4W N=48 40 mg/Q4W N=48 20 mg/Q2W N=48 60 mg/Q4W N=47 20 mg/QW N=48 Pooled Rx N=239 Pooled Placebo N=47 Lp(a), nmol/L, Mean/Median 279.7/246.6 236.6/220.0 250.6/238.2 233.9/204.5 248.2/233.7 249.9/224.3 258.2/231.6 Lp(a), mg/dL, estimated Mean/Median 111.9/98.6 94.7/88.0 100.3/95.3 93.6/81.8 99.3/93.5 100.0/89.7 103.3/92.6 OxPL-apoB, nmol/L, median (IQR) 24.6 (18.1, 33.1) 23.1 (16.2, 32.5) 23.9 (17.9, 29.2) 20.3 (16.6, 28.5) 23.7 (17.2, 30.7) 23.3 (17.4, 30.5) 21.2 (17.2, 31.5) OxPL-apo(a), nmol/L, median (IQR) 66.3 (57.8, 75.0) 65.9 (56.6, 71.9) 67.3 (60.8, 73.2) 61.9 (53.4, 72.7) 67.1 (60, 74.6) 65.8 (58.6, 73.8) 69.2 (59.6, 76.5) LDL*, mg/dL, mean (SD) 89.3 (37.1) 77.4 (39.5) 74.4 (28.8) 67.6 (28.3) 76.1 (28.4) 77.0 (33.3) 79.4 (29.2) ApoB, mg/dL, mean (SD) 80.7 (23.6) 71.9 (23.4) 69.3 (19.8) 68.5 (18.8) 70.6 (19.2) 72.2 (21.3) 73.8 (16.9) HDL, mg/dL, mean (SD) 54.1 (15.5) 54.1 (19.3) 54.1 (19.3) 50.3 (11.6) 58.0 (19.3) 54.1 (19.3) 50.3 (19.3) Triglycerides, mg/dL, median (IQR) 97 (44, 230.3) 97 (35, 283) 106 (35, 204) 106 (53, 567) 89 (35, 266) 97 (35, 567) 106 (35, 576) hsCRP, mg/L, mean (SD) 2.9 (5.3) 2.3 (4.5) 1.6 (2.5) 2 (2.5) 2.2 (4.4) 2.2 (4.0) 2.4 (4.4) AKCEA-APO(a)-LRx dose/regimen * LDL-C is uncorrected for Lp(a)-Cholesterol Tsimikas et al AHA 2018

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• 6
• 35
• 56
• 58
• 72
• 80
• 90
• 70
• 50
• 30
• 10

10

Pooled Placebo 20 mg/Q4W 40 mg/Q4W 20 mg/Q2W 60 mg/Q4W 20 mg/QW

LSMean % change in Lp(a)

P-values represent comparison to pooled placebo

Primary endpoint: Mean percent change (95% CI) in Lp(a) from baseline to week 25-27

P-values from an ANCOVA model with treatment as fixed factor and log-scale baseline as a covariate. Adjusted % change = (ratio of endpoint/baseline – 1) ×100. CI, confidence interval; Lp(a), lipoprotein(a); LS, least squares

P=0.0032 P<0.0001 P<0.0001 P<0.0001 P<0.0001

Primary efficacy endpoint was not affected by baseline Lp(a) levels, statin or PCSK9i use Tsimikas et al AHA 2018

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Primary endpoint: Mean percent change (SEM) in Lp(a) from baseline to week 25-27

PAT, primary analysis timepoint; QW, once a week; Q2W, every 2 weeks; Q4W, every 4 weeks; SEM, standard error of the mean.

• 90
• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

2 4 6 8 10 12 14 16 18 20 22 24 26 28 Mean percent change (± SEM) for Lp(a) over time

Weeks

PAT (25-27)

60 mg/Q4W 20 mg/QW 40 mg/Q4W 20 mg/Q2W Pooled placebo 20 mg/Q4W Tsimikas et al AHA 2018

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Absolute change in Lp(a) from baseline to week 25-27

20 mg/Q4W N=48 40 mg/Q4W N=48 20 mg/Q2W N=48 60 mg/Q4W N=47 20 mg/QW N=48 Pooled placebo N=47

Absolute change from baseline in Lp(a), mg/dL Mean (SD) Absolute change from baseline in Lp(a), nmol/L Mean (SD)

• 38.4

(37.7)

• 95.9

(94.4)

• 46.8

(28.7)

• 116.9

(71.7)

• 52.1

(26.4)

• 130.3

(66.1)

• 59.8

(27.0)

• 149.5

(67.4)

• 75.1

(32.1)

• 187.8

(80.3)

• 6.1

(13.8)

• 15.2

(34.6)

AKCEA-APO(a)-LRx dose/regimen Tsimikas et al AHA 2018

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Secondary endpoint: Percent of patients achieving Lp(a) ≤50 mg/dL (≤ 125 nmol/L) at PAT

6,4% 25.0% 62,5% 64,6% 80,9% 97,7% 10 20 30 40 50 60 70 80 90 100 Pooled Placebo20 mg/Q4W 40 mg/Q4W 20 mg/Q2W 60 mg/Q4W 20 mg/QW Percent of patients achieving Lp(a) ≤50 mg/dL (≤125 nmol/L)

P-values represent comparison to pooled placebo

P=0.029 P<0.0001 P<0.0001 P<0.0001 P<0.0001 Tsimikas et al AHA 2018

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Secondary endpoints: Percent change from baseline at week 25-27

P-value vs pooled placebo: * p<0.05; ** p<0.01; *** p<0.001

%change is at primary analysis timepoint. LDL-C, low-density lipoprotein cholesterol; QW, once a week; Q2W, every 2 weeks; Q4W, every 4 weeks.

Treatment (dose/regimen) OxPL-apoB OxPL-apo(a) LDL-C ApoB

AKCEA-APO(a)-LRx 20 mg Q4W 40 mg Q4W 20 mg Q2W 60 mg Q4W 20 mg QW

• 26.8**
• 42.4***
• 52.8***
• 65.5***
• 81.8***
• 24.8
• 37.5*
• 38.6*
• 53.5***
• 61.2***
• 5.2
• 20.4***
• 11.1*
• 6.9*
• 20.5**
• 1.9
• 12.8***
• 7.6*
• 4.0*
• 14.5***

Pooled placebo 22.4

• 17.6

1.2 2.0

Tsimikas et al AHA 2018

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Summary of treatment emergent adverse events

Event, N (%) 20 mg/Q4W N=48 40 mg/Q4W N=48 20 mg/Q2W N=48 60 mg/Q4W N=47 20 mg/QW N=48 Pooled Rx N=239 Pooled placebo N=47 At least one TEAE* 46 (95.8) 41 (85.4) 41 (85.4) 43 (91.5) 42 (87.5) 213 (89.1) 39 (83.0) At least one serious TEAE 6 (12.5) 7 (14.6) 3 (6.3) 6 (12.8) 3 (6.3) 25 (10.5) 1 (2.1) At least one related serious TEAE** 1 (2.1) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 2 (0.8) 0 (0.0) At least one TEAE leading to treatment discontinuation 2 (4.2) 0 (0.0) 1 (2.1) 3 (6.4) 5 (10.4) 11 (4.6) 2 (4.3) TEAE leading to death*** 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 1 (2.1) 2 (0.8) 0 (0.0) AKCEA-APO(a)-LRx dose/regimen * The most frequent TEAE: Injection site erythema (25% in pooled Rx group) ** Auto accident; Malaise *** Auto accident (same patient); Depression/suicide Tsimikas et al AHA 2018

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Adverse Events Leading to Treatment Discontinuation

Treatment (dose/regimen) Adverse Event

AKCEA-APO(a)-LRx 20 mg Q4W Ureterolithiasis Malaise 20 mg Q2W Arthralgia, Myalgia 60 mg Q4W Lung neoplasm malignant Road traffic accident Myalgia, Paraesthesia, Swelling face, Nausea 20 mg QW Intraductal proliferative breast lesion Depression/suicide Post-injection: throat tightness, hot flush, discomfort, dizziness Myalgia Injection site erythema Pooled placebo Anxiety Cyst

4.6% 4.3%

Tsimikas et al AHA 2018

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Changes in platelet-count, LFTs and renal function categories by treatment group

*2 occurrences across the study (regulatory standard) **LFTs- No patient meet a Liver Safety Stopping Rule; However, 1 patient at the End of Treatment visit had AST 103 U/L (ULN =34 U/L, 3X ULN 102 U/L) and ALT 72 U/L (ULN = 41 U/L), with no change in total bilirubin, INR or Hy’s Law. ***Renal Function - 1 patient had unrelated pre-renal azotemia and 1 patient had unrelated incomplete 24 hour urine collection, creating an artifactual safety alert. Both continued in treatment. n (%) 20 mg/Q4W N=48 40 mg/Q4W N=48 20 mg/Q2W N=48 60 mg/Q4W N=47 20 mg/QW N=48 Pooled Rx N=239 Pooled Placebo N=47 Platelet count, mm3 <140,000* 3 (6.3) 8 (16.7) 3 (6.4) 3 (6.3) 8 (16.7) 25 (10.5) 7 (14.9) No confirmed platelet value <100,000 mm3 LFTs >3X ULN** 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 0 (0.0) 1 (0.4) 0 (0.0) 24 hr CrCl decrease > 40% from baseline*** 0 (0.0) 1 (2.1) 1 (2.1) 0 (0.0) 0 (0.0) 2 (0.8) 0 (0.0) Tsimikas et al AHA 2018

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Conclusions

• This trial achieved its primary endpoint and all of

its secondary endpoints. AKCEA-APO(a)-LRx significantly reduced Lp(a), OxPL-apoB, OxPL- apo(a), LDL-C and apoB levels

• 98% of patients achieved Lp(a) levels ≤50 mg/dL at

the highest dose

• There were no safety concerns related to platelet

counts, liver function or renal function

• A phase 3 outcomes trial to test the “Lp(a)

hypothesis”, namely that lowering Lp(a) levels will reduce cardiovascular events, will start late 2019/early 2020

Tsimikas et al AHA 2018

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Lp(a) cutoffs signifying increased CVD risk and effect of therapeutic agents to achieve these targets

Tsimikas JACC 2017;69:692-711

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NHLBI Recommendations

• Explore mechanisms by which NHLBI could facilitate

basic, mechanistic, preclinical, and clinical research on Lp(a).

• Foster collaborative research and resource sharing,

leverage expertise of different groups and centers with complementary skills, methods, and knowledge, and leverage existing resources such as NHLBI cohorts.

• Support assignment of an ICD-10 code for the diagnosis
• f elevated Lp(a).
• Organize focused working groups comprised of wide

array of stakeholders, including regulatory agencies, to standardize Lp(a) measurements.

• Educate the public, physicians, regulatory agencies,

and funding agencies on the role of Lp(a) in CVD and CAVD.

• Develop evidence-based management plans for

patients.

44

✓ ✓

Specific Research Priorities and Recommendations

• To fully define mechanisms of Lp(a) synthesis, assembly,

clearance and other influences on circulating levels.

• To understand the mechanisms underpinning Lp(a) and its

associated oxidized phospholipids in mediating risk of CVD and aortic stenosis

• To develop a globally standardized measurement of Lp(a)

applicable to commercial laboratories and to define population risk among different ethnic/racial groups

• To understand the mechanisms through which therapeutic

regimens affect Lp(a) levels

• Focused populations at risk for CVD with high Lp(a) requiring

special research emphasis (FH, CAVD, ESRD, high thrombosis risk, refractory angina, lipoprotein apheresis, children with CVA)

45

✓ ✓

New Lp(a) ICD-10 codes

New ICD-10 codes effective Oct. 2018 E78.41 Elevated lipoprotein(a) Z83.430 Family history of elevated lipoprotein(a)

46

What are the mechanisms through which Lpa) mediates CVD and CAVS?

Tsimikas JACC 2017;69:692-711

47

OxPL-apoB Levels and CVD Outcomes

CAD, PAD, CVA

Byun et al JACC 2015;65:1286-95

2,40 1,66 2,55 1,50 2,58 1,90 1,45 4,40 0,0 1,0 2,0 3,0 4,0 5,0

Bruneck EPIC-Norfolk NHS HPFS MAYO TNT Atorva 10 mg TNT Atorva 80 mg SPARCL

OxPL-apoB, OR/HR

Study

Hazard/Odds ratio for primary endpoint, highest tertile/quartile comp No Prior CVD Prior CVD

48

Association of Aortic stenosis and Lp(a)-OxPL

Six Recent Studies

49

Association of Aortic Stenosis and Lp(a)-OxPL

Seven Recent Studies

50

Elevated Lp(a) and OxPL-apoB Predict Progression of CAVS and Need for AVR

Potential explanation

• f the failure of

statins in aortic stenosis

51

J Am Coll Cardiol 2015;66:1236-46

Progression of aortic stenosis according to Lp(a) and OxPL levels

Capoulade et al JAMA Cardiol 2018;3:1212-17

52

Statins increase Lp(a) levels

UCSD Lp(a) data from clinical trials in 5256 patients

Tsimikas et al Eur Heart J 2019

53

In whom should Lp(a) be measured?

• Since it’s a genetic risk

factor whose levels change minimally over a lifetime, everyone should have an Lp(a) measured when they get their first lipid panel.m It is likely cost-effective is test is ~$50. If levels are low (in >75% of patients) it never has to be checked again

• UCSD EPIC ordering
• ptions
• “lipid panel”
• ’lipid panel with Lp(a)”
• Intermediate or high risk
• Premature CVD
• FH
• Family history
• Non-responsive to statins
• Recurrent events≥3% 10-year

risk of fatal CVD

• ≥10% 10-year risk of

fatal/nonfatal CHD

My opinion Guidelines

54

UCSD is a Center of Excellence in Research and Patient Care in Lp(a)

Created World’s First Dedicated “Lp(a) Clinic” in 2014

5 5

Tsimikas Vascular Medicine Clinic (n=150) Physician members of the UCSD Lp(a) Clinic:

Michael Wilkinson, MD Calvin Yeang, MD Joseph Witztum, MD Sotirios Tsimikas, MD

UCSD Hospitals 2010-2015

55

Acknowledgments

56

UCSD Calvin Yeang Xiaohong Yang Kim Weldy Phuong Miu Joseph Witztum Ionis Nick Viney Rosanne Crooke Mark Graham Michelle Fugett Joseph Tami Patricia Wu Lynnetta Watts Richard Geary Stanley Crooke Ionis/Akcea Ewa Prokopczuk Jonathan Guerriero Chelsey Jansen Phil Piscitelli Victoria Bartlett Louis O’Dea Collaborators Peter Willeit Santica Marcovina Erik Stroes

• J. C. van Capelleveen
• F. M. Van der Walk

Romain Capoulade Patrick Moriarty Phil Pibarot Pia Kamstrup Borge Nordestgaard Novartis Anastasia Lesogor Young-Min Kim Tom Thuren