“the imminent danger of lp(a): time to face the challenge ... · faculty disclosure i i have...

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

1

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

3

Association of Lp(a) with CVD risk in Patients on 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 4

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


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


“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 7

AntisenseSingle-Strand

Multiple Mechanisms

DNAPhosphorothioate (PS)

2’-MOE, 2’-OMe, cEt, LNA

siRNADouble-strandRISC Mechanism

RNAPhosphodiester

2’-OMe, 2’-F

Aliphatic substituents

AptamerStructured

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

8

Antisense

Oligonucleotide RNA Target

The Antisense Drug-Receptor Interaction

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

9

9

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

CytoplasmNucleus

Antisense Strand

RNase H like nuclease

DNA

mRNA

RISCSense Strand

siRNA Duplex

10

10

Examples of Chemical Modifications Used in RNA Therapeutic Agents

2ʹ-O-methoxyethyl (MOE)

OB

O

O

B

O

O

B

O

O

O

B

O

O

OP

O

O

OP

O

B

O

OP

O

OP

O

OP

OMe

OO

Me

OO

Me

OO

Me

OO

MeX = S, O

-X

-X

-X

-X

-X

11

11

Significant Advances in Medicinal Chemistry of Antisense Improve Potency and Tolerability

LICALICA

Gen 2.5LICA Gen 2/2+

cEt Gapmer Design GalNac DesignMOE Gapmer Design

LICA 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

12

Genetic architecture of the LPA gene

Schmidt et al J Lipid Res 2016;57:1339-5913

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

14

Graham et al J Lipid Res 2016;57:340-51 14

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

OO

C H3

OO

C H3

OB

O

O

B

O

O

B

O

O

B

O

O

OP

O

O

OP

S

O

OP

S

O

OP

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 MOEDeoxyMOE

Deoxy

15

15

Screening Process for ASOs

In Vivo

IND Toxicology/PK

Monkey Study (Tolerability)

Transgenic MouseRodent PK/Tox

Microwalk DRCs (Multiple Rounds)

Select Lead Sites For Microwalk

DRC (Multiple Rounds)

38 ASOs

6 ASOs

1 ASO

In Vitro

2280 ASOs

16

16

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

17

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 18

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)

19

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

20

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

To

tal C

ho

leste

rol

18

8 m

g/d

L

LDL-Ccorr

56 mg/dL

Lp(a)-C

56 mg/dL

HDL-C

51 mg/dL

VLDL-C

26 mg/dLTo

tal C

ho

leste

rol

18

8 m

g/d

L

To

tal C

ho

leste

rol

16

2 m

g/d

LA

po

B-1

00

95

mg

/dL

Ap

oB

-10

0

95

mg

/dL

Ap

oB

-10

0

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 21

Hepatocyte Targeting Antisense via Asialoglycoprotein Receptor Enhances Drug Delivery to the Liver 10-15xLICA - ligand conjugated antisense

Prakash et al Nucleic Acids Res 2014;42:8796-807 22

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 23

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)

(nm

ol/

L)

Mean

% C

ha

ng

e f

rom

Baseli

ne

(+

/-S

EM

)

Study Day

20 mgPlacebo 80 mg10 mg 40 mg 120 mg

Lp

(a)

(nm

ol/

L)

Mean

% C

ha

ng

e F

rom

Baseli

ne

(+

/-S

EM

) Study Day

20 mgPlacebo 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 24

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-UniversitätsmedizinBerlin 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

25

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 Q4W40 mg or placebo Q4W60 mg or placebo Q4W20 mg or placebo Q2W20 mg or placebo QW

Treatment duration: 6-12 months

Five cohorts*,N per cohort=54, randomized 5:1

(45 active, 9 placebo)

≤4 weeksScreening

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 26

Principal Investigators and Sites

Principal Investigator Investigator Site NamePatients

enrolled, n

Ioanna Gouni-BertholdPolyclinic for Endocrinology, Diabetes and Preventive Medicine, University of

Cologne29

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 CuchelPerelman School of Medicine at The University Perelman School of Medicine at

The University of Pennsylvania Translational Medicine & Human Genetics12

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


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 BallantyneCenter for Cardiovascular Disease Prevention

Baylor College of Medicine and DeBakey Heart & Vascular Center5

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


Objectives, Patient Population and Key Inclusion/Exclusion Criteria

• This was a multicenter, international, randomized, blinded, placebo-controlled, dose-ranging Phase 2bstudy

• 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


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


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


Baseline laboratory variables

20 mg/Q4WN=48

40 mg/Q4WN=48

20 mg/Q2WN=48

60 mg/Q4WN=47

20 mg/QWN=48

Pooled RxN=239

Pooled PlaceboN=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)


* LDL-C is uncorrected for Lp(a)-Cholesterol


-6

-35

-56 -58

-72-80

-90

-70

-50

-30

-10

10

PooledPlacebo 20 mg/Q4W 40 mg/Q4W 20 mg/Q2W 60 mg/Q4W 20 mg/QW

LSM

ean

% c

han

ge 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


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

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Me

an

pe

rce

nt

ch

an

ge

(±

SEM

) fo

r Lp

(a)

ov

er

tim

e

Weeks

PAT(25-27)

60 mg/Q4W

20 mg/QW

40 mg/Q4W

20 mg/Q2W

Pooled placebo

20 mg/Q4W


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/QWN=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)



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%

0

10

20

30

40

50

60

70

80

90

100

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

Pe

rce

nt

of

pat

ien

ts a

chie

vin

g Lp

(a)

≤50

mg/

dL

(≤1

25

nm

ol/

L)P-values represent comparison

to pooled placebo

P=0.029

P<0.0001 P<0.0001

P<0.0001

P<0.0001


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


Summary of treatment emergent adverse events

Event, N (%)20 mg/Q4W

N=4840 mg/Q4W

N=4820 mg/Q2W

N=4860 mg/Q4W

N=4720 mg/QW

N=48Pooled 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)


* The most frequent TEAE: Injection site erythema (25% in pooled Rx group)** Auto accident; Malaise*** Auto accident (same patient); Depression/suicide


Adverse Events Leading to Treatment Discontinuation

Treatment

(dose/regimen)Adverse Event

AKCEA-APO(a)-LRx

20 mg Q4WUreterolithiasis

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 placeboAnxiety

Cyst

4.6%

4.3%


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/Q4WN=48

40 mg/Q4WN=48

20 mg/Q2WN=48

60 mg/Q4WN=47

20 mg/QWN=48

Pooled RxN=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)


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


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

Tsimikas JACC 2017;69:692-711 42

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 of 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 Atorva10 mg

TNT Atorva80 mg

SPARCL

OxP

L-a

po

B, O

R/H

R

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 of the failure of statins in aortic stenosis

51J 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.mIt 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 options

• “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 YeangXiaohong Yang

Kim WeldyPhuong Miu

Joseph Witztum

Ionis

Nick VineyRosanne Crooke

Mark GrahamMichelle Fugett

Joseph TamiPatricia Wu

Lynnetta WattsRichard GearyStanley Crooke

Ionis/Akcea

Ewa ProkopczukJonathan Guerriero

Chelsey JansenPhil Piscitelli

Victoria BartlettLouis O’Dea

Collaborators

Peter WilleitSantica Marcovina

Erik StroesJ. C. van CapelleveenF. M. Van der WalkRomain Capoulade

Patrick MoriartyPhil Pibarot

Pia KamstrupBorge Nordestgaard

Novartis

Anastasia LesogorYoung-Min Kim

Tom Thuren

“the imminent danger of lp(a): time to face the challenge ... · faculty disclosure i i have...

Documents