evolving new therapies for the prevention of ......evolving new therapies for the prevention of...

Evolving new therapies for the

prevention of atherosclerosis:

a glimpse of the near future

G.K. Hovingh MD PhD

([email protected])

Department of Vascular Medicine

AMC Amsterdam

The Netherlands

mailto:[email protected]

Today

BMJ 2013;347:f544

www.chinadaily.com.cn/life/2009-

04/21/content_7698500.htm

http://www.chinadaily.com.cn/life/2009-04/21/content_7698500.htm

What we know

- CVD major burden

- LDL-C causally related with CVD

- LDL-C goals: the lower the better

- Statins : corner stone in therapy

Reduction

in MACE statin vs placebo

(%)

Potential for further

risk reduction

-30

0

-100

How well do we do?

Where do we go?

Reduction

in MACE statin vs placebo

(%)

Potential for further

risk reduction

=

further LDL-C

lowering?

and or

Additional Rx?

-50

0

-100

-30

A glance at the future…

Atherosclerosis

• LDL

• HDL

• TG

• Lp(a)

• Inflammation

Lipid Modifying Drugs

• Cholesterol absorption inhibitors

• Squalene synthase inhibitors (SSI)

• Microsomal triglyceride transfer protein (MTP) inhibitors

• Acyl coenzyme A acyltransferase (ACAT) inhibitors

• Diacylglycerol acyltransferase (DGAT) inhibitors

• Thyroxin receptor agonists

• ApoB mRNA antisense drugs

• PCSK9 antibodies

• ApoA1-based strategies (iv)

• Cholesterol ester transfer protein (CETP) inhibitors

ApoA-1 based therapy

ApoA1 Mimetics, such as APL-180 Novartis

Full-length ApoA1, such as ApoA1 Cerenis Therapeutics

Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc.

Reconstituted HDL, CSL Ltd.

ApoA1 Milano MDCO216, The Medicines Company

Trimeric ApoA1, Borean Pharma and now Roche

RVX-208, as developed by Resverlogix

Fx-5A, as developed by Kinemed Inc.

HDL epidemiology

Emerging Risk Factors Collaboration, JAMA 2009

302K participants in 68 prospective

studies

HDL intervention; failuresTorcetrapib, Dalcetrapib, Niacin

HDL cholesterol remains a

useful marker of MI risk

and

should continue to be

measured routinely to assess

risk

Correlation in observational

epidemiologic studies

does NOT

equal causation

Observational

epidemiologyHypothesis Raised

Result of testing of

hypothesis in clinical

trial

PVCs post MI is

associated with

increased risk of

sudden death

Suppression of PVCs

with medicines will

reduce risk of sudden

death

(CAST trial 1989)

Treatment with

antiarrhythmics

suppressed PVCs,

INCREASED risk of

arrhythmic death

Hormone replacement

therapy use is

associated with lower

risk of CVD

HRT will lower risk of

CVD

(HERS, WHI trials)

HRT INCREASED risk

of MI and stroke

Anemia in patients with

T2D and CKD is

associated with

increased risk of CVD

Correcting anemia with

Epo will lower risk of

CVD

(TREAT trial, 2009)

Epogen administration

corrected anemia but

INCREASED the rate of

stroke

CETP inhibitors

Torcetrapib Dalcetrapib Anacetrapib Evacetrapib

HDL +55-70% +30% +140% +50-130%

LDL -15-25% no effect -35% -20-40%

apoA1 +25% +10% +40% +20-50%

lp(a) no effect no effect -40% na

RR increased no effect no effect no effect

Primary End Point

CV death, MI, stroke, coronary revasc or hospitalization for UA

Sites in North America, Europe and Asia

3 yrs FU

Evacetrapib 130mg

11.000 CVD pts

Placebo

completion 2017

Statin

> 30 days

ACCELERATE

N=42 placebo + placebo

N=42 TA-8995 1mg + placebo

N=42 TA-8995 2.5mg + placebo

N=42 TA-8995 10mg+ Atorvastatin 20mg

N=42 placebo +Atorvastatin 20mg



N=42 placebo + Rosuvastatin 10mg

N=42 TA-8995 10mg + Rosuvastatin 10mg

Washout/run in treatment 12 weeks FU

TULIP Design

- mild dyslipidemia

- no CVD

- LDL-C 2.5- 4.5

mmol/L

- HDL-C 0.8-1.8

mmol/L

- TG <4.5 mmol/L

0%

100% 76%

122%

180%

50%

200%

HDL-C %change at 12 weeks

Placebo

TA-8995 (mg/day)

1 2.5 5 10

150%

2%

166%

0%

-20%

-27%

-34%

-47% -47%

-40%

-60%

LDL-C %change at 12 weeks

Placebo

TA-8995 (mg/day)

1 2.5 5 10

The CETP history

Annu Rev Med 2014;65:385

LDL-C is primary target








• antisense drugs




GENE

DNA

Antisense

RNA

Protein

Disease

mRNA

Small molecule

Antisense Drug

Antisense drug

DiseaseDisease

Antisense Drug

RNAse

68

Human ApoB-100Ideal Target

• ApoB-100:

– expressed in liver

– essential for synthesis

and transport of VLDL

and LDL-C

– biologically validated

– Undruggable for small

molecules

70

Dose Dependent Reduction in

ApoB

70

Other targets for antisense?

70

Other targets for antisense?

http://www.isispharm.com/Pipeline/index.htm status 25-09-2014

http://www.isispharm.com/Pipeline/index.htm

PCSK9; a success story

•Affected family members with:

•Total cholesterol in 90th percentile

•Tendon xanthomas

•CHD

•Early MI

•Stroke

Role of PCSK9 in the regulation of LDL receptor

expression

PCSK9 LOF heterozygosity:

impact on lipids and CAD

• LOF, loss of function

• Adapted from Cohen JC, et al. New Engl J Med 2006; 354: 1264–72.

Plasma LDL-C in black subjects (mg/dL)

30

20

10

0

50 100 150 200 250 300

No nonsense mutation

(n=3278)

50th Percentile

PCSK9142X / PCSK9679X

(N=85)

PCSK9142X or PCSK9679XC

HD

(%

)No Yes

p=0.008

8

0

88%

30

20

10

0

50 100 150 200 250 300

Fre

qu

en

cy (

%)

50th Percentile

4

12

40

PCSK9 inhibitors in development

•EGF-A, epidermal growth factor-like repeat A; IV, intravenous; mAb, monoclonal antibody; SC, subcutaneous; siRNA, small inhibitory RNA

•1http://clinicaltrials.gov/ct2/results?term=REGN727%2F+SAR236553&Search=Search; 2http://clinicaltrials.gov/ct2/results?term=AMG+145&Search=Search; 3http://clinicaltrials.gov/ct2/results?term=PF-04950615&Search=Search; 4http://www.roche.com/irp2q12e-annex.pdf (p.131);

5http://clinicaltrials.gov/ct2/results?term=LY3015014&Search=Search;

•6http://clinicaltrials.gov/ct2/results?term=LGT209&Search=Search; 7http://clinicaltrials.gov/ct2/results?term=ALN-PCS&Search=Search;

•8Shan L, et al. Biochem Biophys Res Commun 2008; 375: 69–73; 9Du F, et al. J Biol Chem 2011; 286: 43054–61 (all accessed August 2013).

Type Compound CompanyPhase of clinical

development

mAb Alirocumab

(REGN7272/SAR236553)1

Sanofi/Regeneron 3

AMG 1452 Amgen 3

RN-316 (PF-04950615)3 Pfizer/Rinat 2 (completed)

RG 76524 Roche/Genentech 2 (on hold)

LY30150145 Eli Lilly 2

LGT2096 Novartis 2 (discontinued)

siRNA ALN-PCS7 Alnylam Pharmaceuticals Phase I (IV formulation)

Pre-clinical (SC formulation)

Mimetic

peptide

EGF-A peptide8 Schering-Plough Pre-clinical

Prodomain and C-terminal

domain interaction

disruption9

Dept. of Cell Biology and Anatomy,

School of Medicine, University of

South Carolina, SC, USA

Pre-clinical

41

Effects on LDL-C of adding

alirocumab to atorvastatin every 2

weeks

•Reproduced with permission from McKenney JM, et al. J Am Coll Cardiol 2012; 59: 2344–53.

LD

L-C

mean (

±S

E)

%

change f

rom

baselin

e

Baseline Week 2 Week 6 Week 10

0

-70

-50

-40

-60

-10

-80

-20

-30

Week 4 Week 8 Week 12

Placebo (n=31) Alirocumab 50 mg Q2W (n=30)

Alirocumab 100 mg Q2W

(n=31)Alirocumab 150 mg Q2W (n=29)

*p<0.0001 vs placebo

Δ –

5.1%

Δ –39.6%*

Δ –

64.2%*Δ –

72.4%*

Effects on LDL-C of adding

alirocumab to atorvastatin every 4

weeks

Δ –

47.7%*

Δ –

43.2%*

Baseline Week 2 Week 6 Week 10

0

-70

-50

-40

-60

-10

-80

-20

-30

Week 4 Week 8 Week 12

Δ –5.1%

LD

L-C

mea

n (

±S

E)

% c

ha

ng

e f

rom

baselin

e

Placebo (n=31)

Alirocumab 200 mg Q4W (n=28)

Alirocumab 300 mg Q4W (n=30)

*p<0.0001 vs placebo

43

Safety summary Alirocumab Phase 2

studies

115651 115662 10033

Safety population Placebo

(n=31)

Rx groups (n;151)

Placebo

(n=31)

Rx groups (n=61)

Placebo

(n=15)

Rx groups (n=62)

Overview of all TEAEs, n (%)

Patients with any TEAE 14 (45.2) 91 (60.3) 19 (61.3) 32 (52.5) 9 (60.0) 50 (80.6)

Patients with any treatment-emergent SAE 1 (3.2) 3 (2.0) 0 (0) 1 (1.6) 1 (6.7) 0 (0)

Patients with any TEAE leading to death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Patients with any TEAE or treatment-emergent SAE leading to permanent

treatment discontinuation0 (0) 6 (4.0) 4 (12.9) 1 (1.6) 0 (0) 1 (1.6)

• The most common TEAE was mild injection-site reactions

• No persistent or prevalent liver or skeletal muscle safety signals were noted

• 5 SAEs were reported in 4 patients in active treatment arms, with 1 patient experiencing

2 SAEs (leukocytoclastic vasculitis and subsequent humerus fracture)

AMG 145 Phase 2 studies: efficacy

1Giugliano RP, et al. Lancet 2012; 380: 2007–17; 2Koren MJ, et al. Lancet 2012; 380: 1995–2006; 3Raal F, et al. Circulation 2012; 126: 2408–17; 4Sullivan D, et al. JAMA 2012; 308: 2497–506.

Data expressed as % change vs placebo (except reference 4: % change vs baseline)

Dose Trial Patient population

LDL-C (%)

ApoB (%)

Lp(a)(%)

TG (%)

140 mgQ2W

LAPLACE-TIMI 571

On stable statin± ezetimibe

-66.1 -56.4 – -33.7

MENDEL2 Monotherapy(no statin)

-47.2 -44.2 -29.3 -12.0

420 mg Q4W

LAPLACE-TIMI 571

On stable statin± ezetimibe

-50.3 -42.0 – -19.4

RUTHERFORD3 Heterozygous FH on stable statin

-56.4 -46.2 -31.5 -19.9

MENDEL2 Monotherapy(no statin)

-52.5 -42.5 -29.2 -3.3

GAUSS4 Statin intolerance(no statin)

-50.7 -42.1 -23.6 -14.2

AMG 145 Phase 3

programme

http://clinicaltrials.gov/ct2/results?term=amg+145&Search=Search (accessed August 2013).

Study Patient population Participants (N)

MENDEL-21 Monotherapy 600

LAPLACE-22 Combination therapy 1700

RUTHERFORD-23 HeFH 300

TESLA4 and TAUSSIG5 HoFH 67 and 125

GAUSS-26 Statin-intolerant patients 300

FOURIER7 Outcomes study 22,500

DESCARTES8 and OSLER9 Safety study 905 and 1400

GLAGOV10 IVUS study 950

ODYSSEY ALTERNATIVE (CL1119) N=250

Patients with defined statin intolerance

LDL-C ≥ 70 mg/dL OR LDL-C ≥ 100 mg/dL

6 months

ODYSSEY OPTIONS I (CL1110) N=350

Patients not at goal on moderate dose atorvastatin


6 months

ODYSSEY FH II (CL1112) N=250

LDL-C ≥ 70 mg/dL OR LDL-C ≥ 100mg/dL

18 months

ODYSSEY HIGH FH (EFC12732) N=105

LDL-C ≥ 160 mg/dL

18 months

12 global phase 3 trials

Including more than 23,500 patients across more than 2,000 study centers

HeFH population HC in high CV risk population Additional populations

ODYSSEY FH I (EFC12492) N=471

LDL-C ≥ 70 mg/dL OR LDL-C ≥ 100mg/dL

18 months

ODYSSEY LONG TERM (LTS11717) N=2,100

LDL-C ≥ 70 mg/dL

18 months

ODYSSEY COMBO I (EFC11568) N=306


12 months

ODYSSEY MONO (EFC11716) N=100

Patients on no background LMTs

LDL-C ≥ 100 mg/dL

6 months

ODYSSEY OPTIONS II (CL1118) N=300

Patients not at goal on moderate dose rosuvastatin


6 monthsODYSSEY OUTCOMES (EFC11570) N=18,000

LDL-C ≥ 70 mg/dL

Add-on to max tolerated statin

(± other LMT)

Add-on to max tolerated statin

(± other LMT)

*ODYSSEY COMBO II (EFC11569) N=660


24 months

ODYSSEY CHOICE (CL1308) N=700


12 months

Alirocumab ODYSSEY Phase 3 program

HC = hypercholesterolemia; LMT = lipid-modifying therapy

*For the ODYSSEY COMBO II other LMT not allowed at entry

Pfizer RN316 program

http://clinicaltrials.gov/.

http://clinicaltrials.gov

49

How low can we go?

35

Trials, trials, trials, and nothing but

trials

will tell us whether

- HDL based therapy

and

- further LDL-C lowering,

reduces risk for CVD....

evolving new therapies for the prevention of ......evolving new therapies for the prevention of...

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