Lipid Update 2015

Jacques Genest MD

Cardiovascular Research Laboratories McGill University Health Center

§    Merck  *  §    Pfizer  §    Novar/s  §    AMGEN  *  §    Roche  *  §    AstraZeneca  

Disclosure J. Genest MD 2015

Relevant  disclosure:  IMPROVE-­‐IT,  CANTOS  ,  CAPREE  steering  CommiHees;  REVEAL  ,  ACCELERATE,  AMG145  ,  Lilly  Clinical  Trials.  

Advisory  Board,  Speaker’s  Bureau,  Consultant,  Grants,  Clinical  Trials    

§    Sanofi/Regeneron  *  §    Lilly  §    Valeant  §    Genzyme  *  §    Aegerion  §    Asca/  

Stock  ownership:  none;      Off  label  use:  none  *  Scien/fic  Advisory    

Outline

►  Understand similarities and differences between the US and Canadian Guidelines

►  Are LDL targets relevant in 2015? ("Fire and forget")

►  Where have we gone wrong with HDL? ►  Is there a role for non-statin drugs using

evidence based medicine ►  Are PCSK9`s poised for a breakthrough in

LDL management?

Changes  in  Lipid  Guidelines  and  Cholesterol  Targets  Have  Typically  Followed  Shortly  aYer  Clinical  Trials  

2001   2002   2003   2004   2005   2006   2007   2008   2009   2010   2011   2012   2013  

US  GUIDELINES  

NCEP  ATP  III,    AHA/ACC  2.6  mmol/L  

NCEP  ATP  III  Revised  2.6mmol/L  1.8mmol/L    Op/onal  

AHA/ACC  2.6mmol/L  

1.8mmol/L  Op/onal  

AHA/ACC  

CANADIAN  GUIDELINES  

CCS  <  2  mmol/L    

or  50%  Reduc/on  

CCS  <  2  mmol/L    

or  50%  Reduc/on  

EU  GUIDELINES  

ESC  4th  Task  Force  1.8mmol/L    

or  50%  Reduc/on  

ESC  3rd  Task  Force  2.6mmol/L  

(2.1  mmol/L  if  feasible)  

ESC  2nd  Task  Force  2.6  mmol/L  

KEY  TRIALS  

HPS   ASCOT   PROVE-­‐IT  TIMI  22  

TNT   CTTC  (27  trials)  

JUPITER  CTTC   CTTC  (14  trials)  

CCS  <  2  mmol/L    

or  50%  Reduc/on  

CCS  <  2.5  mmol/L    

and  TC:HDL-­‐C  <4.0  

Concerns with the US Guidelines

§   Scope is limited to randomized trials only, §   Abolition of LDL-C targets in favor of specific statin

regimens §   Absence of target LDL-C levels in very high-risk

patients §   Reduction in the threshold for treatment in primary

prevention §   Pool risk calculator used to asses CVD risk in the

guidelines for primary prevention has not been fully evaluated.

Ray  KK  et  al.  Eur  Heart  J.  2014  Apr;35(15):960-­‐8  

Unclear Language Not very useful for a clinician

“is reasonable. Can be useful/effective/beneficial Is probably recommended or indicated”

1. ASCVD

2. LDL-C

3. DM

4. Hi Risk

Comparison of Guidelines CCS   EAS/ESC   AHA/ACC  

LDL-­‐C  Targets/Treatment  Recommenda/ons  

Secondary  preven/on  

<  2  mmol/L  or    >  50%  reduc/on  

<  1.8  mmol/L  or    ≥  50%  reduc/on  

High-­‐intensity  sta/n.  (an/cipate  >  50%  reduc/on)  If  50%  cannot  be  achieved,  consider  addi/onal  therapy.  

Sta/n  intolerance  

Same   Same   Same  

Primary  preven/on  LDL  >  5  mmol/L  

>  50%  reduc/on     <  2.5  mmol/L    

High-­‐intensity  sta/n  therapy  (an/cipate  50%  reduc/on)  

Primary  preven/on  in  diabetes  

<  2  mmol/L  or    >  50%  reduc/on    

High  risk  DM:    ≤  1.8  mmol/L,  or  at  least  50%  reduc/on  Low  risk  DM:    <  2.5  mmol/L  

High  risk  DM:    High-­‐intensity  sta/n    Low  risk  DM:  Moderate-­‐intensity  sta/n  

Primary  preven/on  High  risk  

For  FRS  >10%:    <  2  mmol/L  or    >  50%  decrease  

SCORE  ≥  5%  risk  of  fatal  CVD:  <2.5  mmol/L  

For  PCRAE  >7.5%:  Moderate-­‐  to  high-­‐intensity  sta/n    

Evidence for LDL-C Target?

Fire and Forget?

AHA/ACC Statement:

… “Therefore, the Expert Panel was unable to find RCT evidence to support titrating cholesterol lowering drug therapy to achieve target LDL–C or non-HDL-C levels, as recommended by ATP III.”

Stone  NJ,  et  al.  2013  ACC/AHA  Blood  Cholesterol  Guideline  

Absolute  effect  of  sta/n  therapy  on  MAJOR  VASCULAR  EVENTS  

0   1   2   3   4   5  

0  5  

10  

15  

20  

LDL cholesterol, mmol/L  

Five

yea

r ris

k of

a m

ajor

va

scul

ar e

vent

, %  

Control  

21% relative risk reduction per mmol/L  Statin  

15% relative risk reduction per 0.5 mmol/L  More statin  

Combined evidence: ~33% relative risk reduction

per 1.5 mmol/L (0.79 x 0.85 = 0.67)  

Cholesterol Treatment Trialists’ Collaborators Lancet 2012;380:581–90

Less statin  

Propor/onal  effects  on  MAJOR  VASCULAR  EVENTS  per  mmol/L  reduc/on  in  LDL  cholesterol    

0.4   0.6   0.8   1   1.2   1.4  

No. of events (% pa)  Statin/  

More statin  Contr   ol/   Relative risk (CI)  

Statin/more  statin better  

Control/less  statin better  

Nonfatal MI  CHD death  Any major coronary event  CABG  PTCA  Unspecified  Any coronary revascularisation  Ischaemic stroke  Haemorrhagic stroke  Unknown stroke  Any stroke  Any major vascular event  

3485 (1.0)  1887 (0.5)  5105 (1.4)  1453 (0.4)  1767 (0.5)  2133 (0.6)  5353 (1.5)  1427 (0.4)  257 (0.1)  618 (0.2)  

2302 (0.6)  10973 (3.2)  

4593 (1.3)  2281 (0.6)  6512 (1.9)  1857 (0.5)  2283 (0.7)  2667 (0.8)  6807 (2.0)  1751 (0.5)  220 (0.1)  709 (0.2)  

2680 (0.8)  13350 (4.0)  

0.73 (0.69 - 0.78)  0.80 (0.74 - 0.87)  0.76 (0.73 - 0.78)  0.75 (0.69 - 0.82)  0.72 (0.65 - 0.80)  0.76 (0.70 - 0.82)  0.75 (0.72 - 0.78)  0.79 (0.72 - 0.87)  1.12 (0.88 - 1.43)  0.88 (0.76 - 1.01)  0.84 (0.79 - 0.89)  0.78 (0.76 - 0.80)  

99% or   95% CI  

Cholesterol Treatment Trialists’ Collaborators Lancet 2012;380:581–90

More  vs  less  trials:  Propor/onal  effects  on    MAJOR  VASCULAR  EVENTS,  by  baseline  LDL  cholesterol  

unweighted  for  LDL-­‐C  differences  

0.88 (0.77 - 1.00)  0.87 (0.79 - 0.97)  0.90 (0.80 - 1.00)  0.77 (0.66 - 0.90)  0.74 (0.61 - 0.90)  0.85 (0.82 - 0.89)  

No. of events (% pa)  More statin   Less statin   Relative risk (CI)  

More statin  better  

Less statin  better  

99% or   95% CI  

≥  3.5  

Total   3837 (4.5)   4416 (5.3)  

<  2  ≥  2,<2.5  ≥  2.5,<3.0  ≥  3,<3.5  

704 (4.6)  1189 (4.2)  1065 (4.5)  517 (4.5)  303 (5.7)  

795 (5.2)  1317 (4.8)  1203 (5.0)  633 (5.8)  398 (7.8)  

0.5   0.75   1   1.25   1.5  

Cholesterol Treatment Trialists’ Collaborators Lancet 2012;380:581–90

-25% -25%

16

4

160 120 90 67 50

-20%

-15%

-11% -8%

LDL-C [mg/dl]

8

12

80 120 40 160

10.2

15

12

8.3 9.1

Abs

olut

e C

V R

isk

[%]

-25% -25%

Diminishing risk reduction for the same relative LDL-C lowering with lower baseline LDL-C. Calculations based on the CTT analysis (Lancet. 2005;366:1267-78).

But: Clinicians treat patients, not meta-analysis

-­‐120  

-­‐100  

-­‐80  

-­‐60  

-­‐40  

-­‐20  

0  

20  

40  

60  Change  in  LDL-­‐C  (%  baseline)  

-­‐100  

-­‐50  

0  

50  

100   PSCK9  12  months  

Percent LDL-C Reduction in JUPITER Rosuvastatin 20 mg

Awan Z et al. Clin Chem 2011

N=1,000

LDL-C Remains the Primary Target with Emerging Role for Non-HDL-C and ApoB as Alternate Targets

Risk level Initiate therapy if Primary target LDL-C

High FRS ≥ 20%

Consider treatment in all

≤ 2 mmol/L or ≥ 50% decrease in LDL-C

Intermediate FRS 10%-19% •  LDL-C ≥ 3.5 mmol/L ≤ 2 mmol/L or ≥ 50%

decrease in LDL-C

Low FRS < 10%

•  LDL-C ≥ 5.0 mmol/L •  Familial

hypercholesterolemia

≥ 50% decrease in LDL-C

This is based on expert opinion

Monitoring Statin Therapy

Indicators of anticipated therapeutic response and adherence to selected statin intensity: High intensity statin therapy reduces LDL-C approx. 50% from the untreated baseline

“The evidence is less clear regarding the most appropriate tests for determining whether an anticipated therapeutic response to statin therapy has occurred on the maximally tolerated dose. RCT evidence to support the use of specific LDL–C or non-HDL–C targets was not identified. The focus is on the intensity of the statin therapy, but as an aid to monitoring response to therapy and adherence, it is reasonable to use as indicators of anticipated therapeutic response to statin therapy.”

Is HDL-C still relevant?

A time to pause…

2015 Guidelines for microbes

Recent HDL Stories v   Torcetrapib v  Accord (Fenofibrate) v  Mendelian Randomization (ABCA1) v  Aim High (Niacin) v  Mendelian Randomization v  Dalcetrapib v  HPS-2 THRIVE (Niacin +Laropiprant) v  CER, CSL-112, RVX-208

Cholesterol  efflux    ABCA1,  ABCG1  and  SR-­‐BI  

                       An/-­‐infec/ous    trypanosome  lyWc  factor  and    LPS  inacWvaWon  

An/-­‐apop/c    recruitment  of  endothelial  progenitor  

cells  (EPC)  

                                                     Vasodilatory    NO  release,  prostacyclin  (PGI2)  producWon    and  eNOS  acWvaWon  

An/-­‐inflammatory    inhibit  VCAM-­‐1  expression    and  adhesion  molecules  

                         An/oxida/ve    anW-­‐oxLDL,  inacWvate  LOOH    

and  oxPhospholipase  

             An/-­‐thrombo/c    inhibiWon  of  platelet  aggregaWon  and  

prostacyclin  (PGI2)  producWon  

HDL  

Hafiane  A.  Cholesterol  2013  

v   Need  to  iden/fy  new  pathways  of  HDL  biogenesis  and  metabolism  

v   Study  the  structure  of  HDL  in  health  and  in  disease  (proteomics,  lipidomics)  

v   Design  clinical  trials  that  are  highly  focused  (ini/ally)  

The  Long  Term    

HDL  is  a  Biologically  SOUND  Target  

Non-statin Drugs?

Clinical study DATA

§  Fibrates VA-HIT; FIELD; Accord §  Niacin: AIM-HIGH; HPS2-THRIVE §  Ezetimibe §  Bile acid sequestrants §  Cetrapibs (CETP Inhibitors)

Effects  of  CombinaWon  Lipid  Therapy  on  Cardiovascular  Events  in  Type  2  Diabetes  Mellitus:    The  AcWon  to  Control  Cardiovascular  Risk  in  Diabetes  (ACCORD)  Lipid  Trial  

Henry  C.  Ginsberg,  MD  College  of  Physicians  &  Surgeons  ,  Columbia  University,    New  York    For  The  ACCORD  Study  Group  

Effects  of  Combina/on  Lipid  Therapy  in  Type  2  Diabetes  Mellitus  The  ACCORD  Study  Group  Published  at  www.nejm.org  March  14,  2010  (10.1056/NEJMoa1001282)    

ACCORD  Study  www.nejm.org  March  14,  2010  (10.1056/NEJMoa1001282)    

Meta-­‐Analysis  of  Fibrate  trials  

Jun  M,  Lancet  2010;375:1875  

Niacin

AIM-­‐HIGH  :  Results  50  

40  

30  

20  

10  

0  0   1   2   3   4  

P=0.79  by  log-­‐rank  best  

Niacine  plus  staWne  

Placebo  plus  staWne  

Années  

Pourcentage  cumulé  de

 pa/

ents  avec  

des  résultats  prim

aires  

No. à risque

Placebo plus statine 1695 1581 1381 910 436

Niacin plus statine 1718 1606 1366 903 428

Effect  of  ERN/LRPT  on  MAJOR  VASCULAR  EVENTS    

0     1     2     3     4    

Years  of  follow-­‐up    

0    

5    

10    

15    

20    

PaWe

nts    suffe

ring  even

ts  (%

)    

15.0%    14.5%    

Placebo    ERN/LRPT    

Logrank  P=0.29    Risk  raWo  0.96  (95%  CI  0.90  –  1.03)    

Patients hear what they want  

Morris, an 82 year-old man, went to the doctor to get a physical. A few days later, the doctor saw Morris walking down the street with a gorgeous young woman on his arm. A couple of days later, the doctor spoke to Morris and said, 'You're really doing great, aren't you?' Morris replied, 'Just doing what you said, Doc: 'Get a hot mamma and be cheerful.'' The doctor said, 'I didn't say that.. I said, 'You've got a heart murmur; be careful.'

Doctors hear what they want

IMProved  Reduc/on  of  Outcomes:  Vytorin  Efficacy  Interna/onal  Trial  

A  Mul/center,  Double-­‐Blind,  Randomized  Study  to  Establish  the  Clinical  Benefit  and  Safety  of  Vytorin  (Eze/mibe/Simvasta/n  Tablet)  vs  Simvasta/n  Monotherapy  in  High-­‐Risk  Subjects  Presen/ng    

With  Acute  Coronary  Syndrome    

Na/onal  Lead  Inves/gators  and  Steering  CommiHee  (1158  sites,  39  Countries)  

Enrique Gurfinkel¹ Argentina (331) Philip Aylward Andrew Tonkin* Australia (116) Gerald Maurer Austria (249) Frans Van de Werf Belgium (249) Jose C. Nicolau Brazil (423) Pierre Theroux Paul Armstrong* Jacques Genest* Canada (1106) Ramon Cobalan Chile (152) Daniel Isaza Colombia (568)

Jindrich Spinar Czech Rep (371) Peer Grande² Denmark (576) Juri Voitk Estonia (10) Antero Kesaniemi Finland (341) Jean-Pierre Bassand Michel Farnier* France (268) Harald Darius Germany (935) Matayas Keltai Hungary (116) Atul Mathur Sanjay Mittal Krishna Reddy India (259)

Basil Lewis Israel (589) Gaetano DeFerrari Italy (593) Ton Oude Ophuis J. Wouter Jukema* Netherlands (1191) Harvey White New Zealand (164) Terje Pedersen Norway (295) Frank Britto Peru (66) Witold Ruzyllo Poland (589) Manuel Carrageta Portugal (102) Ki-Bae Seung S. Korea (118)

Singapore (75), Malaysia (59), Hong Kong (58) Ecuador (45), Taiwan (46)

*Steering Comm Member, ¹ Deceased, ² 2005–2013

Tibor Duris Slovakia (121) Anthony Dalby S. Africa (186) Jose Lopez-Sendon Spain (551) Mikael Dellborg Sweden (480) Francois Mach Switzerland (263) Sema Guneri Turkey (50) Alexander Parkhomenko Ukraine (159) Adrian Brady United Kingdom (318) Michael Blazing Christopher Cannon Christie Ballantyne* James de Lemos* Neal Kleiman* Darren McGuire* United States (5869)

LDL-­‐C  and  Lipid  Changes  1  Yr  Mean   LDL-­‐C   TC   TG   HDL   hsCRP  

Simva   69.9   145.1   137.1   48.1   3.8  

EZ/Simva   53.2   125.8   120.4   48.7   3.3  

Δ  in  mg/dL   -­‐16.7   -­‐19.3   -­‐16.7   +0.6   -­‐0.5  

Median  Time  avg  69.5  vs.  53.7  mg/dL  

Primary  Endpoint  —  ITT  

Simva  —  34.7%    2742  events    

EZ/Simva  —  32.7%    2572  events    

HR  0.936  CI  (0.887,  0.988)  p=0.016    

Cardiovascular  death,  MI,  documented  unstable  angina  requiring  rehospitalizaNon,  coronary  revascularizaNon  (≥30  days),  or  stroke  

7-­‐year  event  rates  

NNT=  50  

IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.

IMPROVE-IT

Conclusions  •  IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy:

  YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events

  YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dL at 1yr)

  YES: Confirms ezetimibe safety profile •  Reaffirms  the  LDL  hypothesis,  that  reducing    LDL-­‐C  prevents  cardiovascular  events  

•  Results  could  be  considered  for  future  guidelines  

Effects  of  Dalcetrapib  in  Pa/ents  with  a  Recent  Acute  Coronary  Syndrome  

Schawartz  GG.  N  Engl  J  Med.  2012  Nov  5.  [Epub  ahead  of  print]  

44  

DALcetrapib Outcomes

45  

Inhibiting CETP

v    Anacetrapib  (REVEAL  TIMI  55)  v    Evacetrapib  (ACCELERATE)    

Anacetrapib: Effects on LDL-C and HDL-C

HDL-­‐C  

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(mg/

dL) (

SE

)

0

20

40

60

80

100

120

Anacetrapib Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666

LDL-­‐C  

Study Week

Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (m

g/dL

) (S

E)

0

20

40

60

80

100

Anacetrapib Placebo

Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666

-­‐39.8%  (p<0.001)   +138.1%  (p<0.001)  

In Conclusions…

•   To date, only ezetimibe added to optimally used statins change outcomes.

•   Raising HDL-C pharmacologically does not improve CV outcomes

•   The role of niacin and fibrates for CAD prevention is really, really, really unclear.

•   The potential for benefit must be weighed against the concern of harm.

Proprotein Convertase Subtilisin/Kexin Type 9

Evolutionary Conservation: Must be important

Bacillus amyloliquefaciens Saccharomyces cerevisiae Homo sapiens

ER TGN

Endosome Lysosome

LDL-R

PCSK9

Deg

rada

tion

pre-PCSK9

A: LDL-R pathway in absence of PCSK9

B: Intracellular PCSK9 route

C: Extracellular PCSK9 route

Mature PCSK9

LDL

apoB

PCSK9

Terminology  of  Monoclonal  AnWbodies  

1.  Weiner  LM.  J  Immunother.  2006;29:1-­‐9.;  2.  Yang  XD,  et  al.  Crit  Rev  Oncol  Hematol.  2001;38:17-­‐23.;    3.  Lonberg  N.  Nat  Biotechnol.  2005;23:1117-­‐1125.;  4.  Gerber  DE.  Am  Fam  Physician.  2008;77:311-­‐319.  

Mouse  (0%  human)  

Fully  Human  (100%  human)  

Humanized    (>  90%  human)  

Chimeric    (65%  human)  

-­‐umab  -­‐zumab  -­‐ximab  -­‐omab  Generic  suffix:    

Source (% human protein)

High   Low  Poten/al  for  immunogenicity  

PCSK9-­‐directed  Therapies  in  Development  Company   Drug   Agent   Indica/on   Phase  

Inhibi/on  of  PCSK9  binding  to  LDLR  

Amgen   Evolocumab   Fully  Human  mAb   Hypercholesterolemia   3  

Sanofi/Regeneron   Alirocumab   Fully  Human  mAb   Hypercholesterolemia   3  

Pfizer/Rinat  Neuroscience   Bococizumab   mAb   Hypercholesterolemia   3  

NovarWs   LGT209   mAb   Hypercholesterolemia   2  

Roche/  Genentech   RG7652   mAb   Hypercholesterolemia   2  

Eli-­‐Lilly   LY3015014   mAb   Hypercholesterolemia   2  

PCSK9  protein  binding  fragment  

BMS/  Adnexus   BMS-­‐962476   Adnexins   Hypercholesterolemia   1  

Inhibi/on  of  PCSK9  synthesis  (gene  silencing)  

Alnylam     ALN-­‐PCS02   siRNA  oligonucleoWdes   Hypercholesterolemia   2  

Inhibi/on  of  PCSK9  autocataly/c  processing    

Seometrix   SX-­‐PCK9   Small  pepWde  mimeWc   Hypercholesterolemia   Preclinical  

Shifa  Biomedical   TBD   Small  molecule   Metabolic  Disorders   Preclinical  

Cadila  Healthcare   TBD   Small  molecule   Preclinical  

LDL-­‐C  Lowering  with  Monthly  or    Bi-­‐weekly  Evolocumab    

Monotherapy  Study  (n  =  614)  •   Low  Risk  hypercholesterolemia  paWents  (FRS  ≤  10%)  

•   LDL-­‐C  2.6-­‐4.9  mmol/L  •   Placebo  or  EZE  comparator  

•   55-­‐57%  LDL-­‐C  lowering  combined  with  favourable  tolerability  at  12  weeks  

Sta/n-­‐Intolerant  Study  (N  =  307)  •   PaWents  intolerant  to  ≥  2  staWns  •   LDL-­‐C    >1.8  mmol/L  •   Placebo  or  EZE  comparator  

•   Robust  efficacy  combined  with  favourable  tolerability  at    12  weeks  

Placebo  wk10&12  Placebo  wk12  

EvoMab  wk10&12  EvoMab  wk12  

EzeWmibe  wk10&12   EzeWmibe  wk12  

0  

-­‐10  

-­‐20  

-­‐30  

-­‐40  

-­‐50  

-­‐60  

-­‐60  

-­‐50  

-­‐40  

-­‐30  

-­‐20  

-­‐10  

0  

10  

MENDEL-­‐2  

QM  Q2W  

QM  Q2W  

GAUSS-­‐2  

–56.9%  

–0.1%  

10  

–0.4%  

–17.8%  

–17.5%  

–18.6%  

–19.1%  

–1.3%  –1.4%  

–57.0%   –58.8%  –56.1%  

–56.1%  –56.1%   –55.3%  –52.6%  

–19.2%  –18.1%   –16.6%  –15.1%  

%  Change  from

 Baseline  in  LDL

-­‐C†  

Add-­‐on  to  Sta/ns:  Significant  LDL-­‐C  Lowering  with  Monthly  or  Bi-­‐weekly  

†  Reflexive  LDL-­‐C  measurements;  Co-­‐primary  Endpoints:  Mean  %  change  from  baseline  in  LDL  at  week  10/12  and  at  Week  12  Adapted  from  Robinson  JG,  et  al.  JAMA.  2014;311(18):1870-­‐1882  (LAPLACE-­‐2);  Raal  F,  et  al.  Lancet.  2014.  Published  Online  October  2,  2014.  hxp://dx.doi.org/10.1016/S0140-­‐6736(14)61399-­‐4.(RUTHERFORD-­‐2).  

Combo  with  Sta/n  Study  (n  =  1,899)  •   1º  hypercholesterolemia/mixed  

dyslipidemia  •   LDL-­‐C  criteria  ≥  2.1  to  ≥  3.9  mmol/L  

depending  on  baseline  staWn  use  •   CombinaWon  with  staWn:  Atorva  10mg,  

80mg,  Rosuva  5mg,  40mg  or  Simva  40mg  •   Placebo  or  EZE  (not  shown)  controlled  

•   LDL  lowering  consistent  regardless  if  added  to  high  or  moderate  intensity  staWn  

HeFH  Study  (N  =  331)  •   HeFH  paWents  unable  to  achieve  an  

LDL-­‐C  <  2.6  mmol/L  despite  staWn  therapy  with  or  without  ezeWmibe  

•   ~  60%LDL  lowering  in  this  difficult  paWent  group  

Placebo  wk10&12  Placebo  wk12  

EvoMab  wk10&12  EvoMab  wk12  

10  

0  

-­‐10  

-­‐20  

-­‐30  

-­‐40  

-­‐50  

-­‐60  

-­‐60  

-­‐50  

-­‐40  

-­‐30  

-­‐20  

-­‐10  

0  

10  

%  Change  from

 Baseline  in  LDL

-­‐C†  

LAPLACE-­‐2  QM  Q2W  

QM  Q2W  RUTHERFORD-­‐2  

–62%   –63%   –64%  

–58%  

+6.8%  +8.1%  

+3.2%   +4.6%  

–1%   –1%  

+2%  +5%  

–61%   –61%  –64%  

–56%  

Effect of Evolocumab on Other Lipid Parameters across Phase 3 Studies

Without  Sta/ns*    vs  Eze/mibe  

With  Sta/ns  ±  Eze/mibe  vs  Placebo  

MENDEL-­‐2   GAUSS-­‐2   LAPLACE-­‐2   RUTHERFORD-­‐2  

Endpoint    (wk10/12)  

140  mg  Q2W/  420  mg  QM  

140  mg  Q2W/  420  mg  QM  

140  mg  Q2W/  420  mg  QM  

140  mg  Q2W/  420  mg  QM  

TC   Not  reported   -­‐24%  /  -­‐26%*   -­‐41%  /  -­‐40%   -­‐42%  /  -­‐44%  

Non-­‐HDL-­‐C    -­‐36%  /  -­‐36%*   -­‐32%  /  -­‐35%*   -­‐61%  /  -­‐60%   -­‐56%  /  -­‐60%  

ApoB    -­‐34%  /    -­‐35%*   -­‐32%  /-­‐35%*   -­‐56%  /  -­‐56%   -­‐49%  /  -­‐55%  

Lp(a)    -­‐18%  /  -­‐17%*   -­‐24%  /  -­‐25%*   -­‐30%  /  -­‐28%   -­‐31%  /  -­‐31%  

TG      -­‐8%  /    -­‐12%*   -­‐3%  /  -­‐6%*   -­‐18%  /  -­‐23%   -­‐22%  /  -­‐17%  

VLDL-­‐C    -­‐6%  /  -­‐13%*   -­‐2%  /  -­‐4%*   -­‐19%  /  -­‐23%   -­‐23%  /    -­‐16%  

HDL-­‐C   5%  /    4%*   5%  /  6%*   6%  /  8%   8%  /  9%  

ApoA1    3%  /  3%*   6%  /  3%   3%  /  5%   7%  /  5%  

Mean  %  Change  from  Baseline  Versus  Placebo  and/or  Eze/mibe  

Evolocumab  Well  Tolerated  with  No  Notable  Difference  in  the  AE  Profile  Compared  with  Placebo  or  Eze/mibe  

     TEAS  =  Treatment-­‐emergent  adverse  events    SAEs  =  serious  adverse  events      Koren  MJ,  et  al.  J  Am  Coll  Cardiol.  2014;63(23):2531-­‐2540  (MENDEL-­‐2);  Stroes  E,  et  al.  J  Am  Coll  Cardiol.  2014;63(23):2541-­‐8  (GAUSS-­‐2);  Robinson  JG,  et  al.  JAMA.  2014;311(18):1870-­‐1882;  Raal  F,  et  al.  Lancet.  2014.  Published  Online  October  1,  2014.  hxp://dx.doi.org/10.1016/S0140-­‐6736(14)61399-­‐4.(RUTHERFORD-­‐2).  

MENDEL-­‐2   GAUSS-­‐2   LAPLACE-­‐2  RUTHER-­‐FORD-­‐2  

Subject  Incidence   Pbo   Eze   EvoMab   Eze   EvoMab   Pbo   Eze   EvoMab  

Pbo   EvoMab  

N  per  arm           154   154   306   102   205   558   221   1,117   109   220  

All  TEAEs   44%   46%   44%   73%   66%   39%   40%   36%   49%   56%  

SAEs   1%   1%   1%   4%   3%   2%   0.9%   2%   5%   3%  

Leading  to  d/c  IP  

4%   3%   2%   13%   8%   2%   2%   2%   0%   0%  

Fatal  AEs   0%   0%   0%   0%   0%   <1%   0%   0%   0%   0%  

Posi/ve  CV  events  

0%   0%   0%   0%   0%   <1%   1%   <1%   0%   1%  

Neutralizing  ab  NA   NA   0%   NA   0%   NA   NA   0%   NA   0%  

Subject  Incidence  (%)  of  AEs  Reported  in  12  Week  Phase  3  Studies  

Effec/ve  in  Lowering  LDL-­‐C  in  Pa/ents  with  a  Range  of  CV  Risk  over  52  Weeks    

.  

DESCARTES  Study  •   901  paWents,  LDL  >1.94mmol/L  

•   StraWfied  by  risk  category  to  4  background  treatment  regimens  

•   Treated  for  52  weeks  with  monthly  Evolocumab  420  mg    or  placebo    

0  

-­‐20  

-­‐30  

-­‐40  

-­‐50  

-­‐60  

Change  from

 Baseline  vs  Placebo

 (%)  

-­‐70  

-­‐80  

-­‐10  

Overall   Diet  Alone   AtorvastaWn,  10  mg  

AtorvastaWn,  80  mg  

AtorvastaWn,  80  mg  

+EzeWmibe,  10  mg  

Wk  12  

Wk52  

Consistent  LDL-­‐C  ReducWon  at  52  Weeks  with  Monthly  Evolocumab  

*Based  on  screening  LDL-­‐C;  previous  use  of  staWn  therapy,  and  CV  risk  by  ATP  III  guidelines    Adapted  from  Blom  DJ,  et  al.  N  Engl  J  Med.  2014;370(19):1809-­‐19.  

Low   Higher*  Baseline  Risk  

Similar  AE  Profile  in  Placebo  and  Treatment  Groups  at  52  Weeks  

*  All  4  Evolocumab  treatment  arms    Treatment  emergent  adverse  events  are  adverse  events  occurring  between  the  first  dose  of  study  drug  and  end  of  study    Blom  DJ,  et  al.  N  Engl  J  Med.  2014;370(19):1809-­‐19.  

 n  (%)Placebo  N  =  302

Evolocumab*  N  =  599

Any  Treatment  Emergent  Adverse  Event 224  (74.2) 448  (74.8)

Serious 13  (4.3) 33  (5.5)

Adjudicated  atherosclero/c  CV  events   2  (0.7)   6  (1.0)  

Death   0  (0.0)   2  (0.3)  

Leading  to  discon/nua/on  of  study  drug 3  (1.0) 13  (2.2)

Alirocumab:    ODYSSEY  Phase  II/III  Program  Overview    

HeFH  popula/on   HC  in  high  CV  risk  popula/on   Addi/onal  popula/ons  

Add-­‐on  to  max  tolerated  sta/n  (+/-­‐  other  LMT)  

HC  in  high  CV  risk  popula/on  (+/-­‐  other  LMT)*  

ODYSSEY  FH  I  N  =  471;  18  months  

ODYSSEY  FH  II  N  =  250;  18  months  

ODYSSEY  HIGH  FH  N  =  105;  18  months  

ODYSSEY  COMBO  I  N  =  306;  12  months  

ODYSSEY  COMBO  II  N  =  660;  24  months  

ODYSSEY  CHOICE  I  N  =  700;  12  months  

ODYSSEY  LONG  TERM  N  =  2,341;  18  months  

ODYSSEY  OUTCOMES  N  =  18,000  

ODYSSEY  MONO  Pa/ent  on  no  background  LMT  

N  =  103;  6  months  

ODYSSEY  ALTERNATIVE  Pa/ents  with  defined  sta/n  

intolerance  N  =  314;  24  months  

ODYSSEY  OPTIONS  I  Pa/ents  not  at  goal  with  moderate  

dose  atorvasta/n  N  =  355;  6  months  

ODYSSEY  OPTIONS  II  Pa/ents  not  at  goal  with  moderate  

dose  rosuvasta/n  N  =  305;  6  months  

Primary/secondary  Preven/on  N  =  77;  12  weeks  

PII  

PIII  

Primary  Hypercholesterolemia  N  =  92;  8  weeks  

ODYSSEY  CHOICE  II  Pa/ents  with  hypercholesterolemia  

on    non-­‐sta/n  LMT  or  diet  N  =  200;  6  months  

Alirocumab  (PCSK9i  mAb):    Phase  III  LDL-­‐C  Lowering  Summary,  24  Week  Data  

†Alirocumab 75 mg with potential ↑ to 150 mg Q2W SC at week 12 LDL-C >1.8mmol/L ‡Unable  to  tolerate  at  least  2  different  sta/ns,  including  one  at  lowest  dose,  due  to  muscle-related symptoms.

Kastelein JJP, et al. Presented at ESC Sept 2014 (FH I & FH II); Roth EM, et al. Int J Cardiol. 2014 Sep;176(1):55-61 (MONOTHERAPY); Cannon CP, et al. Presented at ESC Sept 2014 (COMBO II): Moriarity PM, et al. Presented at AHA Nov 2014 (Alternative).

%  change  from

 baseline  in  calculated  LD

L-­‐C  

10  

0  

-­‐10  

-­‐20  

-­‐30  

-­‐40  

-­‐50  

-­‐60  

Monotherapy   Alterna/ve  

Q2W†  n=52  

-­‐47%  

EZE  n=51  

-­‐16%  

14.6%  

N=126  

–45.0%  

(StaWn  intolerant‡)  

(26.9% had dose increase at W12)

Alirocumab  

EzeWmibe  

–20.7%  

N=240  N=467  

(Combo  with  StaWn)  

(18.4% had dose increase at W12)

COMBO  II  

–50.6%  

FH  I   FH  II  (HeFH,  Combo  with  StaWn)  

–48.8%   –48.7%  (43.4% had dose increase at W12)

(38.6% had dose increase at W12)

9.1%  

N=163  

N=322  

N=81  

N=166  2.8%  

N=122  

(49.5% had dose increase at W12)

Placebo  

Q2W†  

Q2W†  Q2W†  EZE  EZE  EZE  

Comparable  TEAE  Profile  in  Placebo  and  Treatment  Groups  aYer  at  least  52  Weeks*  of  Treatment  

(ODYSSEY  Long  Term  study)  

 n  (%)  †Placebo  n  =  788

Alirocumab  n=1550

Any  Treatment  Emergent  Adverse  Event 635  (80.6) 1218  (78.6)

Treatment-­‐emergent  SAEs 139  (17.6) 255  (16.5)

TEAE  leading  to  death   8  (1.0)   7  (0.5)  

TEAE  leading  to  treatment  discon/nua/on 43  (5.5) 96  (6.2)

Bococizumab  Phase  II/III  Program  Overview    

ClinicalTrials.gov.    Search  June  23,  2014.  

HeFH  popula/on   HC  in  high  CV  risk  popula/on   Addi/onal  popula/ons  

SPIRE-­‐HF  N  =  300;  52  week  

COMBINATION  with  STATIN  N  =  356;  12  weeks  

SPIRE-­‐HR  N  =  600:  18  months  

SPIRE-­‐LDL  N  =  1,600;  18  months  

SPIRE-­‐I  OUTCOMES  N  =  12,000  

SPIRE-­‐SI  StaWn  Intolerant  N  =  300;  24  week  

PII  

PIII  

SPIRE-­‐II  OUTCOMES  N  =  6,300  

SPIRE-­‐LL  Primary  Hyperlipidemia      

N  =  939;  52  weeks  

Bococizumab:  Efficacy  as  Add-­‐on  Therapy  in  Hypercholesterolemia  24  Week  Study  

Ballantyne  CM,  et  al.  Poster  presentaWon  at  ACC  2014.  Abstract  1183-­‐129.  

LS  Mean  %  Change  in  LDL-­‐C  Level  at  Week  8/12  LOCF  

0  

-­‐10  

-­‐20  

-­‐30  

-­‐40  

-­‐50  

-­‐60  

-­‐70  

150  mg                

Q2W  Q2W  

150  mg                

150  mg    50  mg     100  mg    

           

150  mg                

Q2W    

Q4W  

-­‐34%  

-­‐45%  

-­‐53%  

-­‐28%  

200  mg                

-­‐45%  

300  mg    

Q4W  

Phase  2  Study  Hypercholesterolemia  N=354,  add-­‐on  therapy,    

inclusion  LDL-­‐C  ≥2.1  mmol/L  

Incidence  and  profile  of  adverse  events  similar  across  groups.  

Long-­‐term  safety,  tolerability  and  efficacy  of  alirocumab  versus  placebo  in  high  cardiovascular  risk  pa/ents:  first  results  from  

the  ODYSSEY  LONG  TERM  study  in  2,341  pa/ents  

Jennifer  G.  Robinson,1  Michel  Farnier,2  Michel  Krempf,3    Jean  Bergeron,4  Gérald  Luc,5  Maurizio  Averna,6  Erik  Stroes,7    Gisle  Langslet,8  Frederick  J.  Raal,9  Mahfouz  El  Shahawy,10    Michael  J.  Koren,11  Norman  Lepor,12  Christelle  Lorenzato,13    Robert  Pordy,14  Umesh  Chaudhari,15  John  J.P.  Kastelein7  

OSLER: Effects of Evolocumab (AMG 145) or SOC on LDL-C over 52 weeks

67  

•   Adverse  events  and  serious  adverse  events  occurred  in  81.4%  and  7.1%  of  the  evolocumab+SOC  group  paWents  and  73.1%  and  6.3%  of  the  SOC  group  paWents,  respecWvely.  

•   No  neutralizing  anWbodies  detected.  

Week  12  

UC  LD

L-­‐C  Pe

rcen

tage  Change  from

 Ba

seline  to  W

eek  52,  M

ean  (SE)  

-­‐60  

   0  Baseline  

OSLER  Study  Week  

-­‐50  

-­‐40  

-­‐30  

-­‐20  

-­‐10  

0  10  

Parent  Study  12   24   36   48   52  

Evolocumab / SOC Only (n = 272)

Evolocumab / Evolocumab + SOC (n = 544) -52%

-3%

•   OSLER  is  an  open  label  extension  of  AMG  145  Phase  2  Studies  (MENDEL,  LAPLACE,  RUTHERFORD,  GAUSS)  to  assess  long  term  safety  and  efficacy  

-2%

-52%

Not Evolocumab / SOC Only (n = 96)

Not Evolocumab / Evolocumab + SOC (n = 192)

Alirocumab Maintained Consistent LDL-C Reductions over 52 Weeks

68  

39  

53  

67  

81  

95  

109  

123  

137  

151  

1

1.5

2

2.5

3

3.5

4

0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week

3.1 mmol/L 118.9 mg/dL

1.3 mmol/L 48.3 mg/dL

3.2 mmol/L 123.0 mg/dL

1.4 mmol/L 53.1 mg/dL

mg/dL  

Placebo Alirocumab

LDL-

C, L

S m

ean

(SE)

, mm

ol/L

Achieved  LDL-­‐C  Over  Time    All  paWents  on  background  of  maximally-­‐tolerated  staWn  ±other  lipid-­‐lowering  therapy    

Intent-to-treat (ITT) analysis

PCSK9 Outcome Trials Alirocumab Evolocumab Bococizumab

Trial ODYSSEY Outcomes (secondary prevention)

FOURIER (secondary prevention)

SPIRE1 (secondary prevention)

SPIRE2 (primary prevention)

No of patients 18000 22500 12000 6300 Dosage s/c, Q2W s/c, Q2W or Q4W s/c, Q2W s/c, Q2W

Start date Oct 2012 Jan 2013 Oct 2013 Oct 2013

Expected End date Mar 2018 Feb 2018 Aug 2017 Aug 2017 Primary endpoint

•   CHD death •   non-fatal MI •   fatal and non-fatal ischemic stroke •   high risk UA

requiring hospitalization

•   CV death •   MI •   Stroke •   hospitalization for

UA •   coronary

revascularization

•   CV death •   non-fatal MI •   non-fatal stroke •   hospitalization for

UA needing urgent revascularization

•   CV death •   non-fatal MI •   non fatal stroke •   hospitalization for

UA needing urgent revascularization

Duration Up to Month 64 Up to 5 years Up to Month 60 Up to Month 60

Population Patients 4 to 52 wks post ACS •   LDL-C ≥70 (1.8)

History of clinically evident CVD: MI, stroke or symptomatic PAD and ≥1 major RF or ≥ 2 minor RFs •   LDL-C ≥70 (1.8) or

High risk patients •   LDL-C ≥70 (1.8) and

<100 (2.6) or

High risk subjects •   LDL-C ≥100 (2.6) or

PCSK9 inh: Whom?

Start with the no-brainers

FH + CAD

New Drugs: Whom, When?

FH Not @ Goal

CAD* Not @ Goal

Hi Risk Not @ Goal

Numbers (Guess)

10,000

10,000

250,000

CAD* Approx 1.5 M CDN

>250,000

20-30 HoFH

Canadian Familial Hypercholesterolemia Registry Régistre Canadien d’hypercholestérolémie familiale

Familial  Hypercholesterolemia:    Autosomal  Dominant  GeneWc  Disease    

Goldstein  JL,  Brown  MS.  Arterioscler  Thromb  Vasc  Biol.  2009;29:431-­‐438;  Moorjani  S,  et  al.  Arteriosclerosis.1989;9(2):211-­‐6;  Al-­‐Sarraf  A,  et  al.  Can  J  Cardiol.  2013;29:6-­‐9;  Nordestgaard  BG,  et  al.  Eur  Heart  J.  2013;34(45):3478-­‐90;    Cuchel  M,  et  al.  Eur  Heart  J.  2014;35:2146-­‐2157.  

§   LDL-­‐C  >7.5  mmol/L  §   ½  number  of  LDL  receptors  §   2-­‐fold  increase  in  plasma  LDL  §   ~20-­‐fold  increase  risk  of  CHD  in  

untreated  paWents  §   5%  of  all  heart  axacks  under    

age  60  

§   LDL-­‐C  >  13  mmol/L  §   Few  or  no  funcWonal  LDL  receptors  §   6-­‐  to  10-­‐fold  increase  in  plasma  LDL  §   Widespread  severe  atherosclerosis  §   Heart  axacks  in  childhood  

FH  Heterozygotes  (HeFH)   FH  Homozygote  HoFH  

HeFH clinical features (stigmata) Xanthelasmas

Xanthomas

Xanthomas

Arcus Corneus

0

10

20

30

40

50

60

70

80

Xanthelasma Corneal Arcus

Tendinous xanthomas

1979 (n = 371)

2000 (n = 270)

Fréq

uenc

y (%

)

Heterozygous FH: Clinical Manifestations; 1979 vs 2000

(Men and women> 20 y)

Courtoisie  Dr.  C.  Gagné  Québec  

Definition of FH

v   No “Gold Standard” v   Changing nature of the phenotype v   Mutation analysis of candidate genes: causal or SNP?

Definitions from Global Organizations: •   MedPed (US) •   Simon-Broome (UK) •   Dutch criteria (Netherlands) •   Japanese Atherosclerosis Society

–   Based on Age and LDL-C levels –   LDL-C and DNA, Family Hx, Xanthomas –   Point system (Definite, possible, probable)

FH:  Simon-­‐Broome  Criteria  

Widely used definition. Knowledge of family required

FH:  Dutch  Lipid  Clinics  Criteria  

Point system, cutaneous manifestations important

Proposed  CCS  defini/on  of  FH  Major  criterion   LDL-­‐C   Low   density   lipoprotein-­‐  

cholesterol  *  Adult:  LDL-­‐C  >5.0  Pediatric  >  4.0  

     DNA  Muta/on    

 Definite  

Minor  criteria      

    Affected   first-­‐degree   rela/ve   with  Major  criterion  

 Probable  

    Presence  of  xanthomas  in  proband    Probable  

    First-­‐degree   rela/ve   with   early  onset  CAD  

 Probable  

* secondary causes ruled out (nephrotic syndrome, obstructive jaundice, hypothyroidism)

LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy.

Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273

© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

www.FHCanada.net  or  www.HFcanada.net  

Low LDL-C and AE

Is it unsafe to lower LDL-C<0.5 mmol/L?

Fire and Forget?

Low  LDL-­‐C  and  Adverse  Events  

Conclusions: No increase in AE with low LDL-C

Low  LDL-­‐C  and  Adverse  Events  

Conclusions: No increase in AE with low LDL-C

Low  LDL-­‐C  and  Adverse  Events  

Conclusions: No increase in AE with low LDL-C

Low  LDL-­‐C  and  Adverse  Events  

Conclusions: No increase in AE with low LDL-C

The Future of Guidelines

►   LDL-C reduction ►   Incorporate IMPROVE-IT data ►   Incorporate REVEAL ACCELERATE ►   Incorporate early PCSK9inh trials

►  The data continues to support LDL-C targets and “lower is better”.