What Role do the New PCSK9Inhibitors Have in Lipid Lowering
Treatment?Jennifer G. Robinson, MD, MPH
Professor, Departments of Epidemiology & MedicineDirector, Prevention Intervention Center
University of IowaIowa City, Iowa
Disclosures
Vice-Chair, 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterolto Reduce Atherosclerotic Cardiovascular Disease in Adults
Member, 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk
Received in the past year:
Research grants to the institution: Amarin, Amgen, Astra-Zeneca, Eli Lilly,Esai, Glaxo-Smith Kline, Merck, Pfizer, Regeneron/Sanofi, Takeda
Consultant : Akcea/Ionis, Amgen, Eli Lilly, Esperion, Merck, Pfizer,Regeneron/Sanofi
Proprotein Convertase Subtilisin-like/kexin type 9 (PCSK9) Targetsthe LDL-Receptor for Lysosomal Degradation
LDL=low-density lipoprotein; LDL-R=LDL receptor; mAb=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatoryelement-binding protein-2.Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18–28.
PCSK9 Inhibitory Monoclonal Antibodies Increase LDL-Receptor Expression
LDL=low-density lipoprotein; LDL-R=LDL receptor; mAb=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatoryelement-binding protein-2.Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18–28.
PCSK-9 Monoclonal Antibody (mAb) IndicationsAlirocumab & Evolocumab
• Use as an adjunct to diet and maximally tolerated statin therapy in patientswho require additional LDL-C lowering:• Adults with heterozygous familial hypercholesterolemia• Adults with clinical cardiovascular disease
Evolocumab
Sanofi Aventis, Regeneron Pharmaceuticals Inc. Praluent (alirocumab injection) PI.. July 2015. http://products.sanofi.us/praluent/praluent.pdf.Amgen. Repatha (evolocumab) injection PI. August 2015. http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf
Evolocumab
• Patients with homozygous familial hypercholesterolemia on statins,ezetimibe, and/or LDL apheresis
•
The FDA further noted as a limitation of use that the effect of alirocumab orevolocumab on cardiovascular morbidity and mortality has not yet beendetermined.
LDL-C lowering efficacy of PCSK-9 mAbsBackground statin therapy
Alirocumab 75mg q2W
Alirocumab75/150 mg q2W
Alirocumab 150mg q2W
Evolocumab 140mg q2W
Evolocumab 420mg q4W
-48%-54%
-63% -61% -60%
-47% -46%
-62%
-71%
-63%
Heterozygous Familial Hypercholesterolemia Clinical ASCVD
Alirocumab prescribing information, July 2015. https://www.praluenthcp.com/ Accessed 10/29/15.Evolovumab prescribing information, September 2015. pi.amgen.com/united_states/repatha/repatha_pi_hcp. Accessed 10/29/15; Kereiakes D, et al. Am J Cardiol2015;169:906-915; Robinson JG, et al. NEJM 2015;372:1489-1499.
Achieved LDL-C with PCSK-9 mAbs
HeFH Added to background statin/lipid-lowering therapyODYSSEY FH I & II – Alirocumab 75/150 mg LDL-C -51-58%
Statin/LLT+ Alirocumab Mean LDL-C 135-154 mg/dl 69 mg/dl
RUTHERFORD 2 - Evolocumab 140 mg q2W or 420 mg q4W LDL-C -60-66%
Statin/LLT + Evolocumab Mean LDL-C 150-162 mg/dl 67-69 mg/dl
High CV Risk Added to background statin therapyLAPLACE-2 – Evolocumab: High risk LDL-C >70 mg/dl
Randomized to moderate or high intensity statinRe-randomized to Evolocumab (140 mg q2W vs 420 q4W)or placebo X 12 weeks
LDL-C -63-64% vs placeboModerate intensity statin + Evolocumab Mean LDL-C 115-124 mg/dl
39-49 mg/dlHigh intensity statin + Evolocumab Mean LDL-C 89-94 mg/dl 33-35 mg/dl
Robinson JG, et al. JAMA 2014; 311: 1870-1882; Kastelein JJP, et al. Eur Heart J 2015; 10.1093/eurheartj/ehv370; Raal et al. Lancet 2015; 385: 331-40
LDL-C lowering efficacy of PCSK-9 mAbsMonotherapy
EzetimibeAlirocumab75/150 mg Ezetimibe
Evolocumab140 mg q2W
Evolocumab420 mg q4W
-20%
-53%
-18%
-57% -56%
Roth E,et al. Int J Cardiol, 2014; 176: 55-61.Koren M, et al. J Am Coll Cardiol 2014; 63, 2531-2540.
Effect on Other Blood Lipids and ProteinsDESCARTES 52 weeks: Evolocumab 420 mg Q4W
52 0
-10
0
10
Pe
rce
nt
chan
gefr
om
bas
elin
e
-22
-44
-50
-29-34
-12
-60
-50
-40
-30
-20
-10
Pe
rce
nt
chan
gefr
om
bas
elin
e
Baseline 38 nmol/L 87 mg/dL 124 mg/dL 20 mg/dL 177 mg/dL 105 mg/dL 53 mg/dL 152 mg/dL 1.0 mg/dL(median) (mean) (mean) (mean) (mean) (median) (mean) (mean) (median)
Apo B=apoliporotein B; HDL-C=high-density lipoprotein cholesterol; hs-CRP= high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein(a); VLDL-C=very low density liporotein cholesterol.Blom DJ, et al. New Eng J Med. 2014; 370:1809-1819.
Safety of PCSK9 mAbsODYSSEY LONGTERMPlacebo vs Alirocumab150 mg Q2W, 80 weeks
DESCARTESPlacebo vs Evolocumab420 mg, 52 weeks
OSLER I & IIStandard careEvolocumab420 mg Q4W or 140 mgQ2W, 11 months
Adverse eventsInjection site reactions4.2% vs. 5.9%; P=0.10
Injection site reaction5.0% vs 5.7%
Injection site reactionsNA vs 4.3%4.2% vs. 5.9%; P=0.10
Mylagia2.9% vs. 5.4%; P=0.006Neurocognitive AEs0.5% vs 1.2%; P=0.17Opthalmologic AEs1.9% vs 2.9%; P=0.65
5.0% vs 5.7%Mylagia3.0% vs 4.0%URIs6.3% vs 9.3%ALT > 3X ULN1.0% vs 0.8%
NA vs 4.3%Muscle AEs6.0% vs 6.4%Neurocognitive AEs0.3% vs 0.9%
Post hoc CVD events “Exploratory” CVD events
3.3% vs 1.7%HR 0.52 (0.31-0.90;P=0.02)
2.18% vs 0.95%HR 0.47 (0.28-0.78; p=0.003)
AEs=adverse events; ALT=alanine aminotransferase; CVD=cardiovascular disease; HR=hazard ratio; Q2W=every 2 weeks; Q4W=every 4 weeks; SC=standard care;ULN=upper limit of normal; URIs=upper respiratory infections.Robinson JG, et al. N Engl J Med 2015;372:1489-1499; Blom DJ, et al. N Engl J Med 2014; 370: 1809-1819; Sabatine MS, et al. N Engl J Med 2015;372:1500-1509.
PCSK9 mAbs: Preliminary data - CVD event reductionODYSSEY LONG TERM – Alirocumab 150
mg q2WMean 80 week follow-up
OSLER – Evolocumab 140q2W/420 q4W
Mean 11 month follow-up
HR 0.52(95% CI 0.31-0.90)
HR 0.47(95% CI 0.28-
FromFrom N Engl J MedN Engl J Med,, Sabatine MS et alSabatine MS et al, Efficacy and, Efficacy andsafety of evolocumab in reducing lipids andsafety of evolocumab in reducing lipids andcardiovascular events, 372, 1500cardiovascular events, 372, 1500--1509.1509.
FromFrom N Engl J MedN Engl J Med,, Robinson JG et alRobinson JG et al, Efficacy and, Efficacy andsafety of alirocumab in reducing lipids andsafety of alirocumab in reducing lipids andcardiovascular events, 372, 1489cardiovascular events, 372, 1489--1499.1499.
CVD=cardiovascular disease; HR=hazard ratio; PCSK9=proprotein convertase subtilisin/kexin Type 9.
(95% CI 0.31-0.90)Nominal P =0.02
(95% CI 0.28-0.78)P=0.003
Magnitude of PCSK-9 mAb CV Risk Reduction &Longer-term Safety Awaits CV Outcomes Trials
Alirocumab N
MinLDL-C
(mg/dL) Evolocumab N
MinLDL-C
(mg/dL) Bococizumab N
MinLDL-C
(mg/dL)
ODYSSEY ACS CVDSPIRE-1
CVDHR PP12,000
≥70 &<100ODYSSEY
OUTCOMESACS
18,000≥70 FOURIER
CVD27,500
≥70
SPIRE-112,000
<100
SPIRE-2CVD
HR PP6300
>100
ClinicalTrials.gov. http://clinicaltrials.gov. Accessed November 2015.
PCSK9 mAbs in clinical practicePCSK9 mAbs in clinical practice
2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD RiskMajor recommendations for initiating statin therapy based on
patient’s level of RISK
I AI A
I AI A
I BI B
I AI A
IIaIIa BB
Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934
4.9 mmol/L
2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD Risk
Major recommendations for initiating statin therapy based onpatient’s level of RISK (cont)
I BI B
IIbIIb CC
I AI A IIaIIa BB
IIaIIa BB
Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934.
2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD RiskMonitoring Therapeutic Response and Adherence
*
I AI A
IIaIIa BB
If baseline LDL-Cunknown, may use LDL-C<100 mg/dl
High intensity statin >50% LDL-CMod intensity statin 30-<50% LDL-C
Regularlymeasure lipid
panel
Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934
**
Nonstatinsshown toreduce ASCVDevents in RCTspreferred
IIaIIa BB
<100 mg/dl
Nonstatins
Shown to reduce CVD events added to background statintherapy
•Ezetimibe•IMPROVE-IT 2015•IMPROVE-IT 2015
•PCSK9 monoclonal antibodies•Preliminary – ODYSSEY LONG TERM & OSLER•CV outcomes RCTs pending
Cannon, C.P., et al., NEJM 2015. 372(25): p. 2387-2397; Robinson, J.G., et al., NEJM 2015. 372(16): p. 1489-1499.Sabatine, M.S., et al., NEJM 2015. 372(16):p. 1500-1509;
Not clearly shown to reduce CVD events added tobackground moderate intensity statin therapy
•Niacin (harmful in diabetic subgroup)
Nonstatins
•Niacin (harmful in diabetic subgroup)
•Fenofibrate (trend to benefit low HDL-C/high TG butharmful in women)
The HPS2-THRIVE Collaborative Group, NEJM 2014. 371: p. 203-2012; The ACCORD Study Group, N Engl J Med, 2010. 362: p. 1563-1574; The AIM-HIGHInvestigators, N Engl J Med, 2011. 365: p. 2255-2267.
ACC nonstatin clinical pathway – LDL-C thresholdsfor considering nonstatin therapy
Lloyd-Jones D, et al. JACC 2016; 68: 92-125
ACC nonstatin clinical pathway - Clinical ASCVD with comorbidities (2)
Lloyd-Jones D, et al. JACC 2016; 68: 92-125
How can patients be betteridentified for addednonstatin therapy?nonstatin therapy?
Robinson JG, et al. J Am Coll Cardiol 2016 in press
Ezetimibe, PCSK-9 mAbs and the CTT Statin line
ODYSSEY LONGTERM12248
ODYSSEY pooled
OSLER I & II12048JUPITER
10850
CTT Collaboration. Lancet 2005; 366:1267-78; Cannon CP, et al. NEJM 2015;372:2387-2397; Robinson JG, et al. NEJM 2015;372:1489-1499; Robinson JG, et al. AHA Scientific Sessions2014, Chicago IL. Nov 2014; Sabatine MS, et al. NEJM 2015;372:1500-1509
IMPROVE-IT ezetimibe major CVD7054
IMPROVE-IT ezetimibe hard CVD
Very high risk groups>30% 10-year ASCVD risk ON statin therapy in RCTs
• Clinical ASCVD + Diabetes
• Clinical ASCVD + Chronic kidney disease
• Clinical ASCVD with poorly controlled risk factors
• Recent acute coronary syndrome (<3 months)• Recent acute coronary syndrome (<3 months)
• Clinical ASCVD + primary LDL-C >190 mg/dl or familialhypercholesterolemia
• Clinical ASCVD with multiple recurrent events*
• Clinical ASCVD with elevated lipoprotein (a)*
Robinson JG, et al. J Am Coll Cardiol 2016 in press; *Lloyd-Jones DL, et al. ACC expert nonstatin pathway. JACC 68: 92-125.
Very high risk (>30% 10-year ASCVD risk)
5-year NNT to prevent 1 ASCVD event
Initial LDL-CEzetimibe
LDL-C 20%
PCSK9 mAb
LDL-C50%
PCSK9 mAb
65%
190 mg/dl 32 13 10
160 mg/dl 38 15 12160 mg/dl 38 15 12
130 mg/dl 47 19 15
100 mg/dl 61 25 19
70 mg/dl 88 35 27
Robinson JG, et al. J Am Coll Cardiol 2016 in press; Steel N. Br Med J 2000; 1446-15447
Reasonable NNT thresholds: Physicians: NNT < 50 Patients: NNT <30
PCSK9 mAbsStatin intolerant patientsStatin intolerant patients
Muscle symptoms in statin intolerant patientsODYSSEY ALTERNATIVE – Alirocumab double-blind RCT
33%
41%
46%
24%22%
78%toleratedblinded
atorvastatin20 mg
8%
24%
7%
16%
20%22%
2%
Placebo Alirocumab Ezetimibe Atorvastatin 20 mg Open labelAlirocumab
Any musculoskeletal symptoms Musculoskeletal symptoms leading to discontinuation
98%tolerated
open-labelalirocumab
Moriarity PM, et al. J Clin Lipidol. 2015;9:758-69.
Muscle symptoms in statin intolerant patientsGAUSS-3– Evolocumab double-blind RCT – mean intolerant >2 statinsTime to muscle symptoms resulting study drug discontinuation
Phase A1: Nocebo effect “Power of expectation” Phase A2: ≈20% truly intolerant?
Phase B: Ezetimibe 29% vs Evolocumab 21% DC due to intolerable muscle symptomsNissen et al. JAMA 2016; 315(15):1580-1590
Maximize statin therapy
• Same rate of muscle & other adverse events in statintrials
• Most patients with statin-related symptoms cantolerate blinded statin therapytolerate blinded statin therapy
• Clinician needs to believe statins are safe and effectiveto convince the patient
• Statins reduce nonfatal & fatal coronary & stroke events• Statins reduce total mortality in 1 & 2 prevention
Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934; Nissen et al. JAMA 2016; 315(15):1580-1590; Moriarity PM, etal. J Clin Lipidol. 2015;9:758-69
Lower might be better
It matters how you get thereIt matters how you get thereand in whom
Robinson, J.G.. Eur Heart J 2016. 37(17): p. 1380-1383.