PCSK9-Inhibitor Treatment for Hypercholesterolemia: Primary Care Update Eliot A. Brinton, MD, FAHA, FNLA Immediate Past-President, American Board of Clinical Lipidology Director, Atherometabolic Research Utah Foundation for Biomedical Research President, Utah Lipid Center Salt Lake City [email protected]25th Annual Southwestern Conference on Medicine Tucson Osteopathic Medical Foundation Tucson, AZ; April 28, 2016
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PCSK9-Inhibitor Treatment for Hypercholesterolemia:
Primary Care Update
Eliot A. Brinton, MD, FAHA, FNLAImmediate Past-President, American Board of Clinical Lipidology
Director, Atherometabolic ResearchUtah Foundation for Biomedical Research
PROVE-IT/TIMI 22 Substudy. Wiviott SD et al. JACC. 2005;46:1411-1416.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.
Wiviott, SD, et al for the PROVE-IT TIMI-22 Investigators. Am J Cardiol. 2005;46(8):1411-16.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.
0
5
10
15
20
25
Achieved LDL-C (mg/dL)
But LDL-C Can Still be Elevated on a High-Intensity Statin!
LDL-C levels at 4 months on Atorvastatin 80 mg
% o
f Sub
ject
s
37.1% of patients ≥70 mg/dL (1.81 mmol/L)
0.1
15.2
19.2
8.2
1.70.5
18
13.3
8.3
5.6
3.22.1
1.4
3.2
Why Not Just Use a High-Intensity Statin?
Isn’t that what the 2013 ACC/AHA Guidelines Say?
Lower is betterGoals help us direct treatment with statins and statin-adjuncts
to get lower LDL-C
Why Not Just Use a High-Intensity Statin?
Isn’t that what the 2013 ACC/AHA Guidelines Say?
The 2013 Guidelines: 1.Are NOT the “official” US guidelines2.Saw no evidence for LDL-C goals
because they had excluded it3.Are being updated to add back
LDL thresholds and goals
ACC Statement on Lipid Rx Thresholds for Non-statins
Dynamic Relationship Between mAb Levels, Free PCSK9, and LDL-C
Stein et al. N Engl J Med. 2012;366:1108-18.
0 1000 20000
20
Free
/ To
tal P
CSK
9 C
onc.
(ng/
mL)
Tota
l REG
N72
7 (n
g/m
L) x
0.0
1
200
40
120
160
80
500 2500 30001500-70
-60
LDL-C
Mean C
hange (%)
0
-50
-30
-20
-40
Free PCSK9, Total REGN727 / SAR236553 Concentration,and LDL-c Mean % Change vs Time
60
140
180
100
-10
Total REGN727 / SAR236553
Free PCSK9
LDL-C
3 6 9 12 15Weeks
Phase 3 Data from Alirocumab and
Evolocumab
AMG 145 Antibody to PCSK9 Clinical TrialsLAPLACE- TIMI 57
PCSK9-I mAb LDL-C Dose-Response
Drug Dosage % LDL-C Lowering
Alirocumab 75 mg every 2 wks. 40-45%
150 mg every 2 wks. 50-60%
Evolocumab 140 mg every 2 wks. 50-65%
420 mg every 4 wks 50-60%
After Eckel, R. unpublished
Robinson, JG. NEJM epub 3/15/15 Suppl.
LDL-C Decrease By Subgroup
Robinson, JG. NEJM epub 3/15/15 Suppl.
LDL-C Decrease By Subgroup
Possible sub-additivity of statins and CAI?
Similar LDL-C Decrease FH vs non-FH
Robinson, JG. NEJM epub 3/15/15 Suppl.
Little or No LDL-C Lowering Efficacy with More Severe HoFH (TESLA)
LDL Receptor Mutations
Number of Subjects
Change in LDL-C*
Defective/Defective 8 -32% (-19 to -45%)Defective/Negative 6 -21% (-11 to -31%)Negative/Negative 1 +10%ARH** 1 +4%
Raal, FJ; Lancet 2015; 385: 341–50
*Rx was evolocumab 420 mg sc q 4 weeks x 12 weeks.Trial was placebo-controlled but due to low and variable N of placebo control patients in each of these rarer categories, placebo effects are not given and placebo subtraction not done.**ARH = autosomal recessive hypercholesterolemia which is due to a defect in internalization of the LDL/LDL-receptor complex.
Alirocumaba Alirocumaba
PCSK9 Inhibitors:Lipid Efficacy Beyond LDL-C
ParameterRange of Mean Changes with
PCSK9 InhibitorsApo B -32 to -53%Non-HDL-C -37 to -52%Lipoprotein(a) -17 to -30%Triglycerides -6 to -26% HDL-C +3 to +9%Apo A-1 +2 to +7%
After Eckel, R. unpublished
Long-Term PCSK9-I Effects
• Lipid Efficacy• Safety and Tolerability • CVD Efficacy (preliminary)
PCSK9-I Maintain Consistent LDL-C Reductions over 1 yr +
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 52Week
3.1 mmol/L118.9 mg/dL
1.3 mmol/L48.3 mg/dL
3.2 mmol/L123.0 mg/dL
1.4 mmol/L53.1 mg/dL
mg/
dL
PlaceboAlirocumab
LDL-
C, L
S m
ean
(SE)
, mm
ol/L
Alirocumab achieved LDL-C Over Time on 150 mg q 2 wksAll patients on background of maximally-tolerated statin ±other lipid-lowering therapy
Intent-to-treat (ITT) analysisRobinson, JG. NEJM
2015 epub Mar 15.
Treatment-Emergent Adverse EventsAt least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit
% (n) of patientsAll on max-tolerated statin ±other lipid-lowering therapy
Alirocumab(n=1550)
Placebo(n=788)
TEAEs 78.6% (1218) 80.6% (635)
Treatment-emergent SAEs 16.5% (255) 17.6% (139)
TEAE leading to death 0.5% (7) 1.0% (8)
TEAEs leading to treatment discontinuation 6.2% (96) 5.5% (43)
Mean treatment duration: 65 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) completed 78
weeks
Robinson, JG. NEJM 2015 epub Mar 15.
Treatment-Emergent Adverse EventsAt least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit
% (n) of patientsAll on max-tolerated statin ±other lipid-lowering therapy
Alirocumab(n=1550)
Placebo(n=788)
TEAEs 78.6% (1218) 80.6% (635)
Treatment-emergent SAEs 16.5% (255) 17.6% (139)
TEAE leading to death 0.5% (7) 1.0% (8)
TEAEs leading to treatment discontinuation 6.2% (96) 5.5% (43)
Mean treatment duration: 65 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) completed 78
weeks
Robinson, JG. NEJM 2015 epub Mar 15.
ODYSSEY LONG TERM Study: TEAEs ≥5%Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients
†Company MedDRA Queries (CMQ).Statistical analyses have not been performed. Robinson, JG. NEJM 2015 epub Mar 15.
Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin or Ezetimibe
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00Cum
ulat
ive
prob
abili
ty o
f eve
nt
Week
Atorvastatin
Alirocumab
0 4 8 12 16 20 24 28 32 36
Kaplan-Meier estimates for time to first skeletal muscle event
Cox model analysis:HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042
Ezetimibe
HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096
Moriarty PM JCL (2015) 9, 758–769
Can LDL-C be Too Low?• Abetalipoproteinemia & homozygous
hypobetalipoproteinemia (LDL-C 0-25 mg/dL)– Autosomal recessive LoF MTP or apo B gene mutations– V. Low-absent apo B-cont. lipos (chylos, VLDL, LDL)– Neurological/ophthalm sequelae prevented by fat-
After J. Robinson et al NEJM 372:1489, 2015, Appendix
PCSK9 Safety w/ LDL-C <25 mg/dL
(N=575 of 1550)
• No increase in:– Total mortality– Cancer– Myopathy– Cognitive symptoms– Metabolic/reproductive disorders– Skin disorders
Most AEs↓(!) →↑compliance/healthy-user? Robinson, JG. NEJM 2015 epub March 15.
Can LDL-C be Too Low?• Abetalipoproteinemia & homozygous
hypobetalipoproteinemia (LDL-C 0-25 mg/dL)– Autosomal recessive LoF MTP or apo B gene mutations– V. Low-absent apo B-cont. lipos (chylos, VLDL, LDL)– Neurological/ophthalm sequelae prevented by fat-
PROVE-IT/TIMI 22 Substudy. Wiviott SD et al. JACC. 2005;46:1411-1416.Similar result reported in 8-study meta-analysis: Boekholdt SM, et al. JACC 2014;64;485–94.
†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy
Kaplan-Meier Time to First Adjudicated Major CV Event/TEAEsSafety Analysis (> 52 wks for all patients continuing Rx, incl. 607 at W78 visit)
No. at RiskPlaceboAlirocumab
Weeks
Mean treatment duration: 65 weeks
Placebo + max-tolerated statin ± other LLT
Cum
ulat
ive
prob
abili
ty o
f eve
nt Alirocumab + max-tolerated statin ± other LLT
Cox model analysis:HR=0.46 (95% CI: 0.26 to 0.82)Nominal p-value = <0.01
847260483624120
0.06
0.05
0.04
0.02
0.01
0.00
0.03
7881550
7761534
7311446
7031393
6821352
6671335
321642
127252
Alirocumab Post-hoc CVD Events†
Robinson et al . Presented at ESC hotline session; Barcelona, Aug 31, 2014Robinson, JG. New Eng J Med 2015 epublished March 15
*Cumulative Incidence of Cardiovascular Events: CV death, MI, USA req hospit, correvasc, stroke TIA, CHF hospitalization.Inset shows expanded y axis. P value by log-rank test.Sabatine MS et al. N Engl J Med. Published March 15, 2015. doi: 10.1056/NEJMoa1500858.
nasal congestion, allergic rxn)• Unlikely to replace statins, but • Likely to be “gold-standard” (after ezetimibe) as
– Statin adjuncts for FH & severe CVD– Statin alternatives for statin intolerance
Alirocumab vs EvolocumabAlirocumab• IgG1 (most Rx mAbs,
more complement activation, more placental transfer)
• Half-dose available• Less Efficacy? (likely not)• More robust phase-III• More solid early CVD data
– More events– All Rx double-blind
Evolocumab• IgG2• HoFH efficacy (only one
tested)• More q 4 wk data• Less anti-drug
antibodies? (likely not)• Larger ongoing CVOT
Similarities >> any differences:• Appear equally efficacious re: ↓LDL-C, apo B, Lp(a)• Appear equally safe/well tolerated
Alirocumab vs Evolocumab vs BococizumabAlirocumab• IgG1 (most Rx mAbs,
more complement activation, more placental transfer)
• Half-dose available• Less Efficacy? (likely not)• More robust phase-III• More solid early CVD data
– More events– All Rx double-blind
Evolocumab• IgG2• HoFH efficacy (only one
tested)• More q 4 wk data• Less anti-drug
antibodies? (likely not)• Larger ongoing CVOT
Similarities >> any differences:• Appear equally efficacious re: ↓LDL-C, apo B, Lp(a)• Appear equally safe/well toleratedBococizumab• Potential disadvantage: humanized vs human • Otherwise v. similar to alirocumab & evolocumab
Advent of PCSK9-I Requires Return to On-Rx LDL-C
(albeit Thresholds > Goals)• Main question: WHO “requires more
LDL Rx in PCSK9-I Era• Establish LDL-C goal, then:• Use statins to max as needed/tolerated• Establish LDL-C non-statin threshold, then:• Add ezetimibe (chol. absorp. inhib.—CAI)• Consider referral to Lipidologist for:
– PCSK9-I for 40-65% further ↓ LDL-C– BAS for 10-18% further ↓LDL-C– Niacin for 10-18% further ↓LDL-C– Other: LDL apheresis, lomitapide, mipomersen
for 25-70% further ↓LDL-C
Referral to a LipidologistWhen?*• To consider LDL Rx beyond statin & CAI (BAS,
depending on age, ASCVD risk, and Rx response– ASCVD bad/progressive (adv. testing & Rx)– Statin intolerant/phobic
To Whom?• ABCL certified physician—see lipidboard.org• Other lipid experts—NLA members (lipid.org),
FH foundation, etc.• Become a lipidologist—as noted above*Also consider Lipidology referral for: • Severe HTG (> ~700, or 200-500 if risk/history ASCVD)• High Lp(a)