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Article

PCSK9 inhibition: A promise fulfilled?

Khendi White, MD, Chaitra Mohan, MD and Michael Rocco, MD
Cleveland Clinic Journal of Medicine November 2016, 83 (11 suppl 2) S36-S44; DOI: https://doi.org/10.3949/ccjm.83.s2.05
Khendi White
Fellow, Department of Cardiovascular Medicine, Cleveland Clinic
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Chaitra Mohan
Resident, Department of Internal Medicine, Cleveland Clinic
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Michael Rocco
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    Effect of PCSK9 inhibitors on cardiovascular events.50,51

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    TABLE 1

    Gain-of-function and loss-of-function PCSK9 mutations

    Gain-of-function mutations
    PCSK9 variantPopulationClinical characteristics
    D374YBritish, Norwegian, families;1 Utah familyPremature CVD, tendon xanthomas, severe hypercholes terolemia
    S127RFrench, South African, Norwegian familiesTendon xanthomas, CVD, early MI, stroke
    R215HNorwegian familyBrother died at 31 from MI; strong family history of CVD
    Loss-of-function mutations
    PCSK9 variantPopulationLDL-CCVD risk
    R46LARIC, DHS↓ 15%↓ 47%
    Y142X or C679XARIC, DHS↓ 28%–40%↓ 88%
    R46L CGPS↓ 11%↓ 46%
    • ARIC = Atherosclerotic Risk in Communities study; CGPS = Copenhagen General Population Study; CVD = cardiovascular disease; DHS = Dallas Heart Study; MI = myocardial infarction

    • Data from references 25–29.

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    TABLE 2

    Studies of PCSK9-inhibitor therapies

    DrugSponsorStage of developmentFDA approval
    Monoclonal antibodies
    Alirocumab, (SAR236553, REGN727)Sanofi, RegeneronPhase 3July 2015
    Evolocumab (AMG145)AmgenPhase 3August 2015
    Bococizumab (PF0499614, RN316)PfizerPhase 3No
    LY3015014LillyPhase 2No
    PCSK9-binding adnectin
    BMS-962476Bristol-Meyers SquibbPhase 1No
    siRNA
    ALN-PCSAlnylam PharmaceuticalsPhase 1No
    • Data from reference 32.

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    TABLE 3

    Clinical trials of PCSK9 inhibitors

    StudyDrugDescriptionNo. patientsWeeksBaseline LDLMean % LDL lowering
    Phase 3 efficacy trials
    MENDEL-235EvolocumabMonotherapy vs ezetimibe and placebo61412140–14455–57
    DESCARTES36EvolocumabLong-term tolerability/efficacy atorvastatin 10–80 ± ezetimibe90152104 (95–120)55–57
    RUTHERFORD-237EvolocumabLDL-C goal achievement in HeFH on statin33112151–16159–61
    LAPLACE-238EvolocumabCombined with different statins vs ezetimibe and placebo2,0671210855–76
    GAUSS-239EvolocumabStatin intolerant vs ezetimibe30712192–19553–56
    GAUSS-340EvolocumabStatin intolerant vs ezetimibe51124212–21953
    TAUSSIG41EvolocumabHomozygous FH statin ± ezetimibe, open label941232120.9
    ODYSSEY FH I42AlirocumabHeFH vs ezetimibe4862414558
    ODYSSEY FH II42AlirocumabHeFH vs ezetimibe2492413551
    ODYSSEY-High FH43AlirocumabHeFH on statin vs placebo10624196–20146
    ODYSSEY-COMBO I44AlirocumabHypercholesterol vs placebo3162495–10048
    ODYSSEY-COMBO II45AlirocumabHigh CVD risk with ezetimibe vs placebo/ezetimibe70724105–10951
    ODYSSEY CHOICE I46AlirocumabMaximum statin or statin intolerant vs placebo80324112–14852 (no statin)
    59 (+ statin)
    ODYSSEY CHOICE II47AlirocumabCombined with ezetimibe or fenofibrate or as monotherapy vs placebo23324154–16456
    Phase 2 trials
    NCT0159224048BococizumabDose ranging, added to statins25024105–11834–53
    • CVD = cardiovascular disease; DESCARTES = Durable Effect of PCSK9 Antibody Compared With Placebo Study; GAUSS-2 = Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; GAUSS-3 = Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3; HeFH = heterozygous familial hypercholesterolemia; LAPLACE-2 = LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2; LDL-C = low-density lipoprotein cholesterol; MENDEL-2 = Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2; ODYSSEY CHOICE I = Study to Evaluate the Efficacy and Safety of an Every Four Weeks Treatment Regimen of Alirocumab (REGN727/ SAR236553) in Patients With Primary Hypercholesterolemia; ODYSSEY CHOICE II = Phase III Study To Evaluate Alirocumab in Patients With Hypercholesterolemia Not Treated With a Statin; ODYSSEY COMBO I = Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia; ODYSSEY COMBO II = Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia; ODYSSEY FH = Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy; ODYSSEY-High FH = Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia; RUTHERFORD-2 = Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholester-olemia Disorder Study-2; TAUSSIG = Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders

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    TABLE 4

    Outcome and safety data of evolocumab and alirocumab trials

    Pooled OSLER-1, OSLER-250 evolocumabODYSSEY LONG TERM51 alirocumab
    No. patients4,4652,341
    Follow-up11.1 months78 weeks
    Study typeOpen-label, randomized evolocumab and standard care (n = 2,976) vs standard care (n = 1,489)Randomized, alirocumab (n = 1,553) vs placebo (n = 788) (post hoc events)
    % Reduction LDL-C (median mg/dL)61 (120 to 48)61.9 (122 to 48)
    CV eventsCV death, MI, CVA, UA revascularization, CHFCV death, MI, CVA, UA
    Rate CV events (HR)0.95% vs 2.18% (0.47)1.7% vs 3.3% (0.52)
    Other adverse events, % of patients
     Severe adverse events7.5 vs 7.518.7 vs 19.5
     Liver function tests1.0 vs 1.21.8 vs 2.1
     Creatine phosphokinase0.6 vs 1.13.7 vs 4.9
     Musculoskeletal6.4 vs 6.05.4 vs 2.9
     Neurocognitive0.9 vs 0.61.2 vs 0.5
    • CHF = congestive heart failure; CV = cardiovascular; CVA = cerebral vascular accident; HR = hazard ratio; LDL-C = low-density-lipoprotein cholesterol; MI = myocardial infarction; OSLER-1, OSLER-2 = Open-Label Study of Long-Term Evaluation Against LDL-Cholesterol 1, 2; ODYSSEY LONG TERM = Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid Modifying Therapy; UA = unstable angina

    • View popup
    TABLE 5

    Ongoing trials of PCSK9 inhibitors

    TrialDrugPrimary outcomeNo. patientsExpected completionLDL-C on background therapy (mg/dL)
    FOURIER53EvolocumabTime to CV death, MI, hospitalization for UA, stroke, or coronary revascularization27,5002016–2017> 70
    ODYSSEY54AlirocumabTime to CV death, nonfatal MI, hospitalization for UA, stroke18,0002017> 70
    SPIRE-1,55
    SPIRE-256
    BococizumabTime to composite major CV event (CV death, nonfatal MI, nonfatal stroke, and hospitalization for UA)26,0002017–201870–99 SPIRE-1
    > 100 SPIRE-2
    • CV = cardiovascular; FOURIER = Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; LDL-C = low-density-lipoprotein cholesterol; MI = myocardial infarction; ODYSSEY OUTCOMES = Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; SPIRE-1, SPIRE-2 = The Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects; UA = unstable angina

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Cleveland Clinic Journal of Medicine: 83 (11 suppl 2)
Cleveland Clinic Journal of Medicine
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1 Nov 2016
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PCSK9 inhibition: A promise fulfilled?
Khendi White, Chaitra Mohan, Michael Rocco
Cleveland Clinic Journal of Medicine Nov 2016, 83 (11 suppl 2) S36-S44; DOI: 10.3949/ccjm.83.s2.05

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PCSK9 inhibition: A promise fulfilled?
Khendi White, Chaitra Mohan, Michael Rocco
Cleveland Clinic Journal of Medicine Nov 2016, 83 (11 suppl 2) S36-S44; DOI: 10.3949/ccjm.83.s2.05
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  • Article
    • ABSTRACT
    • A CASE FOR ADDITIONAL THERAPIES
    • PCSK9 INHIBITORS: DISCOVERY, MECHANISM, AND THERAPEUTIC INTERVENTIONS
    • PCSK9 INHIBITORS: CLINICAL TRIALS
    • CURRENT FDA INDICATIONS AND GUIDELINES
    • CONCLUSION
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