Article Figures & Data
Figures
- FIGURE 1
Effect of PCSK9 inhibitors on cardiovascular events.50,51
Tables
Gain-of-function mutations PCSK9 variant Population Clinical characteristics D374Y British, Norwegian, families;1 Utah family Premature CVD, tendon xanthomas, severe hypercholes terolemia S127R French, South African, Norwegian families Tendon xanthomas, CVD, early MI, stroke R215H Norwegian family Brother died at 31 from MI; strong family history of CVD Loss-of-function mutations PCSK9 variant Population LDL-C CVD risk R46L ARIC, DHS ↓ 15% ↓ 47% Y142X or C679X ARIC, 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.
Drug Sponsor Stage of development FDA approval Monoclonal antibodies Alirocumab, (SAR236553, REGN727) Sanofi, Regeneron Phase 3 July 2015 Evolocumab (AMG145) Amgen Phase 3 August 2015 Bococizumab (PF0499614, RN316) Pfizer Phase 3 No LY3015014 Lilly Phase 2 No PCSK9-binding adnectin BMS-962476 Bristol-Meyers Squibb Phase 1 No siRNA ALN-PCS Alnylam Pharmaceuticals Phase 1 No Data from reference 32.
Study Drug Description No. patients Weeks Baseline LDL Mean % LDL lowering Phase 3 efficacy trials MENDEL-235 Evolocumab Monotherapy vs ezetimibe and placebo 614 12 140–144 55–57 DESCARTES36 Evolocumab Long-term tolerability/efficacy atorvastatin 10–80 ± ezetimibe 901 52 104 (95–120) 55–57 RUTHERFORD-237 Evolocumab LDL-C goal achievement in HeFH on statin 331 12 151–161 59–61 LAPLACE-238 Evolocumab Combined with different statins vs ezetimibe and placebo 2,067 12 108 55–76 GAUSS-239 Evolocumab Statin intolerant vs ezetimibe 307 12 192–195 53–56 GAUSS-340 Evolocumab Statin intolerant vs ezetimibe 511 24 212–219 53 TAUSSIG41 Evolocumab Homozygous FH statin ± ezetimibe, open label 94 12 321 20.9 ODYSSEY FH I42 Alirocumab HeFH vs ezetimibe 486 24 145 58 ODYSSEY FH II42 Alirocumab HeFH vs ezetimibe 249 24 135 51 ODYSSEY-High FH43 Alirocumab HeFH on statin vs placebo 106 24 196–201 46 ODYSSEY-COMBO I44 Alirocumab Hypercholesterol vs placebo 316 24 95–100 48 ODYSSEY-COMBO II45 Alirocumab High CVD risk with ezetimibe vs placebo/ezetimibe 707 24 105–109 51 ODYSSEY CHOICE I46 Alirocumab Maximum statin or statin intolerant vs placebo 803 24 112–148 52 (no statin)
59 (+ statin)ODYSSEY CHOICE II47 Alirocumab Combined with ezetimibe or fenofibrate or as monotherapy vs placebo 233 24 154–164 56 Phase 2 trials NCT0159224048 Bococizumab Dose ranging, added to statins 250 24 105–118 34–53 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
Pooled OSLER-1, OSLER-250 evolocumab ODYSSEY LONG TERM51 alirocumab No. patients 4,465 2,341 Follow-up 11.1 months 78 weeks Study type Open-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 events CV death, MI, CVA, UA revascularization, CHF CV 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 events 7.5 vs 7.5 18.7 vs 19.5 Liver function tests 1.0 vs 1.2 1.8 vs 2.1 Creatine phosphokinase 0.6 vs 1.1 3.7 vs 4.9 Musculoskeletal 6.4 vs 6.0 5.4 vs 2.9 Neurocognitive 0.9 vs 0.6 1.2 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
Trial Drug Primary outcome No. patients Expected completion LDL-C on background therapy (mg/dL) FOURIER53 Evolocumab Time to CV death, MI, hospitalization for UA, stroke, or coronary revascularization 27,500 2016–2017 > 70 ODYSSEY54 Alirocumab Time to CV death, nonfatal MI, hospitalization for UA, stroke 18,000 2017 > 70 SPIRE-1,55
SPIRE-256Bococizumab Time to composite major CV event (CV death, nonfatal MI, nonfatal stroke, and hospitalization for UA) 26,000 2017–2018 70–99 SPIRE-1
> 100 SPIRE-2CV = 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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