Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin‐Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3) Trial Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV). Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial.
BACKGROUND The ODYSSEY COMBO I study ( http:// clinical trials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia . METHODS This multicenter , phase 3 , r and omized ( 2:1 alirocumab vs placebo ) , double-blind , 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia .  Alirocumab ( 75 mg every 2 weeks [ Q2W ] ) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen . The alirocumab dose was increased to 150 mg Q2W ( also 1 mL ) at week 12 if week 8 low-density lipoprotein cholesterol ( LDL-C ) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 ( intention-to-treat analysis ) . RESULTS At week 24 , estimated mean ( 95 % CI ) changes in LDL-C from baseline were -48.2 % ( -52.0 % to -44.4 % ) and -2.3 % ( -7.6 % to 3.1 % ) for alirocumab and placebo , respectively , an estimated mean ( 95 % CI ) difference of -45.9 % ( -52.5 % to -39.3 % ) ( P < .0001 ) . Low-density lipoprotein cholesterol < 70 mg/dL was achieved by 75 % alirocumab versus 9 % placebo patients at week 24 . At week 12 , 83.2 % of evaluable alirocumab-treated patients remained on 75-mg Q2W . Treatment-emergent adverse events were comparable between groups . CONCLUSIONS Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals , versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy . The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups BACKGROUND Homozygous familial hypercholesterolaemia is a rare , serious disorder caused by very low or absent plasma clearance of LDL , substantially raised LDL cholesterol , and accelerated development of cardiovascular disease . Conventional lipid-lowering treatments are modestly effective . Evolocumab , a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , reduced LDL cholesterol by 16 % in a pilot study . We now report results with evolocumab in a r and omised , double-blind , placebo-controlled phase 3 trial . METHODS This r and omised , double-blind , placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America , Europe , the Middle East , and South Africa . 50 eligible patients ( aged ≥12 years ) with homozygous familial hypercholesterolaemia , on stable lipid-regulating therapy for at least 4 weeks , and not receiving lipoprotein apheresis  , were r and omly allocated by a computer-generated r and omisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks . R and omisation was stratified by LDL cholesterol at screening ( < 11 mmol/L or ≥11 mmol/L ) and implemented by a computerised interactive voice-response system . Patients , study personnel , and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit . The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo , analysed by intention-to-treat . This trial is registered with Clinical Trials.gov , number NCT01588496 . FINDINGS Of the 50 eligible patients r and omly assigned to the two treatment groups , 49 actually received the study drug and completed the study ( 16 in the placebo group and 33 in the evolocumab group ) . Compared with placebo , evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9 % ( 95 % CI -43·9 % to -18·0 % ; p<0·0001 ) . Treatment-emergent adverse events occurred in ten ( 63 % ) of 16 patients in the placebo group and 12 ( 36 % ) of 33 in the evolocumab group . No serious clinical or laboratory adverse events occurred , and no anti-evolocumab antibody development was detected during the study . INTERPRETATION In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis , evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo . FUNDING Amgen OBJECTIVES This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses . BACKGROUND Statin intolerance , which is predominantly due to muscle-related side effects , is reported in up to 10 % to 20 % of patients . Evolocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , demonstrated marked reductions in plasma low-density lipoprotein cholesterol ( LDL-C ) in a phase 2 study in statin-intolerant patients . METHODS The GAUSS-2 ( Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects ) trial was a 12-week , double-blind study of r and omized patients ( 2:2:1:1 ) to evolocumab 140 mg every two weeks ( Q2W ) or evolocumab 420 mg once monthly ( QM ) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg . Co- primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 , and at week 12 . RESULTS Three hundred seven patients ( age 62 ± 10 years ; LDL-C 193 ± 59 mg/dl ) were r and omized . Evolocumab  reduced LDL-C from baseline by 53 % to 56 % , corresponding to treatment differences versus ezetimibe of 37 % to 39 % ( p < 0.001 ) . Muscle adverse events occurred in 12 % of evolocumab-treated patients and 23 % of ezetimibe-treated  patients . Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups . CONCLUSIONS Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant . ( Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2 ; NCT01763905 ) Lipoprotein(a ) [ Lp(a ) ] is an independent risk factor for cardiovascular disease , with limited treatment options . This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 , alirocumab 150 mg every 2 weeks ( Q2W ) , on Lp(a ) levels in pooled data from 3 double-blind , r and omized , placebo-controlled , phase 2 studies of 8 or 12 weeks ' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy ( NCT01266876 , NCT01288469 , and NCT01288443 ) . Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo .  Alirocumab result ed in a significant reduction in Lp(a ) from baseline compared with placebo ( -30.3 % vs -0.3 % , p < 0.0001 ) . Median percentage Lp(a ) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a ) levels , result ing in greater absolute reductions in Lp(a ) in patients with higher baseline levels . Regression analysis indicated that < 5 % of the variance in the reduction of Lp(a ) was explained by the effect of alirocumab on low-density lipoprotein cholesterol . In conclusion , pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a ) with alirocumab 150 mg Q2W , including patients with baseline Lp(a ) > 50 mg/dl . Reductions in Lp(a ) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering BACKGROUND Statin intolerance has been a major limitation in the use of statins , especially at higher doses . New effective treatments are needed for lowering low-density lipoprotein cholesterol ( LDL-C ) in patients who can not tolerate daily statin doses . OBJECTIVE ODYSSEY ALTERNATIVE ( NCT01709513 ) evaluates efficacy and safety of alirocumab , a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody , in patients with well-documented statin intolerance and moderate to very high cardiovascular risk . METHODS This is a phase 3 , multicenter , r and omized , double-blind , double-dummy study in statin-intolerant patients . Intolerance was defined as inability to take at least 2 different statins because of muscle-related adverse events ( AEs ) , 1 at the lowest approved starting dose . Patients first received single-blind subcutaneous and oral placebo for 4 weeks , and were withdrawn if they developed muscle-related AEs after the placebo treatment . Continuing patients were r and omized ( 2:2:1 ratio ) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day ( statin rechallenge ) , for 24 weeks . Alirocumab dose was increased to 150 mg every 2 weeks ( also 1 mL ) at week 12 depending on week 8 LDL-C level . The primary endpoint is percent change in LDL-C from baseline to week 24 by intent-to-treat analysis . Muscle-related AEs were assessed by spontaneous patient reports and clinic queries . RESULTS A total of 314 patients have been r and omized . CONCLUSIONS This is the first and only study of a new class of LDL-C-lowering agents in patients selected with a rigorously documented intolerance to statins , using a placebo run-in and statin control arm Statins are the accepted st and ard for lowering low‐density lipoprotein cholesterol ( LDL‐C ) . However , 5 % to 10 % of statin‐treated patients report intolerance , mostly due to muscle‐related adverse effects . Challenges exist to objective identification of statin‐intolerant patients . Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , result ing in marked LDL‐C reduction . We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 ( GAUSS‐3 ) , a phase 3 , multicenter , r and omized , double‐blind , ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose . The study incorporates a novel atorvastatin‐controlled , double‐blind , crossover phase to objective ly identify statin intolerance . Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins ( one of which was atorvastatin ≤10 mg/d ) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin . This trial has 2 co‐ primary endpoints : mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24 . Key secondary efficacy endpoints include change from baseline in LDL‐C , percent of patients attaining LDL‐C < 70 mg/dL ( 1.81 mmol/L ) , and percent change from baseline in total cholesterol , non – high‐density lipoprotein cholesterol , and apolipoprotein B. Recruitment of 511 patients was completed on November 28 , 2014 BACKGROUND LDL cholesterol ( LDL-C ) is a well established risk factor for cardiovascular disease . Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) binds LDL receptors , targeting them for degradation . We therefore assessed the efficacy , safety , and tolerability of AMG 145 , a human monoclonal IgG2 antibody against PCSK9 , in stable patients with hypercholesterolemia on a statin . METHODS In a phase 2 , dose-ranging study done in 78 centres in the USA , Canada , Denmark , Hungary , and Czech Republic , patients ( aged 18 - 80 years ) with LDL-C greater than 2·2 mmol/L on a stable dose of statin ( with or without ezetimibe )  , were r and omly assigned equally , through an interactive voice response system , to subcutaneous injections of AMG 145 70 mg , 105 mg , or 140 mg , or matching placebo every 2 weeks ; or subcutaneous injections of AMG 145 280 mg , 350 mg , or 420 mg , or matching placebo every 4 weeks . Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules . The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks . Analysis was by modified intention to treat . This study is registered with Clinical Trials.gov , number NCT01380730 . FINDINGS 631 patients with hypercholesterolaemia were r and omly assigned to AMG 145 70 mg ( n=79 ) , 105 mg ( n=79 ) , or 140 mg ( n=78 ) , or matching placebo ( n=78 ) every 2 weeks ; or AMG 145 280 mg ( n=79 ) , 350 mg ( n=79 ) , and 420 mg ( n=80 ) , and matching placebo ( n=79 ) every 4 weeks . At the end of the dosing interval at week 12 , the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks ( ranging from 41·8 % to 66·1 % ; p<0·0001 for each dose vs placebo ) and AMG 145 every 4 weeks ( ranging from 41·8 % to 50·3 % ; p<0·0001 ) . No treatment-related serious adverse events occurred . The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups ( 39 [ 8 % ] of 474 vs 11 [ 7 % ] of 155 ) ; none of these events were severe or life-threatening . INTERPRETATION The results suggest that PCSK9 inhibition could be a new model in lipid management . Inhibition of PCSK9 warrants assessment in phase 3 clinical trials . FUNDING Amgen BACKGROUND Following acute coronary syndrome ( ACS ) , the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol ( LDL-C ) even within the setting of intensive statin treatment . Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab , a fully human monoclonal antibody to PCSK9 , improves cardiovascular outcomes after ACS . DESIGN This Phase 3 study will r and omize approximately 18,000 patients to receive biweekly injections of alirocumab ( 75 - 150 mg ) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infa rct ion or unstable angina . Qualifying patients are treated with atorvastatin 40 or 80 mg daily , rosuvastatin 20 or 40 mg daily , or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria : LDL-C ≥ 70 mg/dL , non-high-density lipoprotein cholesterol ≥ 100 mg/dL , or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death , acute myocardial infa rct ion , hospitalization for unstable angina , or ischemic stroke . The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years , providing 90 % power to detect a 15 % hazard reduction . Adverse events of special interest include allergic events and injection site reactions . Interim analyses are planned when approximately 50 % and 75 % of the targeted number of primary end points have occurred . SUMMARY ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS OBJECTIVES The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial . BACKGROUND Evolocumab , a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , significantly reduced LDL-C in phase II trials . METHODS Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol ( LDL-C ) ≥100 and < 190 mg/dl and Framingham risk scores ≤10 % were r and omized ( 1:1:1:1:2:2 ) to oral placebo and subcutaneous ( SC ) placebo biweekly ; oral placebo and SC placebo monthly ; ezetimibe and SC placebo biweekly ; ezetimibe and SC placebo monthly ; oral placebo and evolocumab 140 mg biweekly ; or oral placebo and evolocumab 420 mg monthly . RESULTS A total of 614 patients were r and omized and administered  doses . Evolocumab treatment reduced LDL-C from baseline , on average , by 55 % to 57 % more than placebo and 38 % to 40 % more than ezetimibe ( p < 0.001 for all comparisons ) . Evolocumab treatment also favorably altered other lipoprotein levels . Treatment-emergent adverse events ( AEs ) , muscle-related AEs , and laboratory abnormalities were comparable across treatment groups . CONCLUSIONS In the largest monotherapy trial using a PCSK9 inhibitor to date , evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia . ( Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [ MENDEL-2 ] ; NCT01763827 ) Background — Evolocumab ( AMG 145 ) , a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , significantly reduced low-density lipoprotein cholesterol ( LDL-C ) in phase 2 studies of 12 weeks ’ duration . The longer-term efficacy and safety of PCSK9 inhibition remain undefined . Methods and Results — Of 1359 r and omized and dosed patients in the 4 evolocumab phase 2 parent studies , 1104 ( 81 % ) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C ( OSLER ) study . Regardless of their treatment assignment in the parent study , patients were r and omized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with st and ard of care ( SOC ) ( evolocumab+SOC , n=736 ) or SOC alone ( n=368 ) . Ninety-two percent of patients in the evolocumab+SOC group and 89 % of patients in the SOC group completed 52 weeks of follow-up . Patients who first received evolocumab in OSLER experienced a mean 52.3 % [ SE , 1.8 % ] reduction in LDL-C at week 52 ( P<0.0001 ) . Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions ( mean reduction , 50.4 % [ SE , 0.8 % ] at the end of the parent study versus 52.1 % [ SE , 1.0 % ] at 52 weeks ; P=0.31 ) . In patients who discontinued evolocumab on entry into OSLER , LDL-C levels returned to near baseline levels . Adverse events and serious adverse events occurred in 81.4 % and 7.1 % of the evolocumab+SOC group patients and 73.1 % and 6.3 % of the SOC group patients , respectively . Conclusion — Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date . Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT01439880 BACKGROUND Statin-mediated low-density lipoprotein cholesterol ( LDL-C ) lowering fails to prevent more than half of cardiovascular events in clinical trials . Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering , with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels < 70 mg/dL. Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitors permit LDL-C-lowering by a further 54 % to 75 % in statin-treated patients . The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated . AIMS To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor , evolocumab , will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy . METHODS A phase 3 , multicenter , double-blind , r and omized , placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinical ly indicated coronary angiogram with angiographic evidence of coronary atheroma , and after 78 weeks of treatment . Subjects ( n = 968 ) were r and omized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections . CONCLUSIONS The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy . GLAGOV will provide important mechanistic , safety , and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis ( www . clinical trials.gov identifier NCT01813422 ) OBJECTIVE LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria . The proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation . We tested whether plasma PCSK9 is elevated in proteinuric states , and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction . METHODS Thirty-nine kidney patients ( e-GFR 61 ± 29 mL/min/1.73 m(2 ) , proteinuria 1.9 [ 0.9 - 3.3 ] g/day ; 19 on statin treatment ) were studied during 2 r and omized double-blind 6-week periods on either lisinopril ( 40 mg/day ) and a regular sodium diet ( 194 ± 49 mmol Na+/day ; baseline treatment ) or lisinopril plus valsartan ( 320 mg/day ) and a low sodium diet ( 102 ± 52 mmol Na(+)/day ; maximal treatment ) , and compared to age- and sex-matched controls . Maximal treatment decreased proteinuria to 0.5 [ 0.3 - 1.1 ] g/day ( P < 0.001 ) . RESULTS Plasma PCSK9 was increased at baseline in proteinuric subjects ( 213 [ 161 - 314 ] vs. 143 [ 113 - 190 ] ug/L in controls , P ≤ 0.001 ) , irrespective of statin use , e-GFR and BMI . PCSK9 correlated with proteinuria at baseline ( R = 0.399 , P = 0.018 ) and at maximal antiproteinuric treatment ( R = 0.525 , P = 0.001 ) , but did not decrease during proteinuria reduction ( P = 0.84 ) . Individual changes in total cholesterol ( R = 0.365 , P = 0.024 ) , non-HDL cholesterol ( R = 0.333 , P = 0.041 ) , and LDL cholesterol ( R = 0.346 , P = 0.033 ) were correlated positively with individual PCSK9 responses . PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment ( P = 0.04 ) . CONCLUSION Plasma PCSK9 was elevated in proteinuria , predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction . Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects BACKGROUND Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) is a regulator of LDL-cholesterol receptor homeostasis and emerges as a therapeutic target in the prevention of cardiovascular ( CV ) disease . This prospect i ve cohort study analyzes risk prediction with PCSK9 serum concentrations in patients with stable coronary artery disease ( CAD ) on statin treatment .  METHODS AND RESULTS Fasting PCSK9 concentrations were measured in 504 consecutive patients with stable CAD confirmed by angiography .  Oral glucose tolerance tests were performed in all patients without known diabetes . Patients were followed up for 48months . The primary outcome was the composite of cardiovascular death and unplanned cardiovascular hospitalization . Serum concentrations of PCSK9 predicted CV outcomes ( PCSK9>622 ng/ml vs. < 471 ng/ml : HR 1.55 , 95%-CI 1.11 - 2.16 , p=0.009 ) . Higher PCSK9 concentrations were associated with female gender , hypertension , statin treatment , C-reactive protein , HbA1c , insulin , total cholesterol and fasting triglycerides , but not with LDL- or HDL-cholesterol . The association of  PCSK9 levels with CV events was reduced after adjustment for fasting TG . CONCLUSION  PCSK9 concentrations predict cardiovascular events in patients with coronary artery disease on statin treatment . Serum triglycerides are correlated with PCSK9 and modify risk prediction by PCSK9 BACKGROUND Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) increases serum LDL-cholesterol ( LDL-C ) concentrations . We assessed the effects of AMG 145 , a human monoclonal antibody against PCSK9 , in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment . METHODS In a phase 2 trial done at 52 centres in Europe , the USA , Canada , and Australia , patients ( aged 18 - 75 years ) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were r and omly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg , 105 mg , or 140 mg , or placebo every 2 weeks ; subcutaneous AMG 145 280 mg , 350 mg , or 420 mg or placebo every 4 weeks ; or oral ezetimibe 10 mg/day . The primary endpoint was percentage change from baseline in LDL-C concentration at week 12 . Analysis was by modified intention to treat . Study personnel and patients were masked to treatment assignment of AMG 145 or placebo . Ezetimibe assignment was open label . This trial is registered with Clinical Trials.gov , number NCT01375777 . FINDINGS 406 patients were assigned to AMG 145 70 mg ( n=45 ) , 105 mg ( n=46 ) , or 140 mg ( n=45 ) every 2 weeks ; AMG 145 280 mg ( n=45 ) , 350 mg ( n=45 ) , or 420 mg ( n=45 ) every 4 weeks ; placebo every 2 weeks ( n=45 ) or every 4 weeks ( n=45 ) ; or ezetimibe ( n=45 ) . AMG 145 significantly reduced LDL-C concentrations in all dose groups ( mean baseline LDL-C concentration 3·7 mmol/L [ SD 0·6 ] ; changes from baseline with every 2 weeks AMG 145 70 mg -41·0 % [ 95 % CI -46·2 to -35·8 ] ; 105 mg -43·9 % [ -49·0 to -38·7 ] ; 140 mg -50·9 % [ -56·2 to -45·7 ] ; every 4 weeks AMG 145 280 mg -39·0 % [ -44·1 to -34·0 ] ; 350 mg -43·2 % [ -48·3 to -38·1 ] ; 420 mg -48·0 % [ -53·1 to -42·9 ] ; placebo every 2 weeks -3·7 % [ -9·0 to 1·6 ] ; placebo every 4 weeks 4·5 % [ -0·7 to 9·8 ] ; and ezetimibe -14·7 % [ -18·6 to -10·8 ] ; p<0·0001 for all doses vs placebo or ezetimibe ) . Treatment-emergent adverse events occurred in 136 ( 50 % ) of 271 patients in the AMG 145 groups , 41 ( 46 % ) of 90 patients in the placebo groups , and 26 ( 58 % ) of 45 patients in the ezetimibe  group ; no deaths or serious treatment-related adverse events were reported . INTERPRETATION The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse population s including patients with documented statin intolerance . FUNDING Amgen Proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol ( LDL-C ) by upregulating LDL receptor availability . In early 2014 , the US Food and Drug Administration ( FDA ) directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials . Available trial evidence indicates that neurocognitive adverse events may occur more commonly in individuals receiving an antibody to PCSK9 , but these events are uncommon and have not been associated with on-treatment LDL-C levels . Moreover , it is unclear to what extent closer monitoring of trial participants allocated to PCSK9 inhibitors has led to an ascertainment bias . Regardless , further trial data are needed , and long-term outcomes trials are ongoing , with at least one including a neurocognitive sub study . Considering lessons learned from the statin experience , high- quality prospect i ve cohort studies and r and omized trials may not be enough to allay concerns or settle debate since the focus of effect in these studies is the group average . Therefore , we suggest that n-of-1 trials could be considered to bring the focus to the individual while retaining the benefits of blinding and r and omization in evidence generation . Ultimately , any neurocognitive adverse effects that might exist with PCSK9 inhibition and lipid lowering must be weighed against potential benefits of therapy , including avoidance of myocardial infa rct ion and stroke , and a reduced risk of dementia due to neurovascular benefits from long-term lipid lowering BACKGROUND Alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 , has been shown to provide significant reductions in low-density lipoprotein cholesterol ( LDL-C ) . Data about its efficacy and safety in patients from South Korea and Taiwan are limited . OBJECTIVE ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan . METHODS Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were r and omized ( 1:1 ) to alirocumab ( 75 mg every 2 weeks , with dose increase to 150 mg every 2 weeks at week 12 if LDL-C ≥70 mg/dL at week 8) or placebo for 24 weeks . The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24 . Safety was assessed throughout . RESULTS At week 24 , alirocumab  changed LDL-C levels by -57.1 % ( placebo : + 6.3 % ) . In the alirocumab group , 9 patients ( 9.5 % ) received dose increase at week 12 . At week 24 , 85.8 % of patients in the alirocumab group reached LDL-C < 70 mg/dL ( placebo : 14.2 % ; P ≤ .0001 vs placebo ) . Alirocumab significantly improved non-high-density lipoprotein cholesterol ( non-HDL-C ) , apolipoprotein B , total cholesterol , lipoprotein ( a ) , and HDL-C vs placebo ( P ≤ .05 ) . Two consecutive calculated LDL-C values < 25 mg/dL were recorded in 27.8 % of alirocumab-treated patients . Overall , 58.8 % ( alirocumab ) and 61.8 % ( placebo ) of patients experienced treatment-emergent adverse events ; 2.1 % and 1.0 % discontinued treatment due to treatment-emergent adverse events , respectively . CONCLUSION Alirocumab  significantly improved LDL-C , apolipoprotein B , non-HDL-C , lipoprotein ( a ) , HDL-C , and total cholesterol  in Asian patients . Alirocumab was generally well tolerated . These findings are consistent with ODYSSEY findings to date Importance Reducing levels of low-density lipoprotein cholesterol ( LDL-C ) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels . Proprotein convertase subtilisin kexin type 9 ( PCSK9 ) inhibitors produce incremental LDL-C lowering in statin-treated patients ; however , the effects of these drugs on coronary atherosclerosis have not been evaluated . Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients . Design , Setting , and Participants The GLAGOV multicenter , double-blind , placebo-controlled , r and omized clinical trial ( enrollment May 3 , 2013 , to January 12 , 2015 ) conducted at 197 academic and community hospitals in North America , Europe , South America , Asia , Australia , and South Africa and enrolling 968 patients presenting for coronary angiography . Interventions Participants with angiographic coronary disease were r and omized to receive monthly evolocumab ( 420 mg ) ( n = 484 ) or placebo ( n = 484 ) via subcutaneous injection for 76 weeks , in addition to statins . Main Outcomes and Measures The primary efficacy measure was the nominal change in percent atheroma volume ( PAV ) from baseline to week 78 , measured by serial intravascular ultrasonography ( IVUS ) imaging . Secondary efficacy measures were nominal change in normalized total atheroma volume ( TAV ) and percentage of patients demonstrating plaque regression . Safety and tolerability were also evaluated . Results Among the 968 treated patients ( mean age , 59.8 years [ SD , 9.2 ] ; 269 [ 27.8 % ] women ; mean LDL-C level , 92.5 mg/dL [ SD , 27.2 ] ) , 846 had evaluable imaging at follow-up . Compared with placebo , the evolocumab group achieved lower mean , time-weighted LDL-C levels ( 93.0 vs 36.6 mg/dL ; difference , -56.5 mg/dL [ 95 % CI , -59.7 to -53.4 ] ; P < .001 ) . The primary efficacy parameter , PAV , increased 0.05 % with placebo and decreased 0.95 % with evolocumab ( difference , -1.0 % [ 95 % CI , -1.8 % to -0.64 % ] ; P < .001 ) . The secondary efficacy parameter , normalized TAV , decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab ( difference , -4.9 mm3 [ 95 % CI , -7.3 to -2.5 ] ; P < .001 ) . Evolocumab  induced plaque regression in a greater percentage of patients than placebo ( 64.3 % vs 47.3 % ; difference , 17.0 % [ 95 % CI , 10.4 % to 23.6 % ] ; P < .001 for PAV and 61.5 % vs 48.9 % ; difference , 12.5 % [ 95 % CI , 5.9 % to 19.2 % ] ; P < .001 for TAV ) . Conclusions and Relevance Among patients with angiographic coronary disease treated with statins , addition of evolocumab , compared with placebo , result ed in a greater decrease in PAV after 76 weeks of treatment . Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes . Trial Registration clinical trials.gov Identifier : NCT01813422
Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes .
Although no overall benefit was noted in all-cause or cardiovascular mortality , such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol
BACKGROUND We sought to examine the efficacy and safety of 2 PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitors : alirocumab and evolocumab .