Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. 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 a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease 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 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. Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia: The Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterole PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials 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). 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 Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. 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). Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial
OBJECTIVES The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 ( SAR236553 ) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy . Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of < 100 mg/dl ( 2.59 mmol/l ) and < 70 mg/dl ( 1.81 mmol/l ) . BACKGROUND Serum proprotein convertase subtilisin kexin 9 ( PCSK9 ) binds to low-density lipoprotein receptors , increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9 . METHODS This double-blind , parallel-group , placebo-controlled trial r and omized 183 patients with LDL-C ≥100 mg/dl ( 2.59 mmol/l ) on stable-dose atorvastatin 10 , 20 , or 40 mg for ≥6 weeks to : subcutaneous placebo every 2 weeks ( Q2W ) ; SAR236553 50 , 100 , or 150 mg Q2W ; or SAR236553 200 or 300 mg every 4 weeks ( Q4W ) , alternating with placebo for a total treatment period of 12 weeks . RESULTS SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration : 40 % , 64 % , and 72 % with 50 , 100 , and 150 mg Q2W , respectively , and 43 % and 48 % with 200 and 300 mg Q4W . LDL-C reduction with placebo at week 12 was 5 % . SAR236553 also substantially reduced non-high-density lipoprotein cholesterol , apolipoprotein B , and lipoprotein(a ) . SAR236553 was generally well tolerated . One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis . CONCLUSIONS When added to atorvastatin , PCSK9 inhibition with SAR236553  further reduces LDL-C by 40 % to 72 % . These additional reductions are both dose- and dosing frequency-dependent . ( Efficacy and Safety Evaluation of SAR236553 [ REGN727 ] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy ; NCT01288443 ) 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 Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease ( PCSK9 ) result ed in large reductions of low-density lipoprotein cholesterol ( LDL-C ) in phase 1 trials . We assessed the efficacy and safety of various doses and dosing intervals of REGN727 , a monoclonal antibody to PCSK9 , added to statins , to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia . METHODS This multicentre , r and omised , placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada . Between Jan 18 , 2011 , and Nov 7 , 2011 , we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose , with or without ezetimibe . Patients were r and omly assigned to receive REGN727 150 mg , 200 mg , or 300 mg every 4 weeks , or 150 mg every 2 weeks , or placebo every 2 weeks ( ratio 1:1:1:1:1 ) . R and omisation was stratified by concomitant use of ezetimibe at baseline . Investigators , study staff , and patients were masked to treatment group . Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing . The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance ( ANCOVA ) model with treatment group . This trial is registered in Clinical Trials.gov , number NCT 01266876 . FINDINGS 77 patients were r and omly assigned to study groups ( 15 - 16 patients per group ) and all were analysed . Least-squares ( LS ) mean LDL-C reduction from baseline to week 12 was 28·9 % ( SE 5·08 ) for 150 mg every 4 weeks ( p=0·0113 ) , 31·54 % ( 4·91 ) for 200 mg every 4 weeks ( p=0·0035 ) , 42·53 % ( 5·09 ) for 300 mg every 4 weeks ( p<0·0001 ) , and 67·90 % ( 4·85 ) for 150 mg every 2 weeks ( p<0·0001 ) , compared with 10·65 % ( 5·04 ) with  placebo . One serious adverse event was reported with placebo and none with REGN727 . No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase . The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment . INTERPRETATION REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose  statins , with or without ezetimibe . REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder . FUNDING Sanofi US and Regeneron Pharmaceuticals Incorporated 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 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 CONTEXT An estimated 10 % to 20 % of patients can not tolerate statins or adequate doses to achieve treatment goals . Plasma proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) binds to low-density lipoprotein ( LDL ) receptors , promoting their degradation and increasing LDL cholesterol levels . In phase 1 studies , a human monoclonal antibody to PCSK9 , AMG145 , was well tolerated and reduced LDL cholesterol levels . OBJECTIVE To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects . DESIGN , SETTING , AND PATIENTS A 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled , dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites . INTERVENTION Patients were r and omized equally to 1 of 5 groups : AMG145 alone at doses of 280 mg , 350 mg , or 420 mg ; AMG145 at 420 mg plus 10 mg of ezetimibe ; or 10 mg of ezetimibe plus placebo . AMG145 or placebo was administered subcutaneously every 4 weeks . MAIN OUTCOME MEASURES The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol . Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe . RESULTS Of 236 patients screened , 160 were r and omized ( mean age , 62 years ; 64 % female ; mean baseline LDL cholesterol , 193 mg/dL ) ; all patients had intolerance to 1 or more statins because of muscle-related events . At week 12 , mean changes in LDL cholesterol levels were -67 mg/dL ( -41 % ; 95 % CI , -49 % to -33 % ) for the AMG145 , 280-mg , group ; -70 mg/dL ( -43 % ; 95 % CI , -51 % to -35 % ) for the 350-mg group ; -91 mg/dL ( -51 % ; 95 % CI , -59 % to -43 % ) for the 420-mg group ; and -110 mg/dL ( -63 % ; 95 % CI , -71 % to -55 % ) for the 420-mg/ezetimibe group compared with -14 mg/dL ( -15 % ; 95 % CI , -23 % to -7.0 % ) for the placebo/ezetimibe group ( P < .001 ) . Four serious adverse events were reported with AMG145 ( coronary artery disease , acute pancreatitis , hip fracture , syncope ) . Myalgia was the most common treatment-emergent adverse event during the study , occurring in 5 patients ( 15.6 % ) in the 280-mg group ( n = 32 ) ; 1 patient ( 3.2 % ) in the 350-mg group ( n = 31 ) , 1 patient ( 3.1 % ) in the 420-mg group ( n = 32 ) , 6 patients ( 20.0 % ) receiving 420-mg AMG145/ezetimibe , and 1 patient ( 3.1 % ) receiving placebo/ezetimibe . CONCLUSION In this phase 2 study in statin-intolerant patients , subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01375764 Abstract Aim . To evaluate the relation of proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) levels to coronary artery disease ( CAD ) . Methods . A total of 1031 consecutive individuals ( 552 CAD and 479 controls ) were prospect ively enrolled . The associations of plasma PCSK9 levels with the incidence and severity of CAD were investigated . Further , mediator analysis was performed to detect the potential mechanisms of the associations . Results . No difference in PCSK9 levels between CAD patients and controls was detected ( median 224.75 versus 224.64 ng/mL , P > 0.05 ) . However , the CAD group had higher PCSK9 levels than the control group when adjusting for the confounding factors ( 228.03 ± 1.01 versus 219.28 ± 1.02 ng/mL , P = 0.019 )  . PCSK9 levels were also associated with the severity of CAD assessed by the Gensini score ( GS ) system ( P for trend < 0.05 ) . Logistic regression analysis showed that PCSK9 levels were associated with an increased CAD risk ( OR 3.296 and 5.130 for the incidence and severity , respectively ) . Importantly , mediator analysis indicated that the effects of PCSK9 levels on CAD were mediated by lipid ( around 20 % ) and inflammation ( around 15 % ) . Conclusions . PCSK9 levels were positively associated with the severity of CAD ; the relatively important mechanisms including lipid and inflammation pathways were partly involved in this association 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 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 Background — Despite statin treatment , many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol ( LDL-C ) targets . AMG 145 , a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) serine protease , demonstrated significant reductions in LDL-C in phase 1 studies . This phase 2 , multicenter , double-blind , r and omized , placebo-controlled , dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients . Methods and Results — Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L ( 100 mg/dL ) despite statin therapy with or without ezetimibe  were r and omized 1:1:1 to AMG 145 350 mg , AMG 145 420 mg , or placebo-administered subcutaneously every 4 weeks . The primary end point was percentage change from baseline in LDL-C at week 12 . Of 168 patients r and omized , 167 received investigational product and were included in the full analysis set ( mean [ SD ] age , 50 [ 13 ] years ; 47 % female ; 89 % white ; mean [ SD ] baseline LDL-C , 4.0 [ 1.1 ] mmol/L ( 156 [ 42 ] mg/dL ) ) . At week 12 , LDL-C reduction measured by preparative ultracentrifugation ( least squares mean [ st and ard error ( SE ) ] ) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg , respectively , compared with 1 (3)% increase with placebo ( P<0.001 for both dose groups ) . Serious adverse events ( not considered treatment-related ) occurred in 2 patients on AMG 145 . Conclusions — AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use , with or without ezetimibe , with minimal adverse events and good tolerability . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01375751 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 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 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 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 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 ) OBJECTIVES The purpose of this study was assess the effect of  evolocumab  (  AMG 145 ) on lipoprotein (Lp)(a ) from a pooled analysis of 4 phase II trials . BACKGROUND Lp(a ) , a low-density lipoprotein ( LDL ) particle linked to the plasminogen-like glycoprotein apolipoprotein(a ) , shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies . Current therapeutic options to reduce Lp(a ) are limited . METHODS A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of  evolocumab  , a fully human monoclonal antibody to PCSK9 , on Lp(a ) , the relationship between Lp(a ) and lowering of low-density lipoprotein cholesterol ( LDL-C ) and apolipoprotein B , and the influence of background statin therapy . Lp(a ) was measured using a st and ardized isoform-independent method . RESULTS Evolocumab treatment for 12 weeks result ed in significant ( p < 0.001 ) mean ( 95 % confidence interval ) dose-related reductions in Lp(a ) compared to control : 29.5 % ( 23.3 % to 35.7 % ) and 24.5 % ( 20.4 % to 28.7 % ) with 140 mg and 420 mg , dosed every 2 and 4 weeks , respectively , with no plateau of effect . Lp(a ) reductions were significantly correlated with percentages of reductions in LDL-C ( Spearman correlation coefficient , 0.5134 ; p < 0.001 ) and apolipoprotein B ( Spearman correlation coefficient , 0.5203 ; p < 0 . 001 ) . Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins . CONCLUSIONS Inhibition of PCSK9 with evolocumab result ed in significant dose-related reductions in Lp(a ) . While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a ) of ≤125 nmol/l , the absolute reduction was substantially larger in those with levels > 125 nmol/l 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
The reduction in MACEs was observed in White but not in Asian subjects .
Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk .
Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events , but the effect on all-cause mortality remains uncertain
Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia .
However , it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk .
Also , whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types , dosages , race , and indications for PCSK9 monoclonal antibodies remains unclear .
Therefore , we used recently published studies to systematic ally evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles , adverse events , and clinical endpoints in patients at high cardiovascular risk .