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Scott M Wasserman - One of the best experts on this subject based on the ideXlab platform.

  • long term efficacy and safety of Evolocumab in patients with hypercholesterolemia
    Journal of the American College of Cardiology, 2019
    Co-Authors: Michael J. Koren, Scott M Wasserman, Marc S Sabatine, Robert P Giugliano, Gisle Langslet, Stephen D Wiviott, Andrea Ruzza, A Hamer, Frederick J Raal
    Abstract:

    Abstract Background Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over  Objectives The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of Evolocumab during open-label hypercholesterolemia treatment for up to 5 years. Methods Patients randomized to standard of care (SOC) or Evolocumab 420 mg monthly (Evolocumab + SOC) for year 1. After year 1, patients could enter the all-Evolocumab period and receive Evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. Results A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 Evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-Evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during Evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 Evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. Conclusions The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of Evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880 )

  • Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety.
    Clinical pharmacology in drug development, 2019
    Co-Authors: John P. Gibbs, Scott M Wasserman, Lisa Hamilton, Ransi Somaratne, Sreeneeranj Kasichayanula, Maurice Emery, Geoffrey A. Block, Patrick Hanafin, Ogo Egbuna
    Abstract:

    : We evaluated the pharmacokinetics, pharmacodynamics, and safety of Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of Evolocumab. The effects of Evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; Cmax , P = .23; AUClast , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to Evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in Evolocumab exposure, as assessed by Cmax and AUClast , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of Evolocumab without dose adjustment in patients who have severe RI or ESRD.

  • interindividual variation in low density lipoprotein cholesterol level reduction with Evolocumab an analysis of fourier trial data
    JAMA Cardiology, 2019
    Co-Authors: Arman Qamar, Scott M Wasserman, Robert P Giugliano, Sabina A Murphy, Julia Kuder, Anthony C Keech, Peter S Sever, Christopher E Kurtz, Terje R Pedersen, Marc S Sabatine
    Abstract:

    Importance Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications. Objective To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug Evolocumab. Design, Setting, and Participants We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor Evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018. Main Outcomes and Measures Interindividual variation in percent reduction in LDL-C with Evolocumab. Results There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with Evolocumab. During the first year, a total of 10 325 of 10902 patients in the Evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both Evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with Evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups. Conclusions and Relevance There appears to be a highly consistent robust reduction in LDL-C levels with Evolocumab use. Trial Registration ClinicalTrials.gov identifier:NCT01764633

  • consistent ldl c response with Evolocumab among patient subgroups in proficio a pooled analysis of 3146 patients from phase 3 studies
    Clinical Cardiology, 2018
    Co-Authors: Erik S G Stroes, Scott M Wasserman, Frederick J Raal, David R Sullivan, Helina Kassahun, Jennifer G. Robinson, Robert Dufour, Michael J. Koren
    Abstract:

    Background: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. Hypothesis: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. Methods: A total of 3146 patients received ≥1 dose of Evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for Evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. Results: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each Evolocumab dosing regimen or control. Conclusions: Consistent reductions in LDL-C were observed in the Evolocumab group regardless of demographic and disease characteristics.

  • controlled study of the effect of proprotein convertase subtilisin kexin type 9 inhibition with Evolocumab on lipoprotein a particle kinetics
    European Heart Journal, 2018
    Co-Authors: Rob Scott, Scott M Wasserman, Ransi Somaratne, Gerald F Watts, Dick C Chan, Santica M Marcovina, Hugh P R Barrett
    Abstract:

    Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby Evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of Evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, Evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, Evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions: Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, Evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information: NCT02189837.

Ransi Somaratne - One of the best experts on this subject based on the ideXlab platform.

  • A Comparison of Ezetimibe and Evolocumab for Atherogenic Lipid Reduction in Four Patient Populations: A Pooled Efficacy and Safety Analysis of Three Phase 3 Studies
    Cardiology and Therapy, 2020
    Co-Authors: Michael J. Koren, Ransi Somaratne, Peter H. Jones, Jennifer G. Robinson, David Sullivan, Thomas Hucko, J. Antonio G. Lopez, Alex N. Fleishman, Erik Stroes
    Abstract:

    A statin is a type of medication that is used, with diet and exercise, to lower cholesterol levels and help prevent a heart attack or stroke caused by atherosclerosis. Atherosclerosis is the hardening and narrowing of blood vessels known as arteries from a buildup of plaque, usually made up of cholesterol and other fatty substances. LDL cholesterol, also known as “bad” cholesterol, is one of the most important risk factors for having a heart attack, and can be lowered. Patients with a high risk of heart disease may benefit from the additional lowering of LDL cholesterol beyond that achieved by statins alone. The medication Evolocumab reduced LDL cholesterol levels and improved other risk factors more than the medication ezetimibe in four studies. These studies included patients who were receiving statins and those who were not, including those who did not receive statins because of statin-related side effects. Both Evolocumab and ezetimibe had good safety profiles. Introduction Clinicians, payers, guideline committees, and policymakers support the use of high-intensity statins in patients at high risk for complications of cardiovascular disease (CVD). Guidelines and recommendations provide guidance on next steps for patients with inadequate low-density lipoprotein cholesterol (LDL-C) control on maximally tolerated statin or for those who are statin-intolerant. Ezetimibe and Evolocumab improve CV outcomes when added to statins in high-CV-risk populations. The aim of the study was to compare Evolocumab and ezetimibe for lipid-lowering efficacy and safety. Methods We summarized data from 1427 patients from three phase 3 Evolocumab studies comparing double-blinded Evolocumab vs. ezetimibe. These studies evaluated four distinct populations: those free of CVD receiving each agent as monotherapy, patients with CVD receiving add-on therapy to low- or high-intensity statin, and statin-intolerant patients. Lipid efficacy and safety were reported at week 12. Results Across the studies, Evolocumab reduced LDL-C by a mean 55–61% from baseline to week 12; ezetimibe lowered LDL-C by 18–20% from baseline (mean difference = 38–43% favoring Evolocumab; p  

  • Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety.
    Clinical pharmacology in drug development, 2019
    Co-Authors: John P. Gibbs, Scott M Wasserman, Lisa Hamilton, Ransi Somaratne, Sreeneeranj Kasichayanula, Maurice Emery, Geoffrey A. Block, Patrick Hanafin, Ogo Egbuna
    Abstract:

    : We evaluated the pharmacokinetics, pharmacodynamics, and safety of Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of Evolocumab. The effects of Evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; Cmax , P = .23; AUClast , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to Evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in Evolocumab exposure, as assessed by Cmax and AUClast , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of Evolocumab without dose adjustment in patients who have severe RI or ESRD.

  • effect of Evolocumab on coronary plaque composition
    Journal of the American College of Cardiology, 2018
    Co-Authors: Ransi Somaratne, Christie M Ballantyne, Helina Kassahun, Stephen J Nicholls, Rishi Puri, Todd J Anderson, John J P Kastelein, Wolfgang Koenig, Jingyuan Yang
    Abstract:

    Abstract Background Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor Evolocumab regresses coronary atherosclerosis in statin-treated patients. Objectives The purpose of this study was to evaluate the effect of adding Evolocumab to statin therapy on coronary plaque composition. Methods A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or Evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. Results Compared with statin monotherapy, Evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p  3 vs. −0.8 mm 3 ; p = 0.04). No difference was observed between the Evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm 3 vs. 0.6 ± 0.3 mm 3 ; p = 0.49), fibrous (−3.0 ± 0.6 mm 3 vs. −2.4 ± 0.6 mm 3 ; p = 0.49), fibrofatty (−5.0 ± 1.0 mm 3 vs. −3.0 ± 1.0 mm 3 ; p = 0.49), and necrotic (−0.6 ± 0.5 mm 3 vs. −0.1 ± 0.5 mm 3 ; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p  Conclusions The addition of Evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of Evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422)

  • efficacy safety and tolerability of Evolocumab in pediatric patients with heterozygous familial hypercholesterolemia rationale and design of the hauser rct study
    Journal of Clinical Lipidology, 2018
    Co-Authors: Daniel Gaudet, Ransi Somaratne, Gisle Langslet, Andrea Ruzza, Frederick J Raal, Chen Lu, Christopher E Kurtz, Samuel S Gidding, Ilse K Luirink, Albert Wiegman
    Abstract:

    Background Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia. A dedicated study, HAUSER-RCT, is being conducted to examine the efficacy and safety of Evolocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). Objective To present the rationale and design of the HAUSER-RCT study. Methods The HAUSER-RCT study is a double-blind, randomized, multicenter, placebo-controlled study designed to characterize the efficacy, safety, and tolerability of Evolocumab treatment as an add-on to diet and lipid-lowering therapy, including a stable, optimized dose of statin, in pediatric patients aged 10 to 17 years with HeFH. Approximately, 150 patients will be randomized in a 2:1 ratio to receive 24 weeks of monthly Evolocumab or placebo. The study will include approximately 51 sites located in North America, South America, Europe, South Africa, Australia, and New Zealand. The primary efficacy endpoint is the percent change in low-density lipoprotein cholesterol from baseline to week 24. A key secondary efficacy endpoint is the percent change in other lipid parameters from baseline to week 24. Other assessments include Tanner staging, carotid intima-media thickness, and cognitive tests. At the end of the study, consenting patients can participate in an 18-month open-label extension study (HAUSER-OLE). Results The study is ongoing and the results will be communicated at the end of the study. Conclusions The HAUSER-RCT study, the largest randomized, placebo-controlled study with proprotein convertase subtilisin/kexin type 9 inhibitors being conducted in the pediatric HeFH population, aims to provide efficacy, safety, and tolerability data of Evolocumab as an add-on therapy in these patients.

  • persistent safety and efficacy of Evolocumab in patients with statin intolerance a subset analysis of the osler open label extension studies
    Cardiovascular Drugs and Therapy, 2018
    Co-Authors: Ricardo Dent, Ransi Somaratne, Andrea Ruzza, David R Sullivan, Erik S G Stroes, Evan A Stein, Andrea Flower, Robert S Rosenson
    Abstract:

    Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of Evolocumab up to 2 years in statin-intolerant patients. Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to Evolocumab (140 mg biweekly or 420 mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, Evolocumab plus SOC. A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to Evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97–5.02 mmol/L (192–194 mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for Evolocumab plus SOC at year 1, and 59% for Evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and Evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for Evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2 years in statin-intolerant patients.

Frederick J Raal - One of the best experts on this subject based on the ideXlab platform.

  • long term efficacy and safety of Evolocumab in patients with hypercholesterolemia
    Journal of the American College of Cardiology, 2019
    Co-Authors: Michael J. Koren, Scott M Wasserman, Marc S Sabatine, Robert P Giugliano, Gisle Langslet, Stephen D Wiviott, Andrea Ruzza, A Hamer, Frederick J Raal
    Abstract:

    Abstract Background Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over  Objectives The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of Evolocumab during open-label hypercholesterolemia treatment for up to 5 years. Methods Patients randomized to standard of care (SOC) or Evolocumab 420 mg monthly (Evolocumab + SOC) for year 1. After year 1, patients could enter the all-Evolocumab period and receive Evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. Results A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 Evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-Evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during Evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 Evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. Conclusions The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of Evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880 )

  • consistent ldl c response with Evolocumab among patient subgroups in proficio a pooled analysis of 3146 patients from phase 3 studies
    Clinical Cardiology, 2018
    Co-Authors: Erik S G Stroes, Scott M Wasserman, Frederick J Raal, David R Sullivan, Helina Kassahun, Jennifer G. Robinson, Robert Dufour, Michael J. Koren
    Abstract:

    Background: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. Hypothesis: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. Methods: A total of 3146 patients received ≥1 dose of Evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for Evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. Results: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each Evolocumab dosing regimen or control. Conclusions: Consistent reductions in LDL-C were observed in the Evolocumab group regardless of demographic and disease characteristics.

  • efficacy safety and tolerability of Evolocumab in pediatric patients with heterozygous familial hypercholesterolemia rationale and design of the hauser rct study
    Journal of Clinical Lipidology, 2018
    Co-Authors: Daniel Gaudet, Ransi Somaratne, Gisle Langslet, Andrea Ruzza, Frederick J Raal, Chen Lu, Christopher E Kurtz, Samuel S Gidding, Ilse K Luirink, Albert Wiegman
    Abstract:

    Background Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia. A dedicated study, HAUSER-RCT, is being conducted to examine the efficacy and safety of Evolocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). Objective To present the rationale and design of the HAUSER-RCT study. Methods The HAUSER-RCT study is a double-blind, randomized, multicenter, placebo-controlled study designed to characterize the efficacy, safety, and tolerability of Evolocumab treatment as an add-on to diet and lipid-lowering therapy, including a stable, optimized dose of statin, in pediatric patients aged 10 to 17 years with HeFH. Approximately, 150 patients will be randomized in a 2:1 ratio to receive 24 weeks of monthly Evolocumab or placebo. The study will include approximately 51 sites located in North America, South America, Europe, South Africa, Australia, and New Zealand. The primary efficacy endpoint is the percent change in low-density lipoprotein cholesterol from baseline to week 24. A key secondary efficacy endpoint is the percent change in other lipid parameters from baseline to week 24. Other assessments include Tanner staging, carotid intima-media thickness, and cognitive tests. At the end of the study, consenting patients can participate in an 18-month open-label extension study (HAUSER-OLE). Results The study is ongoing and the results will be communicated at the end of the study. Conclusions The HAUSER-RCT study, the largest randomized, placebo-controlled study with proprotein convertase subtilisin/kexin type 9 inhibitors being conducted in the pediatric HeFH population, aims to provide efficacy, safety, and tolerability data of Evolocumab as an add-on therapy in these patients.

  • long term safety tolerability and efficacy of Evolocumab in patients with heterozygous familial hypercholesterolemia
    Journal of Clinical Lipidology, 2017
    Co-Authors: Kees G Hovingh, Ricardo Dent, Frederick J Raal, Claudia Stefanutti, Olivier S Descamps, Luis Masana, Armando Lira, Ian Bridges, Blai Coll, David R Sullivan
    Abstract:

    Background Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9, is safe and effective when dosed biweekly (Q2W) or monthly (QM) in patients with heterozygous familial hypercholesterolemia (HeFH) as demonstrated in two 12-week trials: Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD; phase 2) and RUTHERFORD-2 (phase 3). Objective The objective of the study was to evaluate long-term efficacy, safety, and tolerability of Evolocumab during open-label extension trials. Methods Patients completing parent trials were re-randomized 2:1 to Evolocumab plus standard of care (SOC) or SOC alone for 52 weeks (Open-Label Study of Long-term Evaluation Against LDL-C [OSLER-1]) or 48 weeks (OSLER-2). Evolocumab dosing was 420 mg QM (OSLER-1) and 140 mg Q2W or 420 mg QM (OSLER-2). A pooled analysis of OSLER data was performed from this subset of HeFH patients. Results Four hundred forty HeFH patients from RUTHERFORD (n = 147) and RUTHERFORD-2 (n = 293) (mean [standard deviation] age 51 [12] years, 58% male, 90% White) were randomized to Evolocumab plus SOC (n = 289) or SOC (n = 151). The 48-week period was completed by 425 patients (96.6%). Eight patients discontinued Evolocumab plus SOC (2.8%) and 7 discontinued SOC (4.6%). Compared to parent study baseline, patients receiving Evolocumab plus SOC experienced a mean 53.6% reduction in low-density lipoprotein cholesterol after 48 weeks. No patient experienced an adverse event leading to permanent Evolocumab discontinuation during the 1-year SOC-controlled period. Serious adverse event rates were similar between groups (Evolocumab plus SOC, 7.3%; SOC, 8.6%). Conclusion Continued use of Evolocumab added to SOC in patients with HeFH yields persistent and marked low-density lipoprotein cholesterol reductions during 48 weeks of follow-up. Long-term dosing of Evolocumab with SOC was safe and well tolerated.

  • long term low density lipoprotein cholesterol lowering efficacy persistence and safety of Evolocumab in treatment of hypercholesterolemia results up to 4 years from the open label osler 1 extension study
    JAMA Cardiology, 2017
    Co-Authors: Michael J. Koren, Ransi Somaratne, Marc S Sabatine, Robert P Giugliano, Gisle Langslet, Stephen D Wiviott, Andrea Ruzza, Helina Kassahun, Frederick J Raal
    Abstract:

    Importance The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with Evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective To determine whether LDL-C level reductions with Evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation. Design, Setting, and Participants This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more Evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016. Interventions During year 1, patients were randomized to Evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received Evolocumab, 420 mg, plus SOC. Main Outcomes and Measures Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of Evolocumab. Results At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, Evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, −63% to −60%) vs 2% (95% CI, −5% to −0.2%) with SOC alone ( P Conclusions and Relevance In the longest clinical trial exposure to a PCSK9 inhibitor to date, Evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation. Trial Registration clinicaltrials.gov Identifier:NCT01439880

Michael J. Koren - One of the best experts on this subject based on the ideXlab platform.

  • A Comparison of Ezetimibe and Evolocumab for Atherogenic Lipid Reduction in Four Patient Populations: A Pooled Efficacy and Safety Analysis of Three Phase 3 Studies
    Cardiology and Therapy, 2020
    Co-Authors: Michael J. Koren, Ransi Somaratne, Peter H. Jones, Jennifer G. Robinson, David Sullivan, Thomas Hucko, J. Antonio G. Lopez, Alex N. Fleishman, Erik Stroes
    Abstract:

    A statin is a type of medication that is used, with diet and exercise, to lower cholesterol levels and help prevent a heart attack or stroke caused by atherosclerosis. Atherosclerosis is the hardening and narrowing of blood vessels known as arteries from a buildup of plaque, usually made up of cholesterol and other fatty substances. LDL cholesterol, also known as “bad” cholesterol, is one of the most important risk factors for having a heart attack, and can be lowered. Patients with a high risk of heart disease may benefit from the additional lowering of LDL cholesterol beyond that achieved by statins alone. The medication Evolocumab reduced LDL cholesterol levels and improved other risk factors more than the medication ezetimibe in four studies. These studies included patients who were receiving statins and those who were not, including those who did not receive statins because of statin-related side effects. Both Evolocumab and ezetimibe had good safety profiles. Introduction Clinicians, payers, guideline committees, and policymakers support the use of high-intensity statins in patients at high risk for complications of cardiovascular disease (CVD). Guidelines and recommendations provide guidance on next steps for patients with inadequate low-density lipoprotein cholesterol (LDL-C) control on maximally tolerated statin or for those who are statin-intolerant. Ezetimibe and Evolocumab improve CV outcomes when added to statins in high-CV-risk populations. The aim of the study was to compare Evolocumab and ezetimibe for lipid-lowering efficacy and safety. Methods We summarized data from 1427 patients from three phase 3 Evolocumab studies comparing double-blinded Evolocumab vs. ezetimibe. These studies evaluated four distinct populations: those free of CVD receiving each agent as monotherapy, patients with CVD receiving add-on therapy to low- or high-intensity statin, and statin-intolerant patients. Lipid efficacy and safety were reported at week 12. Results Across the studies, Evolocumab reduced LDL-C by a mean 55–61% from baseline to week 12; ezetimibe lowered LDL-C by 18–20% from baseline (mean difference = 38–43% favoring Evolocumab; p  

  • long term efficacy and safety of Evolocumab in patients with hypercholesterolemia
    Journal of the American College of Cardiology, 2019
    Co-Authors: Michael J. Koren, Scott M Wasserman, Marc S Sabatine, Robert P Giugliano, Gisle Langslet, Stephen D Wiviott, Andrea Ruzza, A Hamer, Frederick J Raal
    Abstract:

    Abstract Background Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over  Objectives The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of Evolocumab during open-label hypercholesterolemia treatment for up to 5 years. Methods Patients randomized to standard of care (SOC) or Evolocumab 420 mg monthly (Evolocumab + SOC) for year 1. After year 1, patients could enter the all-Evolocumab period and receive Evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. Results A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 Evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-Evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during Evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 Evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. Conclusions The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of Evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880 )

  • consistent ldl c response with Evolocumab among patient subgroups in proficio a pooled analysis of 3146 patients from phase 3 studies
    Clinical Cardiology, 2018
    Co-Authors: Erik S G Stroes, Scott M Wasserman, Frederick J Raal, David R Sullivan, Helina Kassahun, Jennifer G. Robinson, Robert Dufour, Michael J. Koren
    Abstract:

    Background: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. Hypothesis: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. Methods: A total of 3146 patients received ≥1 dose of Evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for Evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. Results: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each Evolocumab dosing regimen or control. Conclusions: Consistent reductions in LDL-C were observed in the Evolocumab group regardless of demographic and disease characteristics.

  • effect of the proprotein convertase subtilisin kexin type 9 inhibitor Evolocumab on glycemia body weight and new onset diabetes mellitus
    American Journal of Cardiology, 2017
    Co-Authors: Naveed Sattar, Michael J. Koren, Ransi Somaratne, Peter P Toth, Dirk J Blom, Handrean Soran, Magdalena Uhart, Mary Elliott, Marcoli Cyrille, David Preiss
    Abstract:

    Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor Evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an Evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on Evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [−0.1, 0.2] for both SOC and Evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [−0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [−0.28, 0.44 mmol/L] for Evolocumab plus SOC). Mean weight change (standard error) at 1 year was −0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on Evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on Evolocumab/Evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, Evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment.

  • Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus.
    American Journal of Cardiology, 2017
    Co-Authors: Naveed Sattar, Michael J. Koren, Ransi Somaratne, Peter P Toth, Dirk J Blom, Handrean Soran, Magdalena Uhart, Mary Elliott, Marcoli Cyrille, David Preiss
    Abstract:

    Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor Evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an Evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on Evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [−0.1, 0.2] for both SOC and Evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [−0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [−0.28, 0.44 mmol/L] for Evolocumab plus SOC). Mean weight change (standard error) at 1 year was −0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on Evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on Evolocumab/Evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, Evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment.

Rob Scott - One of the best experts on this subject based on the ideXlab platform.

  • controlled study of the effect of proprotein convertase subtilisin kexin type 9 inhibition with Evolocumab on lipoprotein a particle kinetics
    European Heart Journal, 2018
    Co-Authors: Rob Scott, Scott M Wasserman, Ransi Somaratne, Gerald F Watts, Dick C Chan, Santica M Marcovina, Hugh P R Barrett
    Abstract:

    Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby Evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of Evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, Evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, Evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions: Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, Evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information: NCT02189837.

  • Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with Evolocumab on lipoprotein(a) particle kinetics.
    European Heart Journal, 2018
    Co-Authors: Gerald F Watts, Rob Scott, Scott M Wasserman, Ransi Somaratne, Dick C Chan, Santica M Marcovina, P. Hugh R. Barrett
    Abstract:

    Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby Evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of Evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P 

  • association between circulating baseline proprotein convertase subtilisin kexin type 9 levels and efficacy of Evolocumab
    JAMA Cardiology, 2017
    Co-Authors: Nihar R Desai, Rob Scott, Scott M Wasserman, Robert P Giugliano, John P. Gibbs, Marc S Sabatine
    Abstract:

    Importance Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of Evolocumab varies based on an individual’s baseline PCSK9 level remains unknown. Objective To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with Evolocumab differs based on PCSK9 levels. Design, Setting, and Participants This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of Evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12. Main Outcomes and Measures Placebo-controlled percentage change in LDL-C level with Evolocumab, 140 mg every 2 weeks and 420 mg once monthly, across quartiles of baseline PCSK9 levels. Results Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P P P  = .39, and ρ = 0.03 [95% CI, −0.01 to 0.08] for statin users, P  = .12). Across all quartiles of baseline PCSK9 levels, both Evolocumab 140 mg every 2 weeks and 420 mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both Evolocumab 140 mg every 2 weeks and 420 mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71% ( P P for interaction = .76 and .21, respectively). Conclusions and Relevance Regardless of baseline PCSK9 levels, the doses of Evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.

  • factorial effects of Evolocumab and atorvastatin on lipoprotein metabolism
    Circulation, 2017
    Co-Authors: Gerald F Watts, Rob Scott, Scott M Wasserman, Ransi Somaratne, Ricardo Dent, Dick C Chan, Sally Burrows, Hugh P R Barrett
    Abstract:

    Background:Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as Evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab...

  • Effect of Evolocumab on Cholesterol Synthesis and Absorption
    Journal of Lipid Research, 2016
    Co-Authors: Matthew Peach, Rob Scott, Scott M Wasserman, Ren Xu, Dan Fitzpatrick, Lisa Hamilton, Ransi Somaratne, C. Stephen Djedjos
    Abstract:

    The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-cholesterol (LDL-C), but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with Evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an Evolocumab clinical trial. At 2 weeks, changes in β-sitosterol/total cholesterol (TC) from baseline were 4% for placebo, 10% for Evolocumab 140 mg (nonsignificant vs. placebo), and 26% for Evolocumab 420 mg (P < 0.001 vs. placebo). Changes in campesterol/TC at week 2, relative to baseline between placebo and Evolocumab, were all nonsignificant. Evolocumab had a modest effect on markers of cholesterol synthesis. At 2 weeks, changes in desmosterol/TC were 1% for placebo, 7% for Evolocumab 140 mg (nonsignificant vs. placebo), and 15% for Evolocumab 420 mg (P < 0.01 vs. placebo). Changes from baseline in lathosterol/TC at week 2 between placebo and Evolocumab were nonsignificant. These results suggest that Evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-C lowering.