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
Gregory G. SchwartzLaurence BessacLisa G. BerdanDeepak L. BhattVera BittnerRafael DíazShaun G. GoodmanCorinne HanotinRobert A. HarringtonJ. Wouter JukemaKenneth W. MahaffeyAngèle MoryusefRobert PordyMatthew T. RoeTyrus RorickWilliam J. SasielaCheerag ShirodariaMichael SzarekJean‐François TambyPierluigi TricociHarvey D. WhiteAndreas M. ZeiherPhilippe Gabríel Steg
398
Citation
29
Reference
10
Related Paper
Citation Trend
Abstract:
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.This Phase 3 study will randomize 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 infarction 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 infarction, 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.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.Keywords:
Alirocumab
PCSK9
Alirocumab
PCSK9
Evolocumab
Hyperlipidemia
Proprotein Convertases
Kexin
Cite
Citations (0)
Alirocumab
Evolocumab
PCSK9
Kexin
Proprotein Convertases
Cite
Citations (10)
Alirocumab
PCSK9
Kexin
Proprotein Convertases
Subtilisin
Cite
Citations (1)
Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations.Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships.The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation.The maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150 mg every 2 weeks (Q2W) or 300 mg every 4 weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.
Alirocumab
PCSK9
Pharmacodynamics
Kexin
Cite
Citations (2)
The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomes for intracellular degradation. This results in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol (LDL-C) plasma levels. Since 2003, when the role of PCSK9 in LDL-C metabolism was discovered, there have been major efforts to develop efficient and safe methods to inhibit it. Amongst those, monoclonal antibodies against PCSK9 are the furthest in development, with multiple phase 3 trials already published and with cardiovascular endpoint trials currently underway. Two fully human monoclonal antibodies, evolocumab (AMG 145) and alirocumab (REGN727/SAR236553), have been extensively studied in a wide range of subjects, such as those with statin intolerance, as an add-on to statin therapy, as a monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies result in a consistent and robust decrease in LDL-C plasma levels ranging from 40% to 70%, either on top of statins or as a monotherapy. If the safety data from the on-going phase 3 trials remain as reassuring as the data available till now, PCSK9 antibodies will offer a novel, powerful therapeutic option to decrease LDL-C plasma levels and, hopefully, cardiovascular risk.
PCSK9
Alirocumab
Evolocumab
Kexin
Proprotein Convertases
Cite
Citations (27)
•Changes in proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein cholesterol (LDL-C) assessed after administration of alirocumab 75 or 150 mg every 2 weeks.•Patients on background statin had higher baseline levels of PCSK9 vs no statin.•Alirocumab resulted in reduced PCSK9 with corresponding LDL-C reduction by week 4.•Dose increase from 75 to 150 mg every 2 weeks further reduced PCSK9 and LDL-C.•Results were consistent with the known mechanism of PCSK9 inhibition. BackgroundAlirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9).ObjectiveChanges in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W).MethodsData were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W.ResultsPatients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction.ConclusionsAlirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.
Alirocumab
PCSK9
Kexin
Evolocumab
Proprotein Convertases
Low-density lipoprotein
Cite
Citations (16)
The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.
Alirocumab
PCSK9
Evolocumab
Cite
Citations (3)
FDA on July 24 approved the marketing of alirocumab injection, or Praluent, as an add-on cholesterol-lowering treatment for certain adults whose plasma low-density lipoprotein cholesterol (LDL-C) concentration should be even lower. The monoclonal antibody, the agency said, is the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor approved in this country for use in lowering LDL-C. Alirocumab lowers the plasma LDL-C concentration by interfering with PCSK9’s interference in the liver’s normal work. According to the labeling for alirocumab, PCSK9 binds to hepatocytes’ low-density lipoprotein receptors, which normally would bind LDL-C and serve as the primary cell-surface receptor for removing that type of cholesterol from the bloodstream. By decreasing the amount of PCSK9 that binds to low-density lipoprotein receptors, alirocumab keeps those receptors available to bind LDL-C. The PCSK9 inhibitor, its labeling states, is for use in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who are already adhering to dietary measures and taking as high a statin dosage as can be tolerated.
Alirocumab
PCSK9
Kexin
Evolocumab
Proprotein Convertases
Low-density lipoprotein
Cite
Citations (2)
PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: does reality match the hype?
Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12–26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies.
PCSK9
Alirocumab
Evolocumab
Surrogate endpoint
Kexin
Cite
Citations (30)
The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomal degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation which in turn leads to an increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDLC metabolism has been discovered in 2003 there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human anti-PCSK9 antibodies alirocumab and evolocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and have been shown to decrease LDL-C overall by ~50-70%. Rates of achieving LDL-C goals, depending on individual risk, are up to 87 -98% of treated subjects. Multiple phase III studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016 and 2017 for evolocumab and alirocumab, respectively. In 2015 both alirocumab and evolocumab were approved for the treatment of hypercholesterolemia in the European Union and in the US. Preliminary data show an improvement in cardiovascular morbidity and mortality by ~50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.
Alirocumab
Evolocumab
PCSK9
Kexin
Dyslipidemia
Cite
Citations (7)