Relationship between alirocumab, PCSK9 and LDL-C levels: results from the odyssey mono phase 3 trial of alirocumab 75 mg every 2 weeks

Farnier, Michel; Kastelein, John J.P.; Roth, Eli M.; Taskinen, M.-R.; Ginsberg, Henry N.; Colhoun, Helen M.; Robinson, J; Merlet, Laurence; Brunet, Aurélie; Pordy, Robert; Baccara‐Dinet, Marie T.

doi:10.1016/j.atherosclerosis.2014.05.070

Cited by 3 publications

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“…Phase II trials demonstrated that as monotherapy, alirocumab can reduce LDL-C as much as intensive statin treatment [ 64 ]. The phase III, double-blind, double-dummy ODYSSEY-MONO trial evaluated the safety and efficacy of alirocumab as monotherapy in comparison with ezetimibe, over 24 weeks in patients with primary hypercholesterolemia and moderate cardiovascular risk, not otherwise receiving statins or other lipid-lowering therapy [ 65 ]. A total of 103 patients with LDL-C 2.6–4.9 mmol L −1 (100–190 mg dL −1 ), and 1–5 % 10-year risk of fatal cardiovascular events (estimated via the Systematic COronary Risk Evaluation [SCORE] tool) were randomised to receive either ezetimibe 10 mg or alirocumab, with the aim to achieve target HDL-C using the minimum effective dose of anti-PCSK9 antibody.…”

Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

PCSK9 inhibitors in the prevention of cardiovascular disease

Latimer

Batty

Neely

et al. 2016

J Thromb Thrombolysis

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Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.Keywords Low-density lipoprotein Á Proprotein convertase subtilisin kexin type 9 (PCSK9) Á Prevention Á Monoclonal antibody Á Evolocumab Á Alirocumab

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Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

PCSK9 inhibitors in the prevention of cardiovascular disease

Latimer

Batty

Neely

et al. 2016

J Thromb Thrombolysis

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“…The dynamics between a single alirocumab 75 mg dose, free PCSK9, and LDL-C observed in this study at each injection site are in agreement with the findings of a single ascending dose study in healthy subjects in which a SC injection of alirocumab into the abdomen resulted in reductions in free PCSK9 levels within 3 days of dosing and peak reductions in LDL-C 8–15 days after dosing 7 , 8 . Additionally, in a Phase 3 monotherapy study, alirocumab 75 mg every 2 weeks produced sustained LDL-C reductions over 12 weeks of treatment (least square mean reduction of 53.2% from baseline at Week 12) 9 , 10 .…”

Section: Discussionmentioning

confidence: 99%

A Randomized Study of the Relative Pharmacokinetics, Pharmacodynamics, and Safety of Alirocumab, a Fully Human Monoclonal Antibody to PCSK9, After Single Subcutaneous Administration at Three Different Injection Sites in Healthy Subjects

Lunven

Paehler

Poitiers

et al. 2014

Cardiovascular Therapeutics

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AimsWe investigated the relative pharmacokinetics, pharmacodynamics, and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab following injection at three different sites.MethodsSixty healthy subjects (39 male, 21 female; age 20–45 years) were randomized to receive a single subcutaneous injection of alirocumab 75 mg via 1-mL prefilled pen into the abdomen, upper arm, or thigh (NCT01785329). Subjects were followed for 85 days ± 2 days following study drug administration. Pharmacokinetic (PK) parameters for the systemic exposure of alirocumab were calculated, and levels of free PCSK9 were assessed. Percentage changes from baseline in LDL-C were compared between injection site groups using linear mixed-effects models.ResultsAlirocumab concentration–time profiles were similar, and free PCSK9 levels were reduced to approximately zero between Day 3 and Day 4 postinjection in all groups. LDL-C levels reached nadir on Day 15 postinjection in all groups with mean percentage reductions of 48.4% (abdomen), 39.5% (upper arm), and 45.6% (thigh) at this time point. A similar effect on LDL-C levels was seen across the entire time course of the study at all three injection sites. Treatment-emergent adverse events were experienced by 8/20 (abdomen), 11/20 (upper arm), and 13/20 (thigh) subjects. There were 2 mild/transient injection site reactions. There were no serious adverse events.DiscussionA single subcutaneous administration of alirocumab 75 mg via prefilled pen was well tolerated with similar pharmacokinetics and pharmacodynamics when injected into the abdomen, upper arm, or thigh.ConclusionThese results suggest that alirocumab can be interchangeably injected in the abdomen, upper arm, or thigh.

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“…A lower dose of alirocumab, 75 mg, was able to lower LDL-C to \1.81 mmol/L (70 mg/dL), 47.2 % lower than baseline, and was comparable to, or better than, ezetimibe [196]. Patients with higher baseline values of LDL-C required uptitration to the higher, 150 mg dose of alirocumab [197].…”

Section: Monoclonal Antibodies To Proproteinmentioning

confidence: 92%

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs

Kones¹,

Rumana²

2015

Drugs

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Since their introduction, statin (HMG-CoA reductase inhibitor) drugs have advanced the practice of cardiology to unparalleled levels. Even so, coronary heart disease (CHD) still remains the leading cause of death in developed countries, and is predicted to soon dominate the causes of global mortality and disability as well. The currently available non-statin drugs have had limited success in reversing the burden of heart disease, but new information suggests they have roles in sizeable subpopulations of those affected. In this review, the status of approved non-statin drugs and the significant potential of newer drugs are discussed. Several different ways to raise plasma high-density lipoprotein (HDL) cholesterol (HDL-C) levels have been proposed, but disappointments are now in large part attributed to a preoccupation with HDL quantity, rather than quality, which is more important in cardiovascular (CV) protection. Niacin, an old drug with many antiatherogenic properties, was re-evaluated in two imperfect randomized controlled trials (RCTs), and failed to demonstrate clear effectiveness or safety. Fibrates, also with an attractive antiatherosclerotic profile and classically used for hypertriglyceridemia, lacks evidence-based proof of efficacy, save for a subgroup of diabetic patients with atherogenic dyslipidemia. Omega-3 fatty acids fall into this category as well, even with an impressive epidemiological evidence base. Omega-3 research has been plagued with methodological difficulties yielding tepid, uncertain, and conflicting results; well-designed studies over longer periods of time are needed. Addition of ezetimibe to statin therapy has now been shown to decrease levels of low-density lipoprotein (LDL) cholesterol (LDL-C), accompanied by a modest decrease in the number of CV events, though without any improvement in CV mortality. Importantly, the latest data provide crucial evidence that LDL lowering is central to the management of CV disease. Of drugs that inhibit cholesteryl ester transfer protein (CETP) tested thus far, two have failed and two remain under investigation and may yet prove to be valuable therapeutic agents. Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, now in phase III trials, lower LDL-C by over 50 % and are most promising. These drugs offer new ability to lower LDL-C in patients in whom statin drug use is, for one reason or another, limited or insufficient. Mipomersen and lomitapide have been approved for use in patients with familial hypercholesterolemia, a more common disease than appreciated. Anti-inflammatory drugs are finally receiving due attention in trials to elucidate potential clinical usefulness. All told, even though statins remain the standard of care, non-statin drugs are poised to assume a new, vital role in managing dyslipidemia.

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Relationship between alirocumab, PCSK9 and LDL-C levels: results from the odyssey mono phase 3 trial of alirocumab 75 mg every 2 weeks

Cited by 3 publications

References 0 publications

PCSK9 inhibitors in the prevention of cardiovascular disease

PCSK9 inhibitors in the prevention of cardiovascular disease

A Randomized Study of the Relative Pharmacokinetics, Pharmacodynamics, and Safety of Alirocumab, a Fully Human Monoclonal Antibody to PCSK9, After Single Subcutaneous Administration at Three Different Injection Sites in Healthy Subjects

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs

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