Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years

Farnier, Michel; Colhoun, Helen M.; Sasiela, William J.; Edelberg, Jay M.; Asset, Gaëlle; Robinson, Jennifer G.

doi:10.1016/j.jacl.2017.05.016

Cited by 27 publications

(14 citation statements)

References 39 publications

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“…Importantly, an analysis of patient data (n 5 4197) pooled from six ODYSSEY phase 3 trials, which were also included in this analysis, showed that mean overall treatment adherence over at least 1 year was high with alirocumab 75 or 150 mg Q2W and comparable with control (98.0% vs 97.8%). 43 One of the limitations of this post hoc analysis is that although the efficacy of alirocumab in terms of LDL-C reductions in patients according to MI/ischemic stroke history was assessed, it was not prospectively designed to demonstrate a direct effect on CV outcomes. The effect of alirocumab 75/150 mg Q2Won CVevents has been evaluated in the ODYSSEY OUTCOMES study, in which alirocumab reduced MACE, MI, and ischemic stroke, was associated with a lower rate of all-cause death and was generally well tolerated compared with placebo in 18,924 patients with recent acute coronary syndrome on background statin.…”

Section: Discussionmentioning

confidence: 99%

PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

Bruckert¹,

Kereiakes

Koren

et al. 2019

Journal of Clinical Lipidology

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Section: Discussionmentioning

confidence: 99%

PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

Bruckert¹,

Kereiakes

Koren

et al. 2019

Journal of Clinical Lipidology

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“…The clinical relevance of anti-PCSK9 mAbs administered as selfinjection monthly or biweekly 44 may be also related to a higher adherence to treatment compared with a daily orally administered statin. The adherence to statin therapy may be negatively affected by muscle symptoms, 45 often leading to therapy discontinuation and consequent increase of cardiovascular risk.…”

Section: Targeting Pcsk9mentioning

confidence: 99%

Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

Seidah

Prat

Pirillo

et al. 2019

Cardiovascular Research

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Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2–4 weeks, they trigger a ∼60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in ∼50–60% LDL-C lowering that lasts up to 6 months (Phases II–III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.

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“…The dosing frequency is low compared with other injectable treatments, such as insulin therapy. At the current dosing frequency, a high level of adherence over at least one year was reported for the self-injected anti-PCSK9 MAbs in a pooled analysis of six clinical trials of alirocumab (58). However, the use of injectable PCSK9 agent for essentially asymptomatic patients has several considerations; firstly maintaining the recommended schedule of injections over the long-term, and adequate refrigeration are required.…”

Section: Pcsk9 As a Promising Therapeutic Targetmentioning

confidence: 99%

Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries

Nishikido

Ray

2019

Front. Cardiovasc. Med.

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Low-density lipoprotein (LDL) is one of the principal risk factors for atherosclerosis. Circulating LDL particles can penetrate into the sub-endothelial space of arterial walls. These particles undergo oxidation and promote an inflammatory response, resulting in injury to the vascular endothelial wall. Persistent elevation of LDL-cholesterol (LDL-C) is linked to the progression of fatty streaks to lipid-rich plaque and thus atherosclerosis. LDL-C is a causal factor for atherosclerotic cardiovascular disease and lowering it is beneficial across a range of conditions associated with high risk of cardiovascular events. Therefore, all guidelines-recommended initiations of statin therapy for patients at high cardiovascular risk is irrespective of LDL-C. In addition, intensive LDL-C lowering therapy with statins has been demonstrated to result in a greater reduction of cardiovascular event risk in large clinical trials. However, many high-risk patients receiving statins fail to achieve the guideline-recommended reduction in LDL-C levels in routine clinical practice. Moreover, low levels of adherence and often high rates of discontinuation demand the need for further therapies. Ezetimibe has typically been used as a complement to statins when further LDL-C reduction is required. More recently, proprotein convertase subtilisin kexin 9 (PCSK9) has emerged as a novel therapeutic target for lowering LDL-C levels, with PCSK9 inhibitors offering greater reductions than feasible through the addition of ezetimibe. PCSK9 monoclonal antibodies have been shown to not only considerably lower LDL-C levels but also cardiovascular events. However, PCSK9 monoclonal antibodies require once- or twice-monthly subcutaneous injections. Further, their manufacturing process is expensive, increasing the cost of therapy. Therefore, several non-antibody treatments to inhibit PCSK9 function are being developed as alternative approaches to monoclonal antibodies. These include gene-silencing or editing technologies, such as antisense oligonucleotides, small interfering RNA, and the clustered regularly interspaced short palindromic repeats/Cas9 platform; small-molecule inhibitors; mimetic peptides; adnectins; and vaccination. In this review, we summarize the current knowledge base on the role of PCSK9 in lipid metabolism and an overview of non-antibody approaches for PCSK9 inhibition and their limitations. The subsequent development of alternative approaches to PCSK9 inhibition may give us more affordable and convenient therapeutic options for the management of high-risk patients.

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Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years

Abstract: Alirocumab injections were associated with a high level of adherence over ≥1 year. Infrequent below- or above-planned dosing had minimal impact on LDL-C reductions.

Cited by 27 publications

References 39 publications

PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries

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