Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials

Stein, Evan A.; Giugliano, Robert P.; Koren, Michael; Raal, Frederick J.; Röth, Erzsébet; Weiss, Robert; Sullivan, David; Wasserman, Scott M.; Somaratne, Ransi; Kim, J. B.; Yang, Jingyuan; Liu, T.; Albizem, Moetaz; Scott, Robert C.; Sabatine, Marc S.

doi:10.1093/eurheartj/ehu085

Cited by 120 publications

(64 citation statements)

References 25 publications

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“…This observation confirms previous investigations that have shown that PCSK9 inhibitors, but not statins, reduce levels of this difficult-to-treat lipoprotein. Our results are also consistent with those recently reported for evolocumab, in which a pooled analysis demonstrated LDL-C reduction and favorable changes in atherogenic and anti-atherogenic lipoproteins across various doses and dosing frequencies [15].…”

Section: Discussionsupporting

confidence: 93%

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Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Koren

Roth

McKenney

et al. 2015

Postgraduate Medicine

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Background. Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/ kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. Methods. We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. Results. Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. Conclusion. At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.

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Section: Discussionsupporting

confidence: 93%

“…ADAs occurred infrequently and did not appear to impact the pharmacokinetics, pharmacodynamics, or safety profile of alirocumab. Although the number of patients in our study sample was small, our findings are consistent with those recently reported for evolocumab [15].…”

Section: Discussionsupporting

confidence: 92%

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Koren

Roth

McKenney

et al. 2015

Postgraduate Medicine

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“…Recent data has demonstrated that Lp(a) can be signifi cantly lowered by 20-40% with ASOs to apoB ( 35 ), monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (46)(47)(48), and cholesterol ester transfer protein inhibitors ( 49,50 ). However, in patients at or above the 80th percentile, corresponding to ‫ف‬ 50 mg/dl plasma Lp(a) concentrations, much greater reduction than is currently achieved with these indirect therapeutic agents would be required to signifi cantly reduce CVD risk, which is thought to occur at levels which exceed [25][26][27][28][29][30] or OxPL-apoB concentrations, consistent with the independence of lowering of Lp(a) and OxPL-apoB on isoform size ( Fig.…”

Section: Alternative Therapies To Lower Lp(a)mentioning

confidence: 99%

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Graham

Viney

Crooke

et al. 2016

Journal of Lipid Research

122

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“…Previous studies with evolocumab in patients with heFH on stable lipid-lowering therapy have shown additional reductions in LDL-C of ~60% [15,28,35,36]. In the RUTHERFORD-2 trial [37] study, the relationship between LDL-C response to evolocumab and genotype was also investigated.…”

Section: The Rutherford-2 Trial (The Reduction Of Ldl-c With Pcsk9 Inmentioning

confidence: 99%

PCSK9 antibodies for the treatment of hypercholesterolemia

Gouni‐Berthold¹

2015

EJEA

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Abstract: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.

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Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials

Abstract: In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favourable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.

Cited by 120 publications

References 25 publications

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

PCSK9 antibodies for the treatment of hypercholesterolemia

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