Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

Barter, Philip J.; Tabet, Fatiha; Rye, Kerry‐Anne

doi:10.1194/jlr.c063768

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…In our study, the extent of non-HDL-C reduction for the combination of atorvastatin and DS-9001a was more pronounced than the combination of atorvastatin and anacetrapib. In clinical trials, anti-PCSK9 antibodies typically reduce the LDL-C level by approximately 60%, and anacetrapib reduces LDL-C by about 45% (Barter et al, 2015). Thus, the pharmacologic effect shown in our data were almost consistent with the clinical data.…”

Section: Discussionsupporting

confidence: 85%

Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain–Fused Anticalin Protein

Masuda

Yamaguchi

Suzuki

et al. 2018

J Pharmacol Exp Ther

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Since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces the risk of cardiovascular events in a clinical context, PCSK9 inhibition is thought to be an attractive therapy for dyslipidemia. In the present study, we created a novel small biologic alternative to PCSK9 antibodies called DS-9001a, comprising an albumin binding domain fused to an artificial lipocalin mutein (ABD-fused Anticalin protein), which can be produced by a microbial production system. DS-9001a strongly interfered with PCSK9 binding to low-density-lipoprotein receptor (LDL-R) and PCSK9-mediated degradation of LDL-R. In cynomolgus monkeys, single DS-9001a administration significantly reduced the serum LDL-C level up to 21 days (62.4% reduction at the maximum). Moreover, DS-9001a reduced plasma non-high-density-lipoprotein cholesterol and oxidized LDL levels, and their further reductions were observed when atorvastatin and DS-9001a were administered in combination in human cholesteryl ester transfer protein/ApoB double transgenic mice. Additionally, their reductions on the combination of atorvastatin and DS-9001a were more pronounced than those on the combination of atorvastatin and anacetrapib. Besides its favorable pharmacologic profile, DS-9001a has a lower molecular weight (about 22 kDa), yielding a high stoichiometric drug concentration that might result in a smaller administration volume than that in existing antibody therapy. Since bacterial production systems are viewed as more suited to mass production at low cost, DS-9001a may provide a new therapeutic option to treat patients with dyslipidemia. In addition, considering the growing demand for antibody-like drugs, ABD-fused Anticalin proteins could represent a promising new class of small biologic molecules.

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Section: Discussionsupporting

confidence: 85%

Generation and Characterization of a Novel Small Biologic Alternative to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Antibodies, DS-9001a, Albumin Binding Domain–Fused Anticalin Protein

Masuda

Yamaguchi

Suzuki

et al. 2018

J Pharmacol Exp Ther

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“…Beyond the prominent increase of HDL cholesterol, a marked decrease of LDL cholesterol was observed in these trials. Even though the underlying mechanisms of this increase in LDL cholesterol are not clear, kinetic data of lipid metabolism during anacetrapib administration in humans points to the following potential mechanisms ( Figure 1 ) [ 12 , 13 , 14 , 15 ]:…”

Section: Main Results Of the Reveal Trialmentioning

confidence: 99%

“…(2) Decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) levels (a CETP-independent mechanism) leading to decreased LDL receptors’ degradation and, therefore, increased LDL receptors’ activity and LDL particles’ catabolism [ 14 , 16 ].…”

Section: Main Results Of the Reveal Trialmentioning

confidence: 99%

Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?

2017

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Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established.

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