Curr Atheroscler Rep. 2015 Apr;17(4):499. doi: 10.1007/s11883-015-0499-4.
Targeting PCSK9 for therapeutic gains.
Shapiro MD1, Fazio S, Tavori H.
The Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, USA.
Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both hypercholesterolemia and low cholesterol syndromes, a rich literature has developed describing its unique physiology and the impact of antagonism of this molecule on cholesterol metabolism for therapeutic purposes. Indeed, the PCSK9 story is unfolding rapidly, with many answers and more questions. This review summarizes the most recent data from phase II/III clinical trials of PCSK9 inhibition with the three leading antibodies, highlights the clinical significance of the ongoing studies, and suggests future areas of investigation based on recent basic science discoveries on the physiology of PCSK9.
With regard to Lp(a) levels, Gaudet et al, assessed the impact of alirocumab 150 mg Q2W in pooled data from 3 double-blind, randomized, placebo-controlled, phase II trials []. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (−30.3% vs. −0.3%, p<0.0001). Median percentage Lp(a) reductions in the alirocumab group were of similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Similarly, Raal et al, performed a pooled analysis of 1,359 patients in 4 phase II trials with evolocumab to assess the effects on Lp(a) levels. Evolocumab treatment for 12 weeks resulted in significant (p<0.001) mean dose-related reductions in Lp(a) compared to control: 29.5% (23.3% – 35.7%) and 24.5% (20.4% – 28.7%) with 140 mg and 420 mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect []. Given the consistency and similar magnitude of reduction of Lp(a) lowering effect, this finding is likely to be a class effect. The underlying mechanism of Lp(a) reduction is incompletely understood, since Lp(a) is assembled extracellularly and is not cleared by LDLR, and remains a major unanswered question in the field. Interestingly, reduction of Lp(a) was observed in all clinical trial using mAbs against PCSK9 but not in the single trial using RNAi (which reduces production of PCSK9), suggesting that this effect is specific to the inhibition of circulating PCSK9 action or to the binding of antibodies to the PCSK9 molecule []. Since PCSK9 physically interacts with LDL (but not with VLDL) particles [–], it can be assumed that PCSK9 also interacts with Lp(a). Thus, the injection of anti-PCSK9 mAbs may lead to the formation of immune complexes (mAb-PCSK9-Lp(a) and mAb-PCSK9-LDL) that can be cleared either via target-specific pathways or by the reticulo-endothelial system. A schematic illustration of this proposed mechanism for antibody-mediated lipoprotein clearance is shown in . Clearance of these immune complexes may explain that effect of the mAb on Lp(a) reduction. Alternatively, the reduction in Lp(a) levels may be mediated by reduced apoB synthesis, as was recently shown in clinical data using the apoB synthesis inhibitor mipomersen []. Regardless, reduction of elevated Lp(a) levels in high-risk individuals represents an unmet clinical need and this application of PCSK9 inhibitors needs to be addressed mechanistically in human studies.
Targeting PCSK9 for therapeutic gains
Curr Atheroscler Rep. ;17(4):499-499.
Antibodies, Monoclonal/therapeutic use*
Antibodies, Monoclonal, Humanized/therapeutic use*
Anticholesteremic Agents/therapeutic use*
Cholesterol, LDL/metabolism
Dyslipidemias/drug therapy
Dyslipidemias/metabolism
Hypercholesterolemia/drug therapy*
Hypercholesterolemia/metabolism
Molecular Targeted Therapy
Proprotein Convertase 9
Proprotein Convertases/antagonists & inhibitors*
Serine Endopeptidases
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Anticholesteremic Agents
Cholesterol, LDL
bococizumab
PCSK9 protein, human
Proprotein Convertases
R01 HL106845/HL/NHLBI NIH HHS/United States
R01-HL106845/HL/NHLBI NIH HHS/United States
Cholesterol Levels: What You Need to Know - MedlinePlus Health Information
How to Lower Cholesterol - MedlinePlus Health Information
Cholesterol - MedlinePlus Health Information