New developments in atherosclerosis: clinical potential of PCSK9 inhibition

Ilaria Giunzioni, Hagai Tavori Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA Abstract: Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted 692-amino acid protein that binds surface low-density lipoprotein (LDL) receptor (LDLR) and targets it toward lysosomal degradation. As a consequence, the number of LDLRs at the cell surface is decreased, and LDL-cholesterol (LDL-C) clearance is reduced, a phenomenon that is magnified by gain-of-function mutations of PCSK9. In contrast, loss-of-function mutations of PCSK9 result in increased surface LDLR and improved LDL-C clearance. This provides the rationale for targeting PCSK9 in hypercholesterolemic subjects as a means to lower LDL-C levels. Monoclonal antibodies (mAbs) against PCSK9 that block its interaction with the LDLR have been developed in the past decade. Two companies have recently received the approval for their anti-PCSK9 mAbs by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Regeneron/Sanofi, with alirocumab (commercial name – PRALUENT®) and, Amgen with evolocumab (commercial name – Repatha™). The introduction of anti-PCSK9 mAbs will provide an alternative therapeutic strategy to address many of the unmet needs of current lipid-lowering therapies, such as inability to achieve goal LDL-C level, or intolerance and aversion to statins. This review will focus on the kinetics of PCSK9, pharmacokinetics and pharmacodynamics of anti-PCSK9 mAbs, and recent data linking PCSK9 and anti-PCSK9 mAbs to cardiovascular events. Moreover, it will highlight the unanswered questions that still need to be addressed in order to understand the physiologic function, kinetics, and dynamics of PCSK9. Keywords: PCSK9, LDLR, monoclonal antibodies, pharmacokinetics, cardiovascular ris

Super-Spreaders Out, Super-Spreading In: The Effects of Infectiousness Heterogeneity and Lockdowns on Herd Immunity

Recently, [8] has proposed that heterogeneity of infectiousness (and susceptibility) across individuals in infectious diseases, plays a major role in affecting the Herd Immunity Threshold (HIT). Such heterogeneity has been observed in COVID-19 and is recognized as overdispersion (or "super-spreading"). The model of [8] suggests that super-spreaders contribute significantly to the effective reproduction factor, R, and that they are likely to get infected and immune early in the process. Consequently, under R_0 = 3 (attributed to COVID-19), the Herd Immunity Threshold (HIT) is as low as 5%, in contrast to 67% according to the traditional models [1, 2, 4, 10]. This work follows up on [8] and proposes that heterogeneity of infectiousness (susceptibility) has two "faces" whose mix affects dramatically the HIT: (1) Personal-Trait-, and (2) Event-Based- Infectiousness (Susceptibility). The former is a personal trait of specific individuals (super-spreaders) and is nullified once those individuals are immune (as in [8]). The latter is event-based (e.g cultural super-spreading events) and remains effective throughout the process, even after the super-spreaders immune. We extend [8]'s model to account for these two factors, analyze it and conclude that the HIT is very sensitive to the mix between (1) and (2), and under R_0 = 3 it can vary between 5% and 67%. Preliminary data from COVID-19 suggests that herd immunity is not reached at 5%. We address operational aspects and analyze the effects of lockdown strategies on the spread of a disease. We find that herd immunity (and HIT) is very sensitive to the lockdown type. While some lockdowns affect positively the disease blocking and increase herd immunity, others have adverse effects and reduce the herd immunity.Comment: 25 pages, 6 figure

The biology of PCSK9 inhibition: some unanswered questions

International audienc