An oral antisense oligonucleotide for PCSK9 inhibition

2021 ◽  
Vol 13 (593) ◽  
pp. eabe9117
Author(s):  
Peter Gennemark ◽  
Katrin Walter ◽  
Niclas Clemmensen ◽  
Dinko Rekić ◽  
Catarina A.M. Nilsson ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Antisense Oligonucleotide ◽  
Oral Delivery ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Sodium Caprate ◽  
Subcutaneous Dose

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

Abstract 13307: An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Peter Gennemark ◽  
Katrin Walter ◽  
Niclas Clemmensen ◽  
Dinko Rekic ◽  
Catarina Nilsson ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Antisense Oligonucleotide ◽  
Oral Delivery ◽  
Permeation Enhancers ◽  
Pcsk9 Inhibitors ◽  
Liver Uptake ◽  
Pcsk9 Inhibition ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers

Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation make this ASO highly potent. A single SC dose of 90 mg reduces PCSK9 by >90% in humans with elevated LDL-C (A), and a once monthly SC dose of 25 mg ([20, 30], 90% CI) is predicted to reduce PCKS9 by 80% at steady-state. To investigate the feasibility of oral administration, we developed an oral solid tablet wherein the ASO is co-formulated with a transient permeation enhancer. Repeated oral daily dosing of tablets to dogs resulted in a bioavailability of 7% in the liver (target organ), approximately 5-fold greater than the plasma bioavailability (B). Favourable liver uptake following oral administration is supported by similar bioavailability in plasma and kidney. Since the ASO is not active in rodents or dogs, we used a rat-specific GalNAc- Malat-1 ASO with the same chemistry to confirm target engagement. Intrajejunal administration resulted in ≥78% mRNA knockdown in the liver for single doses of 3-40 mg/kg. A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia.

scholarly journals Naturally Occurring PCSK9 Inhibitors

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1440
Author(s):  
Maria Pia Adorni ◽  
Francesca Zimetti ◽  
Maria Giovanna Lupo ◽  
Massimiliano Ruscica ◽  
Nicola Ferri
Keyword(s):  
Ldl Cholesterol ◽  
Current Knowledge ◽  
Therapeutic Option ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Pcsk9 Inhibitors ◽  
Beneficial Effects ◽  
Naturally Occurring ◽  
Starting Point

Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.

PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1

2019 ◽  
Vol 116 (5) ◽  
pp. 908-915 ◽  
Author(s):  
Zufeng Ding ◽  
Naga Venkata K Pothineni ◽  
Akshay Goel ◽  
Thomas F Lüscher ◽  
Jawahar L Mehta
Keyword(s):  
Inflammatory Cytokines ◽  
Ldl Cholesterol ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Prevention Of Atherosclerosis ◽  
Pro Inflammatory Cytokines

Abstract PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.

scholarly journals Inclisirán as an alternative treatment for Hypercholesterolemia

2021 ◽  
Vol 12 (3) ◽  
pp. 517-521
Author(s):  
Jorge Andrés Ojeda Villota ◽  
Javier Alfredo Pérez Martínez ◽  
Luis Alberto Burgos de Moya ◽  
Rodrigo Alfonso Chavez Vega ◽  
Roxana Rivera Valencia ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Low Density ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Levels ◽  
Lowering Therapy

Hypercholesterolemia (CH) is defined as the elevation of serum cholesterol levels, especially low-density lipoprotein (LDL) cholesterol, which is considered to be one of the most relevant risk factors for triggering cardiovascular disease, for This is vitally important to start treatment, there are several highly useful pharmacological groups for lipid-lowering therapy, among them we highlight the PCSK9 inhibitors, among the molecules that are part of this group we find inclisirán, this being a structure that promises a lot in regarding the management of hypercholesterolemia.

scholarly journals PCSK9 genetic variants and cognitive abilities: a large-scale Mendelian randomization study

2021 ◽  
Vol 17 (1) ◽  
pp. 241-244
Author(s):  
Donald Lyall ◽  
Joey Ward ◽  
Maciej Banach ◽  
George Smith ◽  
Jason Gill ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Cognitive Abilities ◽  
Large Scale ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Continuous Measures ◽  
Rule Out

IntroductionPCSK9 inhibitors lower low-density lipoprotein (LDL) cholesterol and are efficacious at reducing vascular disease, however questions remain about potential effects on cognitive function.MethodsWe examined the association of genetic variants in PCSK9 with continuous measures of cognitive ability in UK Biobank. Six independent polymorphisms in PCSK9 were used in up to 337,348 individuals.ResultsThe PCSK9 allele score was associated with a lower risk of CHD, and weakly with worse log reaction time.ConclusionsWe are unable to rule out meaningful associations of PCSK9 genetic variants with cognition, emphasising the potential need for continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

scholarly journals Update on PCSK9 Inhibitors and New Therapies

2016 ◽  
Vol 12 (01) ◽  
pp. 18
Author(s):  
Evan A Stein ◽  
Frederick J Raal ◽  
◽  
Keyword(s):  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Receptor ◽  
Pcsk9 Inhibitors ◽  
The Us ◽  
Density Lipoprotein Receptor ◽  
Large Phase ◽  
Cutaneous Administration ◽  
Phase Ii And Iii

Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.

Low-density lipoprotein cholesterol lowering for the prevention of cardiovascular outcomes in patients with ischemic stroke

2019 ◽  
Vol 14 (5) ◽  
pp. 476-482 ◽  
Author(s):  
George Ntaios ◽  
Haralampos Milionis
Keyword(s):  
Ischemic Stroke ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Cardiovascular Outcomes ◽  
Stroke Patients ◽  
Pcsk9 Inhibitors ◽  
Cholesterol Levels

Background Low-density lipoprotein (LDL) cholesterol has been long associated with the risk for ischemic stroke, myocardial infarction, and cardiovascular death. For more than a decade, the main pharmacological option to prevent stroke and myocardial infarction through LDL-cholesterol lowering was the use of statins. During the recent years, two novel classes of drugs have proven their efficacy and safety to reduce LDL-cholesterol and prevent cardiovascular events in large, well-conducted randomized controlled trials: ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Aims The present review summarizes the evidence arising from the latest trials of lipid-lowering treatment for cardiovascular outcomes prevention and discusses their implications for secondary prevention strategies in patients with ischemic stroke. Summary of review There is strong evidence which confirms the hypothesis that the lower the LDL-cholesterol, the less frequent the cardiovascular events are and underlines the importance of treating our ischemic stroke patients with intensive statin treatment aiming at low LDL-cholesterol levels. The very low levels of LDL cholesterol seem to be safe, even in the mid/long term but longer follow-up data are needed. Currently there are no tools to reliably predict cardiovascular outcomes in the specific population of ischemic stroke patients. Conclusions Stroke physicians should aim for low LDL-cholesterol levels by intensive statin treatment in all ischemic stroke patients. For those patients who are at the highest risk for recurrent stroke or another cardiovascular event and have unacceptable LDL-cholesterol levels despite intensive statin treatment, PCSK9 inhibitors should be considered.

Moving beyond the “LDL hypothesis”

VASA ◽  
2015 ◽  
Vol 44 (5) ◽  
pp. 333-340 ◽  
Author(s):  
Christian Werner ◽  
Ulrich Laufs
Keyword(s):  
Ldl Cholesterol ◽  
Causal Relation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Clinical Trial Data ◽  
Randomised Clinical Trial ◽  
Trial Data ◽  
Low Density Lipoprotein Cholesterol ◽  
Genetic Studies ◽  
Statin Drug

Abstract. Summary: The term “LDL hypothesis” is frequently used to describe the association of low-density lipoprotein cholesterol (LDL-cholesterol, LDL-C) and cardiovascular (CV) events. Recent data from genetic studies prove a causal relation between serum LDL-C and CV events. These data are in agreement with mechanistic molecular studies and epidemiology. New randomised clinical trial data show that LDL-C lowering with statins and a non-statin drug, ezetimibe, reduces CV events. We therefore believe that the “LDL-hypothesis” has been proven; the term appears to be outdated and should be replaced by “LDL causality”.

Platelet Aggregation and Plasma Lipoproteins in Alcoholics During Alcohol Withdrawal

1986 ◽  
Vol 55 (02) ◽  
pp. 173-177 ◽  
Author(s):  
K Desai ◽  
J S Owen ◽  
D T Wilson ◽  
R A Hutton
Keyword(s):  
Platelet Aggregation ◽  
Alcohol Withdrawal ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Plasma Lipoprotein ◽  
Cholesterol Concentration ◽  
Arachidonic Acid Content ◽  
Low Density

SummaryPlatelet aggregation, platelet lipid composition and plasma lipoprotein concentrations were measured each week in a group of seventeen alcoholics, without overt liver disease, for one month, following acute, total alcohol withdrawal. The platelets were initially hypoaggregable but, within 1-2 weeks of cessation of drinking, they became hyperaggregable and then gradually returned towards normal values. Hyperaggregability could not be explained by increases in either the cholesterol or the arachidonic acid content of the platelets. Plasma very-low-density lipoprotein cholesterol levels remained high throughout the study, but the initially raised levels of high-density lipoprotein (HDL) cholesterol fell by 26%. Low-density lipoprotein (LDL) cholesterol concentration rose by 10% after two weeks of withdrawal but then returned to about the starting level. The resulting changes in the plasma LDL-cholesterol: HDL-cholesterol ratio, which had increased by more than 50% after two weeks of abstinence, essentially paralleled the time course of enhanced platelet reactivity in all but four of the alcoholics. These findings suggest that alterations in plasma lipoprotein concentrations during acute alcohol withdrawal may be a contributory factor to the haemostatic disorders present in such patients.

Sign in / Sign up

Export Citation Format

Share Document