PCSK9 Inhibitors: From Nature’s Lessons to Clinical Utility

Raal, Frederick J.; Chilton, Robert; Ranjith, Naresh; Rambiritch, Virendra; Leisegang, Rory; Ebrahim, Iftikhar O; Tonder, André van; Shunmoogam, Nelusha; Bouharati, Célia; Musa, Moji G.; Karamchand, Sumanth; Naidoo, Poobalan; Blom, Dirk

doi:10.2174/1871530320666200213114138

Cited by 6 publications

(6 citation statements)

References 70 publications

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“…Inhibition of circulating PCSK9 by use of monoclonal antibodies (mAbs) reduces LDL cholesterol and demonstrated an outcome benefit in patients with cardiovascular disease (4)(5)(6). In addition, a gene silencing therapeutic approach to inhibit PCSK9 mRNA by small interfering RNA (siRNA) has recently been filed for marketing approval and showed substantial lowering of plasma LDL cholesterol (7)(8)(9)). Yet, these current therapeutic PCSK9 inhibitors require administration by injection (10).…”

Section: Introductionmentioning

confidence: 99%

An oral antisense oligonucleotide for PCSK9 inhibition

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

An oral antisense oligonucleotide for PCSK9 inhibition

et al. 2021

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“…PCSK9 also binds to LDLR; however, it prevents recycling of LDLR to the plasma membrane and directs it instead to the lysosome for degradation, whereby resulting in higher levels of extracellular and circulating LDL cholesterol. Because of this, PCSK9 inhibitors have gained significant attention in recent years as LDL-lowering drugs [83, 84]. Moreover, it has been shown that loss-of-function mutations in the PCSK9 gene result in lower fasting glycemia and LDL, suggesting that elevated PCSK9 could have the opposite effect [85]; although, we did not find significant changes in the HDL/LDL composition in our cohort, which was likely due to the current small sample size.…”

Section: Discussionmentioning

confidence: 99%

A Composite Biomarker Signature of Type 1 Diabetes Risk Identified via Augmentation of Parallel Multi-Omics Data from a Small Cohort

Alcazar,

Chuang,

Ren

et al. 2024

Preprint

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(1) Background: Biomarkers of early pathogenesis of type 1 diabetes (T1D) are crucial to enable effective prevention measures in at-risk populations before significant damage occurs to their insulin producing beta-cell mass. We recently introduced the concept of integrated parallel multi-omics and employed a novel data augmentation approach which identified promising candidate biomarkers from a small cohort of high-risk T1D subjects. We now validate selected biomarkers to generate a potential composite signature of T1D risk; (2) Methods: Twelve candidate biomarkers, which were identified in the augmented data and selected based on their fold-change relative to healthy controls and cross-reference to proteomics data previously obtained in the expansive TEDDY and DAISY cohorts, were measured in the original samples by ELISA; (3) Results: All 12 biomarkers had established connections with lipid/lipoprotein metabolism, immune function, inflammation, and diabetes, but only 7 were found to be markedly changed in the high-risk subjects compared to the healthy controls: ApoC1 and PON1 were reduced while CETP, CD36, FGFR1, IGHM, PCSK9, SOD1, and VCAM1 were elevated; (4) Conclusions: Results further highlight the promise of our data augmentation approach in unmasking important patterns and pathologically significant features in parallel multi-omics datasets obtained from small sample cohorts to facilitate the identification of promising candidate T1D biomarkers for downstream validation. They also support the potential utility of a composite biomarker signature of T1D risk characterized by the changes in the above markers.

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“…Other therapies, including ezetimibe, fibrates, PCSK9 inhibitors, lomitapide, and mipomersen, may be required when statins that are administered at the highest tolerated dose in combination with other medications do not achieve target LDL cholesterol levels 80) . Pasta et al 81) and Raal et al 82) have recently published reviews on the role of PCSK9 inhibitors in the management of hypercholesterolemia. Table 6 provides a summary of findings from clinical trials and meta-analyses for PCSK9 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region

Kalra

Chen

Deerochanawong

et al. 2021

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/ kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.(LDL) receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) cause FH. FH poses a major threat to public health because affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) 1) . Untreated individuals with homozygous

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PCSK9 Inhibitors: From Nature’s Lessons to Clinical Utility

Cited by 6 publications

References 70 publications

An oral antisense oligonucleotide for PCSK9 inhibition

An oral antisense oligonucleotide for PCSK9 inhibition

A Composite Biomarker Signature of Type 1 Diabetes Risk Identified via Augmentation of Parallel Multi-Omics Data from a Small Cohort

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region

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