PCSK9 inhibitor valuation: A science‐based review of the two recent models

Baum, Sharon; Cannon, Christopher P.

doi:10.1002/clc.22924

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…Moreover, in view of the delayed onset of action of statins and the early risk of recurrent events following an ACS, early initiation of PCSK9‐inhibitors (ie, rapidly acting, highly potent LDL‐lowering agents) may be of clinical value in this setting. The EVOPACS trial will provide new insights into the safety and efficacy of evolocumab in the acute setting of ACS, and thus improve our understanding of the potential role of PCSK9 inhibition in the management of these patients . In addition, the study will explore mechanistic evidence regarding potential beneficial effects of PCSK9 inhibition beyond the primary impact on LDL‐C in the ACS setting.…”

Section: Resultsmentioning

confidence: 99%

“…The EVOPACS trial will provide new insights into the safety and efficacy of evolocumab in the acute setting of ACS, and thus improve our understanding of the potential role of PCSK9 inhibition in the management of these patients. 43 In addition, the study will explore mechanistic evidence regarding potential beneficial effects of PCSK9 inhibition beyond the primary impact on LDL-C in the ACS setting.…”

Section: Discussionmentioning

confidence: 99%

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Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Koskinas

Windecker

Buhayer³

et al. 2018

Clinical Cardiology

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Statins lower low‐density lipoprotein cholesterol (LDL‐C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL‐C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9)‐inhibitor resulting in rapid, marked LDL‐C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL‐cholesterol levels in patients with ACS (EVOPACS), a phase‐3, multicenter, randomized, double‐blind, placebo‐controlled trial to assess the feasibility, safety, and LDL‐C‐lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL‐C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL‐C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C‐reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast‐induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub‐study will investigate the change from baseline in the lipid core burden index in non‐culprit lesions, as assessed by serial near‐infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Koskinas

Windecker

Buhayer³

et al. 2018

Clinical Cardiology

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“…In addition, another drug (inclisiran) that uses a gene silencing approach that specifically destroys PCSK9 mRNA and inhibits the synthesis of PCSK9 protein has been given an approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) to be used in European Union in December 2020 [ 34 , 35 , 36 ]. However, these drugs are biotechnology-based and the cost of prescribing these drugs to patients are extremely high [ 15 , 37 ], therefore, not economical to prescribe to all patients suffering from hypercholesterolemia as compared to statin, a natural product-based, which is more economical [ 16 ]. Thus, natural product-based drugs still offer a cost effective and an economic value for patients in the treatment of various illnesses.…”

Section: Discussionmentioning

confidence: 99%

Acanthaster planci Inhibits PCSK9 and Lowers Cholesterol Levels in Rats

et al. 2021

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Atherosclerosis is the main cause of cardiovascular diseases which in turn, lead to the highest number of mortalities globally. This pathophysiological condition is developed due to a constant elevated level of plasma cholesterols. Statin is currently the widely used treatment in reducing the level of cholesterols, however, it may cause adverse side effects. Therefore, there is an urgent need to search for new alternative treatment. PCSK9 is an enzyme responsible in directing LDL-receptor (LDL-R)/LDL-cholesterols (LDL-C) complex to lysosomal degradation, preventing the receptor from recycling back to the surface of liver cells. Therefore, PCSK9 offers a potential target to search for small molecule inhibitors which inhibit the function of this enzyme. In this study, a marine invertebrate Acanthaster planci, was used to investigate its potential in inhibiting PCSK9 and lowering the levels of cholesterols. Cytotoxicity activity of A. planci on human liver HepG2 cells was carried out using the MTS assay. It was found that methanolic extract and fractions did not exhibit cytotoxicity effect on HepG2 cell line with IC50 values of more than 30 µg/mL. A compound deoxythymidine also did not exert any cytotoxicity activity with IC50 value of more than 4 µg/mL. Transient transfection and luciferase assay were conducted to determine the effects of A. planci on the transcriptional activity of PCSK9 promoter. Methanolic extract and Fraction 2 (EF2) produced the lowest reduction in PCSK9 promoter activity to 70 and 20% of control at 12.5 and 6.25 μg/mL, respectively. In addition, deoxythymidine also decreased PCSK9 promoter activity to the lowest level of 60% control at 3.13 μM. An in vivo study using Sprague Dawley rats demonstrated that 50 and 100 mg/kg of A. planci methanolic extract reduced the total cholesterols and LDL-C levels to almost similar levels of untreated controls. The level of serum glutamate oxalate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) showed that the administration of the extract did not produce any toxicity effect and cause any damage to rat liver. The results strongly indicate that A. planci produced a significant inhibitory activity on PCSK9 gene expression in HepG2 cells which may be responsible for inducing the uptake of cholesterols by liver, thus, reducing the circulating levels of total cholesterols and LDL-C. Interestingly, A. planci also did show any adverse hepato-cytotoxicity and toxic effects on liver. Thus, this study strongly suggests that A. planci has a vast potential to be further developed as a new class of therapeutic agent in lowering the blood cholesterols and reducing the progression of atherosclerosis.

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“…[172] The costeffectiveness ratio may be acceptable for patients currently with familial hypercholesterolemia, but for patients with conventional vascular disease, these antibodies are not so cost effective. [173,174] The appeal of small-molecule inhibitors of PCSK9 over antibodies is rather clear, because you can achieve the same goal with only hundreds of dollars, let alone the potential for delivering the inhibitors via oral pills instead of injectable antibodies. In addition, despite antibodies perturbing the binding of PCSK9 to LDLR, by their nature, anti-PCSK9 mAbs are unable to modulate PCSK9 and LDL-C levels in an intermediate fashion, while the inhibition of PCSK9 synthesis by a small molecule could provide additional options for patients and physicians by offering different levels of inhibition to balance safety and efficacy.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Small molecules as inhibitors of PCSK9: Current status and future challenges

Luo

Zhu

et al. 2019

European Journal of Medicinal Chemistry

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed.

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PCSK9 inhibitor valuation: A science‐based review of the two recent models

Cited by 6 publications

References 42 publications

Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Acanthaster planci Inhibits PCSK9 and Lowers Cholesterol Levels in Rats

Small molecules as inhibitors of PCSK9: Current status and future challenges

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