In Vitro Demonstration of Direct Platelet-Related Effects of PCSK9 Enzyme

NCT06675994 | Not Yet Recruiting FDA Drug

• 1 other identifier: 2253810
• Study Type: observational
• Target: 80
• Locations: 0 countries
• Sites: N/A

Brief Summary

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and therapeutic target for hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Furthermore, research from in-vitro and in-vivo animal models suggest that the inhibition of PCSK9 expression may suppress platelet activation, and systemic inflammation thereby reducing thrombotic risk. Taken together, these data support the lower rates of myocardial infarction, stroke, and coronary revascularization in subjects with increased CVD risk in clinical trials with alirocumab (Praluent) and evolocumab (Repatha) as compared to placebo. The main aim of this single center, exploratory in-vitro evaluation is to investigate the direct role of PCSK9 on platelet activation and aggregation using blood collected from a diverse population of antiplatelet naïve healthy volunteers (n=40) and subjects with CVD risk factors (n=40) between the 18-50 years of age. All procedures including consenting, collection of clinical data, and lab processing will occur at the Sinai Center for Thrombosis Research. The results of this study will provide a better understanding of cardioprotective effects of PCSK9 inhibition beyond lipid lowering.

Conditions

Healthy; Hypercholesterolemia; Hypertension; Overweight; Prediabetes; Diabetes; Family History of Coronary Artery Disease; Family History of Peripheral Artery Disease; Family History of Cerebrovascular Disease

Outcome Measures

Primary Outcomes (2)

• Difference in ADP-induced platelet aggregation (%) with and without PCSK9 enzyme

  Difference in ADP-induced platelet aggregation (%) with and without addition of PCSK9 enzyme in blood collected from healthy volunteers and subjects with cardiovascular risk factors.

  Throughout study completion, an average of about 1 year

• Difference in collagen related peptide -induced platelet aggregation (%) with and without PCSK9 enzyme

  Difference in collagen related peptide-induced platelet aggregation (%) with and without PCSK9 enzyme in blood collected from healthy volunteers and subjects with cardiovascular risk factors.

  Throughout study completion, an average of about 1 year

Secondary Outcomes (2)

• Difference in ADP-induced platelet aggregation (%) with PCSK9 enzyme alone and with addition of PCSK9 antibody

  Throughout study completion, an average of about 1 year

• Difference in collagen related peptide-induced platelet aggregation (%) with PCSK9 enzyme alone and with addition of PCSK9 antibody

  Throughout study completion, an average of about 1 year

Study Arms (2)

Healthy

Participants (approximately 40) 18-50 years old male and female without any major medical conditions or taking any agents or food supplements that may influence platelet function as determined by the study principal investigator.

Drug: PCSK9 Antibody, PCSK9 Enzyme

Cardiovascular Risk Factor

Participants (approximately 40) 18-50 years old male and female with at least three of the following risk factors: history of hypercholesterolemia, hypertension, overweight, current smoker, prediabetes or diabetes who are only on metformin and insulin, and a family history of coronary artery, peripheral artery, or cerebrovascular disease.

Drug: PCSK9 Antibody, PCSK9 Enzyme

Interventions

PCSK9 Antibody, PCSK9 Enzyme DRUG

In-vitro demonstration of the direct effect if the PCSK9 enzyme on platelets. The study will use commercially available recombinant PCSK9 enzyme to promote platelet activity and the PCSK9 antibody to inhibit activity. In each patient, platelet function testing will occur in the absence of PCSK9 enzyme, after the addition of PCSK9 enzyme, and after the addition of both PCSK9 enzyme and antibody reagent to the blood sample prior to testing.

Cardiovascular Risk Factor; Healthy

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

This trial has been designed to ensure enrollment of healthy volunteers and subjects with CV risk to allow for comparisons across disease states in order to fulfill study objectives. Compared to healthy volunteers, subjects with CV risk factors are highly prothrombotic and exhibit a high platelet reactivity phenotype. Coexistence of at least three risk factors indicate a high risk for future CV events. African Americans and women are inherently at elevated risk for CVD, associated ischemic events, and exhibit higher serum PCSK9 levels. Therefore, equal inclusion of race and genders should provide robust variability in PCSK9 levels for evaluation of platelet related effects of PCSK9.

You may qualify if:

• Healthy subjects (n=40): 18-50 years old male and female subjects without any conditions or taking any agents or food supplements that may influence platelet function as determined by the study principal investigator.
• Subjects with CV risk factors (n=40): 18-50 years old male and female subjects with at least three of the following CV risk factors:
• History of hypercholesterolemia, hypertension, overweight, current smoker, prediabetes or diabetes who are only on metformin and insulin, and family history of coronary artery, peripheral artery, or cerebrovascular disease.
• Overweight is defined as subjects with BMI ≥25 kg/m2 (https://www.heart.org/en/healthy-living/healthy-eating/losing-weight/bmi-in-adults).
• Diabetes is defined as haemoglobin (Hb)A1c ≥6.5%, prediabetes =5.7%-6.4%) (https://diabetes.org/about-diabetes/diagnosis)

You may not qualify if:

• Subjects with Diabetes mellitus, who are on GLP-1 agonists or SGLT2 inhibitors.
• Subjects on high dose statin therapy or PCSK9 therapy.
• Prior coronary of cerebrovascular event requiring intervention.
• Use of any antiplatelet or anticoagulant therapy within 14 days of enrollment.
• Subjects with a history of chronic kidney disease, liver disease, pancreatitis, HIV, hepatitis, and active cancer, active infection, or any other medical condition or concomitant medications as determined by the investigator that may affect study results.
• Pregnant

Sponsors & Collaborators

• LifeBridge Health: lead
• Merck Sharp & Dohme LLC: collaborator

Related Publications (17)

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  PMID: 20124137 BACKGROUND

• Gurbel PA, Fox KAA, Tantry US, Ten Cate H, Weitz JI. Combination Antiplatelet and Oral Anticoagulant Therapy in Patients With Coronary and Peripheral Artery Disease. Circulation. 2019 Apr 30;139(18):2170-2185. doi: 10.1161/CIRCULATIONAHA.118.033580.

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• Navarese EP, Kolodziejczak M, Winter MP, Alimohammadi A, Lang IM, Buffon A, Lip GY, Siller-Matula JM. Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: The PCSK9-REACT study. Int J Cardiol. 2017 Jan 15;227:644-649. doi: 10.1016/j.ijcard.2016.10.084. Epub 2016 Oct 29.

  PMID: 27810295 BACKGROUND

• Leander K, Malarstig A, Van't Hooft FM, Hyde C, Hellenius ML, Troutt JS, Konrad RJ, Ohrvik J, Hamsten A, de Faire U. Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors. Circulation. 2016 Mar 29;133(13):1230-9. doi: 10.1161/CIRCULATIONAHA.115.018531. Epub 2016 Feb 19.

  PMID: 26896437 BACKGROUND

• Ding Z, Liu S, Wang X, Deng X, Fan Y, Shahanawaz J, Shmookler Reis RJ, Varughese KI, Sawamura T, Mehta JL. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res. 2015 Sep 1;107(4):556-67. doi: 10.1093/cvr/cvv178. Epub 2015 Jun 19.

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• Camera M, Rossetti L, Barbieri SS, Zanotti I, Canciani B, Trabattoni D, Ruscica M, Tremoli E, Ferri N. PCSK9 as a Positive Modulator of Platelet Activation. J Am Coll Cardiol. 2018 Feb 27;71(8):952-954. doi: 10.1016/j.jacc.2017.11.069. No abstract available.

  PMID: 29471945 BACKGROUND

• Petersen-Uribe A, Kremser M, Rohlfing AK, Castor T, Kolb K, Dicenta V, Emschermann F, Li B, Borst O, Rath D, Muller KAL, Gawaz MP. Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease. Int J Mol Sci. 2021 Oct 16;22(20):11179. doi: 10.3390/ijms222011179.

  PMID: 34681838 BACKGROUND

• 15. Pastori D, Nocella C, Farcomeni A, et al. ATHERO-AF Study Group. Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2017 Sep 19;70(12):1455-1462. doi: 10.1016/j.jacc.2017.07.743. PMID: 28911508. Cammisotto V, Pastori D, Nocella C, et al. PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation. Antioxidants (Basel). 2020;9:296.

  BACKGROUND

• Cammisotto V, Pastori D, Nocella C, Bartimoccia S, Castellani V, Marchese C, Scavalli AS, Ettorre E, Viceconte N, Violi F, Pignatelli P, Carnevale R. PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation. Antioxidants (Basel). 2020 Apr 2;9(4):296. doi: 10.3390/antiox9040296.

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• Gerstein HC, Branch K, Heenan L, Del Prato S, Khurmi NS, Lam CSP, Pratley R, Rosenstock J, Sattar N. Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist. Diabetes Obes Metab. 2021 Feb;23(2):318-323. doi: 10.1111/dom.14223. Epub 2020 Oct 22.

  PMID: 33026143 BACKGROUND

• Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol. 2005 Nov 15;46(10):1820-6. doi: 10.1016/j.jacc.2005.07.041. Epub 2005 Oct 21.

  PMID: 16286165 BACKGROUND

• Lev EI, Bliden KP, Jeong YH, Pandya S, Kang K, Franzese C, Tantry US, Gurbel PA. Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients. J Am Heart Assoc. 2014 Oct 20;3(5):e001167. doi: 10.1161/JAHA.114.001167.

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• Kent ST, Rosenson RS, Avery CL, Chen YI, Correa A, Cummings SR, Cupples LA, Cushman M, Evans DS, Gudnason V, Harris TB, Howard G, Irvin MR, Judd SE, Jukema JW, Lange L, Levitan EB, Li X, Liu Y, Post WS, Postmus I, Psaty BM, Rotter JI, Safford MM, Sitlani CM, Smith AV, Stewart JD, Trompet S, Sun F, Vasan RS, Woolley JM, Whitsel EA, Wiggins KL, Wilson JG, Muntner P. PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. Circ Cardiovasc Genet. 2017 Aug;10(4):e001632. doi: 10.1161/CIRCGENETICS.116.001632.

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• Chaudhary R, Sukhi A, Chaudhary R, Jindal M, Vyas A, Rout A, Bliden K, Tantry U, Gurbel P. Gender differences in thrombogenicity among patients with angina and non-obstructive coronary artery disease. J Thromb Thrombolysis. 2019 Oct;48(3):373-381. doi: 10.1007/s11239-019-01901-1.

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MeSH Terms

Conditions

Hypercholesterolemia; Hypertension; Overweight; Prediabetic State; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Vascular Diseases; Cardiovascular Diseases; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Glucose Metabolism Disorders; Endocrine System Diseases

Study Officials

• Paul Gurbel, MD, FACC

  LifeBridge Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kevin Bliden, BS, MBA

CONTACT

4432441497; kbliden@lifebridgehealth.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Cardiovascular Research

Study Record Dates

• First Submitted: November 1, 2024
• First Posted: November 6, 2024
• Study Start: December 1, 2024
• Primary Completion: December 1, 2025
• Study Completion: December 30, 2025
• Last Updated: November 6, 2024

Record last verified: 2024-11