Emerging Anti-Atherosclerotic Therapies
Abstract
:1. Introduction
2. Cyclodextrins
3. 2-HOBA
4. Inclisiran
5. Molecules Targeting ANGPTL3
6. Colchicine
7. Canakinumab
8. Ziltivekimab
9. Losmapimod
10. MK2206
11. Monoclonal Antibody against P-Selectin
Drug Name Intervention | Intervention | Type of Study | Most Relevant Effects of Drug | Safety/Potential Serious Side Effects | Ref. |
2-hydroxypropyl-β-cyclodextrin | Animal study (mice) |
| Generally well tolerated, but the latest research indicated the increased risk of ototoxicity in the form of iatrogenic hearing loss [148] | [6] | |
Animal study (rabbits fed a high-fat diet) |
| [35] | |||
2-hydroxybenzylamine (2-HOBA) | Animal study (hypercholesterolemic Ldlr−/− mice) – model of FH |
| 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers [45]. Adverse events reported in this trial were mild and considered unlikely to be related to 2-HOBA | [37] | |
Inclisiran | One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo | Randomized, double-blind, placebo-controlled multicentre phase 2 clinical trial (ORION-1) |
| Well tolerated Mild rash in some participants | [54] |
One intravenous dose (doses ranging from 0.015 to 0.400 mg/kg) or placebo | Randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3.00 mmol/L or higher |
| No drug-related serious adverse events. Mild to moderate treatment-emergent adverse events A transient mild, macular, erythematous rash | [52] | |
Subcutaneous injection. Single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran | Phase 2, multicentre, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels |
| Rarely symptoms of immune activation. Rare transient elevations in hepatic enzyme levels | [53] | |
ORION-10 trial: patients with atherosclerotic cardiovascular disease with elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose |
| injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9%) Adverse reactions were generally mild, and none were severe or persistent | [49] | ||
ORION-11 trial: patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent with elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose |
| injection-site adverse events were more frequent with inclisiran than with placebo (4.7% vs. 0.5%) Adverse reactions were generally mild, and none were severe or persistent | [49] | ||
Antisense oligonucleotides targeting Angptl3 mRNA | Subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg/week for 6 weeks) | Clinical trial including 44 human participants (with TG levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) |
| No serious adverse events. Rarely dizziness or headache | [63] |
Evinacumab (fully human anti-ANGPTL3 monoclonal antibody) | Placebo subcutaneously (75, 150, or 250 mg) Intravenously (5, 10, or 20 mg/kg) | A phase 1, first-in-human, randomized, placebo-controlled, double-blind, ascending single-dose clinical trial Healthy persons with a fasting TG level of 150 to 450 mg/dL (1.7 to 5.1 mmol/L) or an LDL cholesterol level of 100 mg/dL (2.6 mmol/L) or greater |
| The most frequent adverse event—headache (11%). Transient, single elevations of the alanine aminotransferase level to more than 3 times the upper limit of the normal range | [59] |
Atorvastatin Alirocumab; Evinacumab | Diet alone (control) or atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks | APOE*3-Leiden.CETP mice (model for hyperlipidemia) |
| - | [68] |
Colchicine | 1 mg daily for 30 days | A pilot randomized controlled trial 80 patients with ACS or acute ischemic stroke |
| Occurrence of diarrhoea (X(2) 4.14, p = 0.04) | [70] |
Low-dose colchicine (0.5 mg/day) or a placebo for 7 days | Double-blind, randomized, placebo-controlled, crossover-within-subject clinical trial 28 patients with CAD |
| - | [71] | |
0.5 mg/day or no colchicine; Follow-up: a median of 3 years. | Clinical trial with a prospective, randomized, observer-blinded endpoint design 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) |
| Intestinal intolerance | [72] | |
1 mg followed by 0.5 mg 1 hour later or no colchicine, 6 to 24 h prior to cardiac catheterization | Randomized controlled trial 40 ACS patients, 33 with stable CAD, and 10 controls |
| [73] | ||
Oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment | Randomized controlled trial 21 ACS patients compared with 9 untreated healthy controls |
| - | [74] | |
Orally 1.5 mg or no treatment | Randomized controlled trial 12 patients with ACS on colchicine vs. 13 assigned to no treatment |
| - | [75] | |
Either 0.5 mg/day colchicine plus OMT or OMT alone; follow-up for 1 year. | Prospective nonrandomized observational study of 80 patients with recent ACS (<1 month) |
| - | [76] | |
Either low-dose colchicine (0.5 mg once daily) or placebo | Randomized, double-blind trial involving 4745 patients with fresh myocardial infarction (within 30 days form event) |
| Pneumonia as a serious adverse event in 0.9% of the patients in the colchicine group vs. 0.4% of those in the placebo group (p = 0.03) | [77] | |
Colchicine or placebo within 30 days post-MI | The COLchicine Cardiovascular Outcomes Trial (COLCOT) |
| - | [80]. | |
Canakinumab | Subcutaneous placebo or canakinumab at doses of 5, 15, 50, or 150 mg monthly (follow-up: 4 months) | Double-blind, multinational phase IIb trial of 556 patients with well-controlled diabetes mellitus and high cardiovascular risk |
| Clinical adverse events were similar in the canakinumab and placebo groups | [101] |
50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months vs. placebo | A randomized, double-blind trial involving 10,061 patients with previous myocardial infarction and a hs CRP level of 2 mg/L or more |
| Higher incidence of fatal infection compared to placebo. | [7] | |
3 subcutaneous doses of canakinumab (50 mg, 150 mg, or 300 mg) once every 3 months | Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) 4833 stable atherosclerosis patients | In patients with on-treatment IL-6 levels <1.65 ng/L:
| No related hepatic or renal toxicities Reduced rates of lung cancer increase in fatal infection | [101] | |
Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months | Multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial involving outpatients with PAD and IC |
| Safe and well tolerated | [102] | |
Ziltivekimab | Subcutaneous administration of placebo or ziltivekimab 7.5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks | RESCUE, a randomised, double-blind, phase 2 trial carried out at 40 clinical sites in the USA. Participants with moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L |
| Well tolerated, No serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. | [104] |
Losmapimod | Losmapimod 7.5 mg once daily (lower dose), twice daily (higher dose) or placebo for 84 days | 99 patients with atherosclerosis on stable statin therapy |
| - | [109] |
Oral losmapimod (7.5 mg or 15.0 mg loading dose followed by 7.5 mg twice daily) or matching placebo | A double-blind, randomised, placebo-controlled trial of patients with NSTEMI |
| Safety outcomes did not differ between groups | [110] | |
Either twice-daily losmapimod (7.5 mg) or matching placebo on a background of guideline-recommended therapy. | LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries 3503 participants (part A) | Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events (primary end point occurrence by 12 weeks: placebo (7.0%) and patients treated with losmapimod: 8.1%; hazard ratio, 1.16; 95% CI, 0.91–1.47; p = 0.24 | Similar on-treatment rates of serious adverse events: 16.0% with losmapimod and 14.2% with placebo | [111] | |
MK2206 | Injection of MK2206 at a dose of 4 mg/kg/d, or equal volume of saline (containing 0.1% DMSO) | In vitro, animal study |
| - | [112] |
Cultured human hepatoma cells |
| - | [115] | ||
Inclacumab | 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 h before PCI) | The Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non-ST-Segment Elevation Myocardial Infarction (SELECT-ACS) 544 patients | Patients receiving inclacumab 20 mg/kg with a short time interval between infusion and PCI:
| - | [145] |
Each dose level (0.03–20 mg/kg) investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo) | Randomized, double-blind placebo-controlled study 56 healthy subjects | - | Inclacumab was well tolerated Most common AEs: headache, cough, sore throat, and upper respiratory tract infection, one serious AE (rhabdomyolysis) | [142] |
12. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Gluba-Brzózka, A.; Franczyk, B.; Rysz-Górzyńska, M.; Ławiński, J.; Rysz, J. Emerging Anti-Atherosclerotic Therapies. Int. J. Mol. Sci. 2021, 22, 12109. https://doi.org/10.3390/ijms222212109
Gluba-Brzózka A, Franczyk B, Rysz-Górzyńska M, Ławiński J, Rysz J. Emerging Anti-Atherosclerotic Therapies. International Journal of Molecular Sciences. 2021; 22(22):12109. https://doi.org/10.3390/ijms222212109
Chicago/Turabian StyleGluba-Brzózka, Anna, Beata Franczyk, Magdalena Rysz-Górzyńska, Janusz Ławiński, and Jacek Rysz. 2021. "Emerging Anti-Atherosclerotic Therapies" International Journal of Molecular Sciences 22, no. 22: 12109. https://doi.org/10.3390/ijms222212109