Investigational Drugs in Phase II Clinical Trials for Acute Coronary Syndromes

Amit Rout, Ajaypaul Sukhi, Rahul Chaudhary, Kevin P Bliden, Udaya S Tantry & Paul A Gurbel

To cite this article: Amit Rout, Ajaypaul Sukhi, Rahul Chaudhary, Kevin P Bliden, Udaya S Tantry & Paul A Gurbel (2019): Investigational Drugs in Phase II Clinical Trials for Acute Coronary Syndromes, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2020.1708324
To link to this article: https://doi.org/10.1080/13543784.2020.1708324

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Opinion on Investigational Drugs

DOI: 10.1080/13543784.2020.1708324
Investigational Drugs in Phase II Clinical Trials for Acute Coronary Syndromes

Amit Rout,1 Ajaypaul Sukhi1 Rahul Chaudhary2 Kevin P Bliden1 Udaya S Tantry1 Paul A Gurbel1
1Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Lifbridge Health, Baltimore, MD, USA
2, Division of Hospital Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

Send Correspondence to:Paul A. Gurbel M.D.
Director, Sinai Center for Thrombosis Research Sinai Hospital of Baltimore, Baltimore, MD, 21215 Fax: 410-367-2590: Phone: 410-367-2596
E-mail: [email protected]


Introduction: Despite current guideline-based, secondary prevention strategies in patients with the acute coronary syndrome, the residual ischemic risk is still at an unacceptable rate, and there is a concomitant high bleeding event rate. These observations mandate investigations of novel treatment strategies to meet the unmet need to improve outcomes in patients with ACS.
Areas covered: In this review, the author(s) focus on new agents with ongoing or recently completed phase II trials for the treatment of ACS. We searched MEDLINE and clinicaltrials.org for Phase II trials in ACS patients, and important original investigations are reviewed.
Expert opinion: Some of the novel drugs evaluated in the Phase II trials hold promise for future therapies such as AZD5178, anakinra, tocilizumab, CSL112, MEDI 6102, inclisiran, PZ128, selatogrel, and RVX-208. Their efficacy and safety should be evaluated in large scale Phase III trials. The higher cost of the drug will be a major limitation for wide-spread use of novel agents in general practice in future.

Keywords: Acute coronary syndrome, antithrombotic drugs, coagulation, inflammation, lipid and cholesterol lowering agents,

Article highlights:

• Despite current rigorous secondary prevention strategy in ACS, the degree of adverse event reduction is far from optimal and there is a high incidence of recurrent thrombotic event occurrence (~10% in first year after an ACS event) along with a significant risk of bleeding.
• Numerous novel agents targeting inflammation, lipid/cholesterol control, and thrombosis pathways that may have important roles in reducing ischemic risk in ACS patients.
• Among anti-inflammatory agents, 5-FLAP inhibitor (AZD5718), anakinra (recombinant IL-Ra), and (anti-Il 6 receptor antibody) demonstrated promising results in phase II trials.
• Among anti-inflammatory agents, AZD5718, anakinra, and tocilizumab , among therapies targeting lipid and cholesterol management, CSL112, MED1 6012 and inclisiran, and among antithrombotic agents, PZ-128, selatogrel, vicagrel and revacept have all demonstrated promising results in early phase trials and some are being further explored.
• DAPT will likely remain the cornerstone strategy during the acute phase of ACS whereas for long term secondary prevention, the above mentioned agents may be included as adjunctive agents.

ACS: Acute Coronary Syndromes CRP: C-Reactive Protein
CV: Cardiovascular
BET: Bromodomain and Extra-Terminal DAPT: Dual antiplatelet therapy
FLAP: 5-Lipooxygenase Activating Protein HDL: High Density Lipoprotein
5-LO: 5- Lipoxygenase IL: Interleukin
LCAT: Lecithin-cholesterol-acyltransferase LT: Leukotriene
LDL: Low Density Lipoprotein LV: Left Ventricle
MI: Myocardial Infarction
MAPK: Mitogen-Activated Protein Kinase MACE: Major Adverse Cardiac Events
NSTEMI: non ST-segment elevation Myocardial Infarction PCI: Percutaneous Coronary Intervention

1. Introduction

Pharmacologic management of patients with acute coronary syndromes (ACS) has been undergoing rapid and dynamic changes in recent years. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been the cornerstone strategy to prevent recurrent arterial thrombotic events in patients with ACS for more than two decades. More efficient P2Y12 inhibitors such as prasugrel and ticagrelor are increasingly being used in patients with ACS [1,2]. In addition, technological advances in revascularization strategies, improvement in lifestyle, and rigorous lipid- lowering and antihypertensive therapies have improved clinical outcomes among patients with ACS. However, recent analyses demonstrate the need for better therapies in patients with ACS for secondary prevention. Hospital record data from the USA and three European countries in patients ≥ 65 years old (n=114,364) and one year after discharge for acute myocardial infarction (MI) showed that the 3-year crude cumulative rate of all-cause death was 19.6% to 30.2%; the rate of the composite of non-fatal MI, stroke, or death was 26.0% to 36.2%, and the rate of hospitalization for bleeding was 3.1% to 5.3% [3]. In another nationwide analysis of 55,747 patients with no events in the first 7 days after MI, the first-year cumulative incidence of the composite of non-fatal MI, non-fatal stroke or cardiovascular (CV) death was 20% and the cumulative incidence from day 366 to study completion (mean follow-up of 3.6 years) was 21% in patients surviving the first 365 days without a recurrent CV event [4]. These observations encouraged a paradigm shift in treatment strategies from targeting plaque rupture in the culprit vessel with antithrombotic strategies in ACS patients to targeting vascular inflammation and lipid/cholesterol metabolism pathways.
In this review article, we discuss recent developments in investigational drugs undergoing Phase II trials for ACS. These drugs can be broadly classified into therapies targeting inflammation, lipid and cholesterol, platelets and coagulation and miscellaneous pathways.

2. Inflammation Pathways (Table 1)

2.1 Leukotriene Inhibitors
Leukotrienes are mainly derived from arachidonic acid via the 5- lipoxygenase (5-LO) pathway in leukocytes. 5-LO, along with 5-lipooxygenase activating protein (FLAP), initially leads to the 5formation of precursor leukotriene A4. Leukotriene B4 (LTB4) is a potent leukocyte activator and chemokine. The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are potent vasoactive and inflammatory mediators [5,6]. Coronary artery disease (CAD) is an atheroinflammatory condition involving endothelial dysfunction, infiltration of inflammatory cells, and platelets into the arterial vessel wall, smooth muscle proliferation, and atherogenesis. 5-LO pathway mediators and products are increasingly expressed in the unstable atherosclerotic lesions and play a significant role in inflammation and progression of CAD and ACS [5,6].

2.1.1 VIA-2291 (Atreleuton)
VIA-2291 (Tallikut Pharmaceuticals, San Francisco, California, USA), a 5-LO inhibitor, has been shown to inhibit the synthesis of leukotrienes like LTB4 and LTE4. This drug was initially developed to treat asthma and subsequently evaluated for its role in attenuating vascular inflammation [7]. In the initial phase II trial (NCT00358826) involving 191 patients, VIA-2291 therapy was associated with a significant reduction in whole blood LTB4 and urine LTE4 levels compared to placebo in patients with a recent ACS [8]. Serial computed tomographic (CT) angiography study revealed that at the end of 6-months significant reductions in plaque progression were noted in VIA -2291 group when compared to placebo [9]. Based on these results another phase II trial (NCT00552188) to evaluate the effect of VIA-2291 on vascular inflammation in patients after an ACS was undertaken. In this trial, 52 patients were randomized in a 1:1 fashion to either VIA-2291 or placebo. The primary endpoint of change in vascular inflammation assessed by fluorodeoxyglucose-positron emission tomography (FDG-PET) was not different between the two groups. This study showed a significant decrease in LTB4 and LTE4 levels but failed to show any reduction in inflammatory markers like high sensitivity C- reactive protein (hsCRP) [10]. As of our knowledge, no further studies are planned for VIA- 2291.

2.1.2 AZD5718
AZD5718 (AstraZeneca, Cambridge, United Kingdom) is a selective 5-lipooxygenase activating protein (FLAP) inhibitor that inhibits LTB4 production [11]. In the phase I (NCT02632526), study, pharmacodynamics (PD), pharmacokinetics (PK) and safety in healthy male subjects after single and multiple ascending doses were evaluated. Overall, AZD5718 was well tolerated with 63 adverse events, mainly headache, in a total of 96 subjects. Only 1 % of the drug was cleared renally. Its metabolism mainly involves cytochrome P450 (3A4 and 3A5 isoforms) and uridine 5′-diphosphate glucuronosyltransferase conjugation. The half-life of the drug was around 10-12 hours, and steady state was achieved after 3 days of repeated dosing. Decreased levels of LTB4 in blood and LTE4 in urine were noted after both single and multiple doses [11]. The study suggested that once-daily dosing is optimal to achieve complete inhibition of both LTB4 and LTE4. Currently, AZD5718 is undergoing phase II trial (NCT03317002) in Europe. This is a randomized, single-blind, placebo-controlled, and multicenter trial in patients with CAD and is expected to be completed by 2020. The study aims to evaluate efficacy, safety, and tolerability after 4 or 12 weeks of treatment in patients with ACS [12].

2.2 Cytokine Based therapy

2.2.1 Anakinra (IL-1 Blockade)
Interleukin (IL)-1 is a multifunctional, complex, and pro-inflammatory cytokine, which is released in response to cell injury. IL-1 family consists of multiple different cytokines and receptor antagonists, of which IL-1α and IL-1β are the important ones [13]. IL-1α is released by ischemic myocytes while, inflammatory cells like monocytes are the main source of IL-1β. Both IL-1α and IL-1β bind to their receptor IL-1R1, subsequently leading to phosphorylation of NF- κB, c-Jun N-terminal kinase, (JNK) and p38 MAPK. These signaling pathways induce cardiomyocyte apoptosis in the acute phase of injury and play an essential role in cardiac remodeling, which leads to cardiac dilatation and dysfunction. IL-1 receptor antagonist (IL-1Ra) is the natural antagonist of IL-1α and IL-1β as it competes with them for IL-1R1 [14,15].
Anakinra (Swedish Orphan Biovitrum, Stockholm, Sweden) is a recombinant human IL-Ra which can be given as a subcutaneous injection and is used as a second-line agent for rheumatoid arthritis. In animal models, anakinra had shown to reduce apoptosis of cardiomyocyte and improved post-MI systolic and diastolic function [16,17]. Two small scale human studies, VCU- ART and VCU-ART2 (Virginia Commonwealth University–Anakinra Remodeling Trial), have been conducted to evaluate the safety of anakinra in patients with ST-elevation myocardial infarction (STEMI). The first pilot study, VCU-ART (NCT00789724), randomized 10 patients to 2 weeks of the daily dose of 100 mg subcutaneous injection of Anakinra or placebo in patients with STEMI. The primary endpoint of the difference in the 3 months interval change in the left ventricle (LV) end-systolic volume index on cardiac magnetic resonance (CMR) imaging was significantly lower in the anakinra group compared to placebo (p= 0.033). From safety standpoints, no serious adverse events were reported in the anakinra group [18]. In the next phase II study, VCU-ART 2 (NCT01175018), 30 patients with STEMI were randomized to 100mg/day anakinra or placebo for 14 days. The primary endpoint was similar to the VCU-ART study. The secondary outcomes were the changes in LV end-diastolic volume index, LV ejection fraction, and CRP levels. No significant differences were noted in LV end-systolic volume index, LV end-diastolic volume index, and LV ejection fraction at the end of the 10-14 weeks follow up period between the two groups. CRP levels were significantly reduced within 72 hours in the anakinra group compared to placebo (p= 0.002), but the difference was lost at 14 days. The incidence of heart failure was numerically higher in the placebo group but failed to show any statistical significance [19]. A pooled analysis of the two studies showed that anakinra significantly decreased the incidence of heart failure compare to placebo in 2 weeks follow up (p=0.035) ) [19]. A long term follow up study of these two trials was published later in which the investigators reported no difference in the two groups in terms of ischemic events but there was a reduction in the incidence of death or new-onset heart failure (hazard ratio 0.16 (95% confidence interval 0.03 to 0.76, p = 0.008) [20]. Based on these results, currently, the VCU-ART3 (NCT01950299) trial is undergoing. This is a phase II, randomized, double-blind, placebo- controlled trial. The trial aims to recruit 99 patients with STEMI who will receive either anakinra 100 mg once daily or anakinra 100 mg twice daily vs. placebo for 2 weeks. The primary outcome is the difference in the area under the curve for CRP levels after 14 days. The secondary outcomes include left ventricular end-systolic volume, ejection fraction and new onset heart failure after 12 months follow up. At this time, recruitment for the study is completed, and the the results are awaited [21].

2.2.2 Tocilizumab (IL-6 receptor antibody)

Il-6 plays a significant role in the pro-inflammatory pathway. It leads to the synthesis, and release of acute-phase proteins like CRP, fibrinogen, and hepcidin by hepatocytes while decreasing albumin synthesis [22]. IL-6 in conjunction with transforming growth factor (TGF)- beta leads to Th17 differentiation of CD4+ T cells and cytotoxic differentiation of CD8T cell, while it inhibits Regulatory T (Treg) differentiation of CD4+ T cells. IL-6 binds to IL-6 receptors and leads to downstream activations of JAK-STAT3 and MAPKs pathways. IL-6 pathogenic role is well known in many chronic inflammatory diseases like rheumatoid arthritis, juvenile idiopathic arthritis, systemic sclerosis, and polychondritis [22,23].
Tocilizumab (Chugai Pharmaceutical, Tokyo, Japan and Roche, Basel, Switzerland) is an anti- IL-6 receptor antibody that blocks the IL-6 mediated signaling pathway. Tocilizumab is currently approved for giant cell arteritis, polyarticular juvenile idiopathic arthritis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman’s disease [22,23]. Elevated IL-6 levels are reported after an ACS event, and it was suggested that IL-6 contributes to ischemia-reperfusion injury in the myocardium [24]. In phase II (NCT01491074) double-blind, placebo-controlled, randomized trial, a single dose of tocilizumab was evaluated in 117 patients with non-ST- segment elevation MI (NSTEMI). The primary outcome was the difference in the area under the curve (AUC) for hsCRP and Troponin T between day 1 and day 3. The study found that both CRP and Troponin T levels were significantly elevated in the placebo group compared to the tocilizumab group (p <0.001 and p=0.007). There was no significant difference between the two groups with respect to serious adverse events like MI, death, pericarditis, serious infection or serious bleeding at the end of 6 months follow up. This trial was underpowered for the evaluation of efficacy outcomes [25]. The second trial (NCT02419937), STAT-MI (Short-term application of tocilizumab during myocardial infarction) was a randomized, double-blinded, placebo-controlled trial, in which patients with MI received a single dose of 162 mg tocilizumab or placebo. This trial suffered from slow recruitment and had only 28 patients enrolled; there was no significant difference in the primary outcome of MACE defined as recurrent MI, development of new arrhythmia, new septal/valve rupture, evidence of dissection, pericarditis or tamponade or the secondary outcome of CRP levels between the two groups[26]. Currently, another phase II trial (NCT03004703), ASSAIL-MI (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial) trial is undergoing. In this trial 200, patients with STEMI will be randomly treated with either 280 mg Tocilizumab or placebo. The primary outcome is the difference between myocardial salvage index measured in the acute phase by CMR imaging, and the secondary outcomes include the difference between cardiac biomarkers, infarct, and LV size as measured by CMR [27].

2.2.3 Interleukin-2 (Aldesleukin or Proleukin)
CD4+ T cells are activated in response to autoantigens released from the damaged myocardium. Treg cells are the main subtypes which are shown to play a significant role in cardiac remodeling after ACS [28]. In murine models, Treg cells led to decreased recruitment of neutrophils, macrophages and lymphocytes in the damaged myocardial tissue, and inhibited inflammatory cytokines like IL-1 beta, and tumor necrosis factor-alpha, myocardial matrix metalloproteinase-2 activity, cardiac apoptosis, and interstitial fibrosis. IL- 2 is known to play an important role in the Treg cell maturation, and anti-inflammatory actions. Decreased plaque formation is noted in mice after exogenous IL-2 supplementation [29]. Treatment with low dose IL-2 or Aldesleukin (Clinigen, Burton upon Trent, United Kingdom, and Novartis, Basel, Switzerland) had been studied in healthy volunteers, patients with hepatitis-C infection and type-1 diabetes mellitus.
The main adverse events were local injection reaction and flu like symptoms in a dose-dependent fashion without any serious adverse events [30].
IL-2 in a relatively higher dose is associated with significant toxicity of fever, hypotension, jaundice and azotemia. Low dose IL-2 had been shown to be safe and still maintains anti- inflammatory effects (31). Low dose IL-2 (range 0.3 MIU- 3.0 MIU) has been suggested to improve myocardial recovery and remodeling after ACS. The LILACS (Low Dose Interleukin-2 in Patients With Stable Ischemic Heart Disease and Acute Coronary Syndromes) trial (NCT03113773) is designed to evaluate the efficacy and safety of low dose IL-2 in patients with ischemic heart disease. In the first phase, patients with stable ischemic heart disease will receive subcutaneous injections of Il-2 (0.3 MIU- maximum dose of 3.0 MIU) or placebo for 5 consecutive days. The primary outcome is IL-2 safety and tolerability. In the second phase, patients with NSTEMI will receive IL-2 injections (0.3 MIU- maximum dose of 3.0 MIU) vs. placebo for 5 days. The primary outcome of phase II is the change in Treg cell levels between day 1 and day 6, and secondary outcomes are pharmacokinetics and pharmacodynamics of IL-2 [32].

3. Lipid and Cholesterol pathways (Table 2)
3.1 High Density Lipoprotein (HDL) based Therapy
3.1.1 CSL112 (Apolipoprotein A-I)
CSL112 (CSL Behring, King of Prussia, Pennsylvania, USA) is a reconstituted human plasma- derived apolipoprotein A-1 (apoA-1). ApoA-1 is the primary functional component of HDL, which is synthesized in the liver and intestine. Once in circulation, it acquires phospholipids and free cholesterol to form pre-β-HDL. Pre-β-HDL then acquires more cholesterol and lipids, especially in the arterial wall. ATP-binding cassette transporter A1 (ABCA1) promotes phospholipids and cholesterol efflux into pre-β-HDL. CSL112 increases the plasma level of apoA-1 and also ABCA1 and thus leads to increase cholesterol efflux [33]. Phase I and II trials have demonstrated that multiple infusions of CSL112 increase apoA-I level in a dose-dependent fashion and without any overall serious adverse issues [34-37]. In a phase II a (NCT01499420) multicenter, randomized, placebo-controlled, single ascending dose (SAD) study, compared to placebo, CSL112 had no clinically meaningful time- or dose-dependent effects on maximum platelet aggregation in response to any agonist, by either dose or renal function subgroup when co-administered with DAPT in patients with stable atherosclerotic disease [38]. In phase II (NCT02108262) AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I), 1,258 patients with MI were randomly treated with either different doses of CSL112 or placebo for 4 consecutive weeks. The investigators reported that no significant hepatic or renal impairment was associated with CL112 infusion when compared to placebo. There was a dose-dependent increase in ABCA-1 dependent cholesterol efflux but no difference in MACE, cardiovascular death, MI or stroke. This study was not designed to look for any efficacy outcomes [36].
Currently, AEGIS-II trial (NCT03473223), a phase III, multicenter, randomized, placebo- controlled trial is undergoing to evaluate safety and efficacy of CSL122 in ACS patients. The primary endpoint of this study is the composite of MACE defined as CV death, MI, or stroke in 90 days follow up. The study aims to enroll 17,400 patients and will likely be completed by 2022 [39].
3.1.2 CER-001

CER-001 (Cerenis Therapeutics, Labège, France) is a recombinant HDL mimetic agent which contains apolipoprotein A-I (apoA-I),natural phospholipids sphingomyelin and dipalmitoylphosphatidylglycerol. CER-001 has functional properties similar to nascent HDL or pre-beta HDL [40]. In murine models, infusion of CER-001 transiently increases apoA-1 levels leading to increased transfer of unesterified cholesterol into HDL particles. Efflux of cholesterol and lipids from atherosclerotic plaques and lipid-laden macrophages via the reverse cholesterol transport pathway then leads to increased excretion of cholesterol from the body [40]. In the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) trial (NCT01201837) 517 ACS patients were randomized to receive 6 weekly infusions of either CER-001 at 3mg/kg, 6mg/kg or 12 mg/kg dose or placebo. The study failed to achieve its primary outcome of a reduction in coronary atherosclerosis on intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA) [41]. Later a post-hoc analysis of CHI- SQUARE study showed a dose of 3mg/kg leads to a significant regression of atheroma burden in patients with extensive atherosclerosis [42]. Based on these results, a phase II trial (NCT2484378) comparing the effect of CER-001 vs. placebo on coronary atherosclerosis in patients with ACS was undertaken. In this trial, 272 patients with ACS randomly received weekly intravenous injections of either 3mg/kg CER-001 or placebo for 10 weeks, followed by serial IVUS to assess coronary atheroma volume. At 10 weeks follow-up, no significant regression was noted in a change in atheroma volume from baseline [43]. The authors concluded that the use of CER-001 in the ACS setting is likely futile. The drug is now investigated in other conditions like Familial primary hypoalphalipoproteinemia (FPHA).

3.1.2 MDCO-216

ApoA1 Milano is a mutant variant of apoA-I first identified in Italy [44]. In animal models, apoA-I Milano variant infusion had shown regression in atherosclerosis. In a study conducted in 2003, apoA-I (which was earlier known as ETC-216) therapy in patients with ACS showed promising results of a significant decrease in atheroma volume compared to placebo when assessed by IVUS [45]. Despite initial success, the drug was halted due to concern for serious adverse reactions, mainly systemic inflammatory reaction leading to multiorgan failure. Later, the culprit protein in ETC-216 was identified and removed via gene deletion and improvement in the manufacturing process, apoAI milan was reintroduced as MDCO-216 (The Medicines Company, Parsippany, New Jersey, USA) and its safety was verified in human trials [46,47]. In the MILANO-PILOT Trial (NCT02678923), 122 patients with ACS were randomly treated with weekly infusion of MDCO-216 vs. placebo for 5 weeks. The study failed to show any significant atheroma or plaque regression in patients with ACS when compared to placebo [48].

3.2 Lecithin-cholesterol-acyltransferase
3.2.1 MEDI 6012

Lecithin-cholesterol-acyltransferase (LCAT) is a lipoprotein enzyme responsible for cholesterol esterification and transfer of cholesterol from arterial and peripheral tissue to the nascent or pre- βHDL which is then transported to the liver for further metabolism; a pathway called the reverse cholesterol transport (RCT) [49]. MEDI 6012 (MedImmune LLC, Gaithersburg, Maryland, USA), formerly known as ACP-501 is a recombinant human lecithin-cholesterol-acyltransferase (rhLCAT) [50]. In a phase I study (NCT01554800), safety and tolerability in patients with stable CAD after a single dose- escalation (0.9, 3.0, 9.0, and 13.5 mg/kg intravenous infusion) was evaluated. No serious adverse events were reported at the end of 28 days follow up period. A total of 8 adverse events were reported in 7 patients of whom 2 cases of rash which resolved spontaneously without any treatment and other 6 adverse events were thought to be unrelated to drug treatment. There was a dose-dependent increase in HDL levels, with increasing dose of the drug [51]. In the phase II a (NCT02601560), randomized, double-blind, placebo-controlled study, the safety, PK, and PD of multiple ascending doses in 48 patients with stable atherosclerotic cardiovascular disease were evaluated. In this study, fixed IV doses in four cohorts and subcutaneous dosing in two cohorts and subjects were followed for 28 days. There was no treatment-emergent serious adverse event, but there were 20 cases of non-serious adverse events in 36 drug-treated patients, whereas 12 cases in 5 placebo-treated patients. A dose- dependent increase in HDL-C, HDL-CE, CE and APoA1 was reported while the level of atherogenic LDL particles was reduced in the MEDI 6012 treated group [52]. Currently, a phase II b (NCT03578809) study to evaluate safety and efficacy in acute STEMI patients (REAL-TIMI 63B) is undergoing. In this randomized, double-blind, placebo-controlled study, 414 patients presenting with Acute STEMI who are planned for PCI will be treated with repeat doses of MEDI 6012. The primary outcome is the size of infarct measured on CMR imaging 10-12 weeks post-MI with MED 6012 compared to placebo, while the secondary outcomes include ejection fraction, non-calcified plaque volume, myocardial mass, adverse events, LCAT mass, and left ventricular volumes at end-systole [53]. Another phase II study (NCT03773172) is also currently undergoing, which aims to evaluate the effects of MEDI6012 on the metabolism of apolipoprotein B100 (apoB100) in subjects with stable CAD [54].

3.3 Targeting proprotein convertase subtilsin-kexin type 9 (PCSK9)

Low density lipoprotein (LDL) cholesterol binds to LDL receptors (LDLR) on the hepatocytes cell surface which is then sequestered inside by endocytosis leading to clearance of LDL cholesterol from circulation. LDLR is then recycled back to the cell surface. This recycling occurs multiple times before LDLRs are finally metabolized. Proprotein convertase subtilsin- kexin type 9 (PCSK9) is mainly secreted from hepatocytes, and also from intestine and kidneys. PCSK9 binds to LDLR, changes its configuration, and prevents its recycling, ultimately leading to degradation. Individuals with loss of function of PCSK9 gene have a reduced risk of cardiovascular diseases. Currently, two human monoclonal antibodies alirocumab and evolocumab are FDA approved PCSK9 inhibitors as a second-line agent for elevated cholesterol not controlled with diet and maximally tolerated statin therapy to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease. [55,56].

3.3.1 Inclisiran

Inclisiran (Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA) is a small interfering RNA (siRNA) directed towards PCSK9 [57]. The RNA interference (RNAi) is the process in which siRNA can selectively degrade messenger RNA thereby preventing translational protein synthesis [58]. Inclisiran is a synthetic siRNA which targets PCSK9 RNA in hepatocytes [57]. In the phase I trial (NCT01437059), healthy human volunteers were randomized to receive a single subcutaneous injection of the study drug at different concentrations vs. placebo. A dose- dependent concentration level was seen in the test subjects. In the highest dose group, treatment led to a 70% reduction in circulating PCSK9 and a 40% reduction in LDL cholesterol compared to placebo. Investigators reported a similar rate of adverse events in both groups [59]. In another phase I trial (NCT02314442), investigators randomly treated healthy volunteers with elevated LDL (>100 mg/dl) with inclisiran in either a single ascending dose phase or a multiple dosing schedules vs. placebo for a total of 4 weeks. At the end of the trial, no serious adverse events were reported; commonly reported adverse events were cough, musculoskeletal pain, headache, and diarrhea. Significant and sustained (up to 180 days) reduction in PCSK and LDL cholesterol levels was noted in both drug regimens [60]. ORION 1 was a phase II (NCT02597127), multicenter, double-blind, placebo-controlled, and multiple-dose ascending trial. Patients with a history of cardiovascular disease or with high risk for cardiovascular disease and elevated LDLwere randomized to receive a single dose of subcutaneous injection of 200, 300, or 500 mg of inclisiran or an equivalent placebo or two doses received 100, 200, or 300 mg of inclisiran or equivalent placebo. At the end of 180 days significant dose-dependent reduction was noted in both PCSK9 and LDL cholesterol levels. The highest reductions in LDL levels were noted in the two doses of 300 mg of inclisiran. Serious events were reported in 11% of patients in the inclisiran group and 8% in the placebo group. [61].

Currently, four phase III trials evaluating inclisiran in cardiovascular diseases are undergoing. ORION 10 (NCT03400800) will evaluate inclisiran efficacy in United States patients with ASCVD and elevated LDL cholesterol despite maximally tolerated lipid-lowering therapies [62]. ORION 11 trial (NCT03400800) will assess the efficacy of inclisiran vs placebo in patients with ASCVD or ASCVD- risk equivalents and elevated LDL cholesterol who are on maximally tolerated statin dose [63]. ORION 10 is a multicenter study in the United States, while ORION 11 is a multicenter study outside of the United States. ORION-8 trial (NCT03814187) will assess long term (3 years) effect of inclisiran dosing in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents like diabetes and familial hypercholesterolemia, or heterozygous or homozygous familial hypercholesterolemia and elevated LDL cholesterol [64]. ORION 4 (NCT03705234) is a large multicenter study, which aims to enroll 15,000 patients with atherosclerotic cardiovascular disease. The study will assess efficacy outcomes like MACE (Coronary heart disease death, MI, ischemic stroke, or urgent revascularization) in patients treated with inclisiran vs. placebo with a median duration of follow up of 5 years [65].

4. Platelets and Coagulation (Table 3)
The role of platelet activation and aggregation during the development of arterial thrombosis has been well-established. Platelets can be activated by multiple signaling pathways mediated by thrombin, thromboxane A2, ADP, and collagen. At this time, the relative contribution of these pathways during in vivo thrombus generation at the arterial injury site is unknown, although we know that the synergistic effect of thromboxane A2 and P2Y12 receptor signaling is pivotal at the site of arterial injury with high shear. Therefore, simultaneous inhibition of cyclooxygenase-1 enzyme and P2Y12 receptor has been the cornerstone strategy in the treatment of patients with ACS 66]. The platelet hypothesis suggests that superior platelet inhibition is associated with superior anti-ischemic outcomes.Potent P2Y12, such as prasugrel and ticagrelor is associated with superior anti-ischemic benefits as compared to clopidogrel; there is a ceiling effect with at least 10% of patients are still associated with recurrent thrombotic events in the first year and elevated bleeding events are significant concerns [67]. To reduce residual recurrent ischemic events with acceptable bleeding event risk, novel strategies targeting platelet protease-activated receptor (PAR)-1 and PAR-4 receptors are being explored.

PAR-1 is a high-affinity thrombin receptor, while PAR-4 is a lower affinity thrombin receptor. It has been demonstrated that PAR-1 mediated platelet aggregation is transient, but when P2Y12 provides a condition signal, it strengthens the platelet aggregation [68]. Earlier studies explored PAR-1 inhibition with E5555 (atoxapar) and SCH 530348 (vorapaxar). E5555 (atoxapar) was discontinued due to its side effect profile. Both these drugs demonstrated marked and specific inhibition of PAR-1 receptor inhibition in platelets. Vorapaxar is a high-affinity PAR-1 antagonist that inhibits PAR-1 in a competitive and slowly reversible manner. Vorapaxar is currently indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with the peripheral arterial disease (PAD) [69].

Inhibition of PAR-1 signal by a reversible and rapid-acting parenteral drug has the potential to attenuate the risk of bleeding in high-risk patients undergoing PCI.4.1 PZ-128Pepducins are lipidated peptides targeting the cytoplasmic surface of the cognate receptor. PZ- 128 (Tufts Medical Center, Boston, USA) is a pepducin molecule that mimics the off state of the corresponding intracellular region of PAR-1 that is required for the coupling of G proteins. PZ- 128 has been shown to be associated with a rapid, specific, dose-dependent, and reversible inhibition of PAR-1 through a novel intracellular mechanism. PZ-128 interrupts the signaling of the internally located G protein and thus prevents downstream coupling. The inhibition of PAR-1 by PZ-128 is reversible [70]. In the phase 1 study (NCT01806077), the pharmacokinetics, pharmacodynamics safety, and tolerability associated with the single ascending dose of PZ-128 in subjects with multiple risk factors for coronary artery disease were assessed. This study demonstrated that the platelet inhibitory effects of PZ-128 are dose-dependent and rapid in onset. Its effects are reversible with the recovery of PAR-1 inhibition by 24 hours. No adverse effects were observed on coagulation parameters such as bleeding time, partial thromboplastin time (PTT), international normalized ratio (INR), and activated chronic clotting time. The plasma concentration of the drug generally correlated with the doseMajor adverse eventswere allergic reactions to the highest doses of PZ-128. However, none of these events were deemed life- threatening [71]. In an ongoing phase II(NCT02561000), multicenter, randomized, double-blind, study TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in PCI) study, is undergoing to evaluate the efficacy of PZ-128 in non-emergent percutaneous coronary intervention patients.
The primary objective is to determine if the addition of PZ-128 to standard medical therapy in patients undergoing cardiac catheterization/PCI will increase the risk of bleeding. The secondary objective is to evaluate if patients treated with PZ-128 have fewer cardiac events such as heart attack, bypass surgery, or stroke compared with those persons treated with the standard of care treatment [72].

4.2 Selatogrel (ACT-246475)

The onset of antiplatelet effects of currently available oral antiplatelet agents such as ticagrelor or prasugrel may be delayed in setting the AMI due to opiate induced delayed intestinal absorption [73,74]. Parenteral P2Y12 inhibitor therapy can overcome this delayed absorption. Selatogrel (Idorsia Pharmaceuticals, Allschwil, Switzerland) is a novel class of P2Y12 inhibitor developed for subcutaneous administration in an emergency setting. In a phase II (NCT03384966) double-blind, randomized study of 346 stable CAD patients treated with oral antiplatelet therapy, subcutaneous administration of selatogrel (8 or 16 mg) was compared with placebo. Pharmacodynamics, pharmacokinetics, tolerability, and safety of a single subcutaneous injection of selatogrel were studied. The study results are still pending [75].

4.3 Vicagrel

Vicagrel (Jiangsu Vcare Pharmatech, China) is an analog of clopidogrel and has the same mechanism of action as potent P2Y12 inhibitors. Vicagrel is metabolized to 2-oxo-cidogrel via hydrolyzation from body esterase instead of the cytochrome p450 pathway and is further converted to an active metabolite M15-2 [76]. In the phase I study (ChiCTR-IIR-16009260), pharmacokinetic, and pharmacodynamic properties of vicagrel in healthy Chinese volunteers were evaluated. This study evaluated 5,10, and 15 mg dosing of vicagrel for 10 days with or without aspirin, and the control group patients were treated with clopidogrel or placebo. The maximum plasma concentration of vicagrel was achieved 0.33 to 0.5 hours after dosing. A dose-dependent P2Y12 receptor inhibition measured by VerifyNow P2Y12 assay was observed with vicagrel. The P2Y12 Reaction Units (PRU) levels of 5mg and 10 mg vicagrel were similar to the daily 75 mg dose of clopidogrel. The investigators also reported an overall safety of Vicagrel with different doses of 5, 10, or 15 mg with or without aspirin. The adverse events observed were mild bleeding, ecchymosis and bleeding gums [77]. Currently, a multi-center, randomized, double-blind, dose exploration phase II trial (NCT03599284) is undergoing in patients with coronary atherosclerotic disease and planned PCI. In this trial, 360 patients will be randomly treated in a 1:1:1:1 ratio with 3 different Vicagrel dose regimens and a control group with clopidogrel. The primary outcome is an assessment of inhibition of platelet aggregation by VerifyNow P2Y12 assay after 28 days of treatment [78].

4.4 Factor Xa inhibitor, TAK-442 (letaxaban) (Table 3)

Factor Xa (FXa) and thrombin are known to play a crucial role in the coagulation cascade [78]. It has been shown that FXa and thrombin influence vascular-inflammation pathways the release of monocyte chemoattractant protein and IL-8 from endothelial cells [79, 80]. TAK-442 (Takeda Pharmaceutical Company, Tokyo, Japan) is a FXa inhibitor. The proposed mechanism of TAK- 442 is inhibition of the increase in calcium mobilization in PAR1-overexpressed cells. In in-vitro studies, the anti-inflammatory effects of selective factor Xa (FXa) inhibitor on human endothelial cells were studied. Compared to direct thrombin inhibitor melagatran and PAR1 inhibitor vorapaxar, TAK-442 inhibited the production of MCP-1 induced by FXa, while compared to melagatran, it did not inhibit MCP-1. The authors concluded that TAK-442 might have anti-inflammatory potential in addition to anti-thrombotic effects [80]. In a phase II dose- finding AXIOM study (NCT00677053), the effect of TAK-22 on the incidence of bleeding in patients following an ACS event was studied. In this double-blind study, 2,753 patients were randomized to TAK-442 or placebo in addition to standard of care with aspirin and clopidogrel. The primary endpoint of thrombolysis in MI (TIMI) major bleeding was similar between the groups (0.9% versus 0.5%; P=0.47) but there was a dose-dependent increase in bleeding with the modified International Society on Thrombosis and Haemostasis (ISTH) scale. In addition, there was no reduction in cardiovascular events, although the study was underpowered to assess efficacy for cardiovascular events [81].
6. P-Selectin Inhibitor, Inclacumab (RO4905417) (Table 3)

P- Selectin is a cell adhesion molecule that is present in the endothelial cell and mainly platelets. During inflammation, P- selectin expression leads to leukocytes/macrophage -platelet aggregation [82]. Elevated levels of soluble P-selectin had been noted in patients with NSTEMI [83]. Increased level of P-selectin had been shown to be associated with unsuccessful coronary thrombolysis in patients with MI [84]. Inclacumab (Roche, Basel, Switzerland) is a specific human recombinant monoclonal antibody against human P-selectin. A phase II trial (NCT01327183) SELECT-ACS (Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non-ST-Elevation Myocardial Infarction) evaluated efficacy and safety of inclacumab in patients with NSTEMI scheduled for coronary angiography and PCI. Patients received either 5 or 20 mg/kg inclacumab or placebo before PCI, and the main primary outcome was change from baseline to 24 hours post PCI troponin I levels. Only the 20 mg/kg dose of inclacumab vs. placebo showed a reduction in Tn I levels 24-hour post PCI (p=0.05). Serious adverse events were reported in 24% in 5 mg/kg group, 26% in the 20 mg/kg group, and 18 % in the placebo group. Six patients died in the inclacumab group while none in the placebo group. The investigators also reported an increased number of MI in the treatment group compared to placebo, the significance of which was not clear though it can be related to the definition of MI. Despite the promising results of inclacumab in reduction of myocardial injury in NSTEMI patients, it never went to a phase III trial likely because the benefits were minimal and with possible increase in adverse events [85]. In August 2018 the parent company Roche sold inclacumab to Global Blood Therapeutics for possible use in vaso- occlusive crisis in sickle cell disease.

7. GPVI-Fc dimer, Revacept (PR-15) (Table 3)
Collagen on the atherosclerotic plaques, when exposed to circulating blood, binds to the platelet surface glycoprotein VI (GPVI) receptors and induces platelet activation and aggregation. Revacept (AdvanceCOR GmbH, Martinsried, Germany) is a dimeric soluble GPVI-Fc, which is made by the fusion of an Fc fragment (fragment crystallisable) to the GPVI receptor. It competes with the platelet GPVI receptor for binding to the collagen in the atherosclerotic plaques thereby preventing platelet aggregation locally without affecting systemic hemostasis [86]. In the phase I (NCT01042964) dose-escalation trial, a single intravenous dose was administered in healthy volunteers. Collagen-, ADP- or thrombin related activating peptide-induced platelet aggregation 19was assessed. In this study, revacept was associated with a dose dependent reduction in collagen-induced platelet aggregation without any significant effect on ADP- or thrombin receptor activating peptide-induced aggregation. There was no significant effect of revacept on bleeding time, platelet counts, activated partial thromboplastin time (APTT) and international normalized ratio (INR). When added to single or DAPT, revacept led to increased inhibition of platelet aggregation without affecting primary hemostasis as indicated by bleeding time, INR, platelet count [87]. In the currently undergoing phase II trial (NCT03312855), ISAR-PLASTER (Intracoronary Stenting and Antithrombotic Regimen: Lesion Platelet Adhesion as Selective Target of Endovenous Revacept) efficacy of a single intravenous dose either in 80mg or 160 mg revacept in patients with stable CAD undergoing elective PCI is being evaluated. The primary outcome of this study is death or myocardial injury within 48 hours after randomization, while secondary outcomes are all-cause mortality, MI, Type 4 MI, stent thrombosis, revascularization, stroke and Bleeding Academic Research Consortium (BARC) bleeding Grade 2 or higher within 30 days after randomization [88].

8. Miscellaneous Pathways (Table 4)
8.1 CMX-2043

CMX–2043 (Ischemix, North Grafton, MA, USA) is an analog of alpha-lipoic acid, which is being evaluated for its cardioprotective role, especially in cardiac ischemia-reperfusion injury after MI [89]. In animal studies, alpha-lipoic acid has been shown to protect liver, kidney, heart, and brain tissues from oxidative damage. CMX 2043 also has antiapoptotic activity. The exact mechanism of action remains unclear, but the two important properties of CMX-2043 are antioxidants and cryoprotection during ischemia-reperfusion. Work by Lader et al. suggested that activation of tyrosine kinase pathway and Akt phosphorylation play a significant role in membrane stability and decrease calcium release from endoplasmic reticulum which then attenuates cellular apoptosis [89,90]. In the phase II (NCT00984802) SUPPORT-1 (Study Safety and Efficacy of CMX-2043 in Subjects Undergoing PCI and Peri-Operative Reperfusion Treatment) trial, 142 patient undergoing elective PCI were randomly treated with CMX-2043 (0.8, 1.6 and 2.4 mg/kg) vs. placebo in a 3:1 ratio. The creatinine kinase (CK)-MB and Troponin T levels (primary outcome) were significantly reduced with high dose CMX-2043 (2.4mg/kg) vs. placebo. All doses were safe in the study population [91]. In 2014 another phase II

(NCT02103959) multicenter randomized, double-blind, placebo-controlled study CARIN trial (Coronary Angiography at Risk of Radio-contrast Induced Nephropathy) was conducted to evaluate the safety and efficacy of CMX-2043 in reducing acute kidney injury (AKI) in patients undergoing PCI. Patients (n=361) were randomly treated in a 1:1:1:1 ratio with different doses of CMX-2043 (2.4, 3.6, 4.8 mg/kg) vs placebo. Patients with ACS except STEMI were followed for 90 days, and the primary outcome was an incidence of AKI and secondary outcomes were MACE (CV death, non-fatal MI and stroke), MI, mean eGFR and major adverse kidney events (sustained eGFR >20%, prolonged hospitalization, rehospitalization, death or dialysis). This study demonstrated no difference with any doses of CMX-2043 vs placebo in reducing post-PCI AKI/contrast-induced nephropathy. No significant improvement in MI or MACE was noted between CMX-2043 vs. placebo [92].

8.2 RVX-208 (Apabetalone or RVX000222)

RVX-208 or Apabetalone (Resverlogix Corporation, Calgary, Canada) is a bromodomain and extra-terminal (BET) protein inhibitor [93]. BET proteins are associated with the regulation of inflammation and thrombosis in the pathogenesis of cardiovascular disease at the gene transcription level. BET proteins bind to chromatin, which then recruits protein complexes, which regulates transcription in various cells like hepatocytes and intestinal cells [93]. Binding of RVX-208 to the BET bromodomains leads to dissociation of BET proteins from chromatin, ultimately altering transcription, which leads to apoA-I production and suppression of IL-6 related inflammation pathways. ApoA-I, in-turn, leads to the generation of preβ-HDL, which in turn facilitates reuptake cholesterol from macrophages and atherosclerotic plaques [93,94]. Three phase II trials evaluating RVX-208 in CAD patients had been done so far. The ASSERT (ApoA- I Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease) study (NCT01058018) evaluated 299 statin-treated CAD patients who received 50-150 mg apabetalone vs. placebo for 12 weeks. There was a dose dependent increase in apoA-I (P=.035) and simultaneous HDL level (P=.02). A total of 18 patients treated with the study drug had >3 times transaminase elevation [95]. In the SUSTAIN (Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation) trial (NCT01423188), the impact of treatment with apabetalone 100 mg twice daily vs placebo for 24 weeks in 172 statin treated patients was evaluated. Similar to ASSERT study, there was an increase in apoA-I levels and >3 times increase in transaminases [96]. The ASSURE (ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation, NCT01067820) study evaluated the impact of apabetalone 100 mg twice daily vs. placebo for 26 weeks in 323 patients with angiographic CAD and low HDL-C levels. The primary outcome was the progression of coronary atherosclerosis using serial intravascular ultrasound. This trial failed to show any significant improvement in total atheroma volume in two groups, while the elevation of transaminases was significantly higher in the RVX-208 group when compared to placebo [997]. A pooled analysis of the three studies showed a significant increase in the apoA-I, HDL-C, and a decrease in hsCRP levels. Interestingly, this analysis also showed a decrease in MACE in the treatment group compared to the placebo group (5.9 vs. 10.4%; P = 0.02), especially in patients with diabetes, low baseline HDL-C and elevated hsCRP [98]. Currently, a phase III study (NCT02586155) BETonMACE (Bromodomain Extraterminal Domain Inhibition Treatment With RVX000222 Increases the Time to Major Adverse Cardiovascular Events, NCT02586155), is underway. This is a multicenter, double-blind, randomized and placebo-controlled study evaluating the role of apobetalone in 2,425 post ACS, and type 2 diabetic patients treated with high-intensity statin therapy (atorvastatin or rosuvastatin). The study is expected to be completed by 2019. The primary outcome of this study is the first occurrence of MACE (CV death, non- fatal MI, or stroke) with a follow-up time of 120 weeks [99].

8.3 Losmapimod, p38 Mitogen-activated protein kinase (MAPK) inhibitor

p38 MAPK has been implicated in the preclinical models to contribute to cardiac fibrosis, and inhibition of p38 MAPK can reduce the risk of recurrent cardiovascular events [100]. In the LATITUDE-TIMI 60 (LosmApimod To Inhibit p38 MAP Kinase as a TherapeUtic Target and moDify Outcomes After an Acute Coronary syndrome), a phase 3 trial (NCT02145468), the effects of p38 Mitogen-activated protein kinase (MAPK) inhibitor Losmapimod (GlaxoSmithKline, Brentford, UK) in 3,503 patients with NSTEMI were studied. This study was a randomized, placebo-controlled, double-blind, parallel-group trial. In this study, losmapimod did not reduce the risk of the primary endpoint of a composite of CV death, MI, or severe recurrent ischemia requiring urgent coronary revascularization at 12 weeks compared to placebo, and these results did not justify proceeding to a larger efficacy trial [101].

8.4 Danegaptide (ZP1609), Gap junction modulating peptide

Connexins are proteins that are structurally assembled to form the gap junctions. Connexin 43 is the isoform found in cardiomyocytes and vascular endothelium. It plays an important role in electrochemical signaling and ischemia-reperfusion injury. Connexin 43 found in mitochondria of cardiomyocytes is involved in the formation of reactive oxygen species and plays a role in ischemic preconditioning [102]. Danegaptide (Zealand pharma, Copenhagen, Denmark) is a dipeptide and, a second-generation oral gap junction modifier, which is similar to its parent drug rotigaptide and has antiarrhythmic properties [103]. This drug had shown cardio-protective effects in terms of reducing infarct size in animal models [104]. In a phase II trial (NCT01977755), STEMI patients were randomized to either two different doses of danegaptide or placebo, which was administered 10 minutes prior to PCI and lasted for 6 hours. The primary outcome of myocardial salvage evaluated by cardiac MRI at 3 months was similar between danegaptide and placebo (p=0.88). The secondary outcome of infarct size and left ventricular ejection fraction was also similar between the two groups [105]. So far, no further studies are planned for danegaptide.

8.5 MTP-131 (Bendavia or Elamipretide), Mitochondria Targeting Peptide

Cardiolipin is a phospholipid present on the inner mitochondrial membrane. Cardiolipin plays an important role in several mitochondrial biochemical processes and maintenance of inner membrane stability. Loss of cardiolipin from aging or damage by reactive oxygen species leads to cell death [106]. MTP-131(Stealth BioTherapeutics Inc. Newton, MA, USA) is a mitochondria targeting peptide that selectively binds to cardiolipin and preserves its integrity. Reactive oxygen species (ROS) play a significant role in myocardial injury after ACS. MTP-131 reduces ROS levels in cardiomyocyte mitochondria and can reduce reperfusion injury after an ACS event. In animal models, MTP-131 was shown to reduce infarct size in STEMI models and also improved left ventricular ejection fraction [107,108]. EMBRACE STEMI (Evaluation of Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events), a phase II study (NCT01572909), evaluated the safety and efficacy of MTP-131 in patients with STEMI undergoing PCI. The primary endpoint of the study was infarct size evaluated by the area under the curve of CK-MB, and the important secondary outcomes were the change in volume of infarcted myocardium on cardiac MRI, myocardial function and TIMI flow grade. The investigators concluded that MTP-131 had good safety outcomes but was not associated with any significant improvement in primary or secondary outcomes [109]. No further studies are planned for MTP-131 in ACS patients. It is now investigated for mitochondrial disorders.

9. Conclusions

Newer targets are being explored for secondary prevention among patients with ACS on top of standard DAPT to improve ischemic outcomes. These targets include inflammation pathways, lipid and cholesterol pathways, new antithrombotic drugs, and other novel targets such as alpha lipoic analog, p38 MAPK inhibition, and gap junction modifier. These therapies may be associated with lower bleeding risk than potent antithrombotic therapies. Some, but not all, phase II studies demonstrated promising preliminary results, but larger Phase III trials are needed to confirm the safety and efficacy of these agents.

10. Expert opinion

The current secondary prevention strategy in ACS patients involves treatment with potent P2Y12 inhibitors plus aspirin on top of aggressive control of lipids, blood pressure, and other modifiable cardiovascular risk factors. Despite this, the degree of adverse event reduction is far from optimal, and there is a high incidence of recurrent thrombotic event occurrence (~10% in first year after an ACS event) along with a significant risk of bleeding. The elevated risk is more prevalent in patients with high-risk factors such as diabetes, renal failure, a history of stroke, and the elderly. Recent studies revealed that recurrent ischemic event occurrence is not just due to events occurring in the culprit vessel but it also in the nonculprit vessels that may partly be due to persistent coronary inflammation after an ACS event. It has been well established that inflammation plays a major role throughout atherosclerotic plaque development, instability, rupture, and ischemic event occurrences.
In this line, novel agents such as PCSK9 inhibitors, IL-1β inhibitor (canakinumab), or icosapent ethyl are shown to be associated with significant ischemic risk reduction when added to standard therapy in patients with cardiovascular disease [110-112]. But a nonspecific approach with low- dose methotrexate in inhibiting inflammation in the ambitious CIRT trial was not associated with improved clinical outcomes [113]. Replacing aspirin with rivaroxaban on top of P2Y12 inhibitors for ACS has been explored in a phase 2 trial and adding very low dose rivaroxaban to aspirin for long term therapy in patients with a history of ACS or with polyvascular disease has been recently investigated in a large phase 3 trial. The final goal in this area is a further reduction in the residual ischemic event occurrences, particularly in high-risk patients, without any added risk of bleeding.

In addition, there are numerous agents targeting inflammation, lipid/cholesterol control, and thrombosis pathways that are discussed in this article. Anti-inflammatory agents such as the 5- FLAP inhibitor (AZD5718), anakinra (recombinant IL-Ra), and tocilizumab (anti-Il 6 receptor antibody) and agents targeting lipid and cholesterol management, CSL112 (reconstituted human plasma-derived apo A-1), MED1 6012 (recombinant lecithin cholesterol-acyltransferase) and inclisiran (small interfering RNA directed towards PCSK9), showing some promise. However, clinical efficacy and more importantly, safety concern with respect to bleeding should be addressed in adequately powered Phase III trials. Currently, it is very challenging to conduct Phase III trials involving thousands of patients due to the high cost. The higher cost of the drug will be a major limitation for wide spread use of novel agents in general practice in futureWith respect to antiplatelets, there is an unmet need for fast-acting and reversible therapies associated with a favorable safety profile. Selatogrel with its ease of subcutaneous administration, provides a favorable option for emergent therapy in ACS and in settings where rapid P2Y12 inhibition s desirable. Similarly, PZ-128 with its rapid onset and reversible effect may be a suitable agent for adjunctive therapy in the PCI setting. Finally, DAPT will likely remain the cornerstone strategy during the acute phase of ACS whereas for long term secondary prevention, the above-mentioned agents may be included as adjunctive agents.


This study is funded by Sinai Center for Thrombosis Research.

Declaration of Interests
P Gurbel reports receiving grants from the National Institutes of Health, Bayer, Medicure, Instrumentation labs, Haemonetics, Amgen, Idorsia, Ionis, Haemonetics, Janssen, and Merck; receiving honoraria and payment for lectures, consultations including service on speakers’ bureaus from Bayer, Janssen, Merck, UptoDate, and Medicure. U Tantry reports receiving honoraria from Astra Zeneca, UptoDate, and Medicure. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

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