Apabetalone (RVX-208): A Potential Epigenetic Therapy for the Treatment of Cardiovascular, Renal, Neurological, Viral, and Cancer Disorders

Abstract

Bromodomain and extra-terminal domain proteins (BET proteins) are epigenetic reader proteins that have been implicated in regulating gene expression through binding to chromatin and interaction with transcription factors. These proteins are located in the nucleus and are responsible for recognizing acetylated lysine residues on histones, reading epigenetic messages, recruiting key transcription factors, and thereby regulating gene expression. BET proteins control the transcription of genes responsible for maladaptive effects in inflammation, cancer, and renal and cardiovascular diseases. Given the multifaceted role of BET proteins in the pathogenesis of various diseases, several small molecule inhibitors of BET proteins have been developed as potential therapeutic targets for treating different diseases in recent years. However, while many nonselective BET inhibitors are indicated for the treatment of cancer, a selective BET inhibitor, apabetalone, is the only oral BET inhibitor in phase III clinical trials for the treatment of cardiovascular diseases and others. Thus, this review aims to present and discuss the preclinical and clinical evidence for the beneficial effects and mechanism of action of apabetalone for treating various diseases.

Epigenetics is a process by which chromatin is subjected to a chemical modification as a result of the surrounding environment, influencing transcription.¹ Acetylation of lysine residues on histones is an example of such modification.¹ Bromodomain and extra-terminal domain (BET) proteins are a family of nuclear bromodomain-containing proteins (BRD)-containing proteins, including BRD2, BRD3, BRD4, and the testis-restricted BRDT, that recognize acetylated lysine residues on histones, read epigenetic messages, recruit key transcription factors, and thereby regulate gene expression.^2,3

The structure of BET proteins consists of an extra-terminal domain, a C-terminal domain, and two conserved N-terminal bromodomains (BD1 and BD2).⁴⁻⁶ Notably, the C-terminal domain of BRD4 recruits the positive transcription elongation factor (PTEF-b), and the bromodomains interact with histones and transcription factors, such as Nuclear factorκB (NFκB) subunit p65.^4,5 Of interest, the bromodomains BD1 and BD2 are the sites where BET proteins interact with proteins and function as epigenetic readers.⁴ The structure of the BD itself consists of four helices, α_Z, α_A, α_B, and α_C, with a left-handed up-and-down fold that is connected by two loops.^4,5 The α_Z and α_A helices are attached by the ZA loop whereas, α_B and α_C are linked through the BC loop.^4,5 Of importance, the acetylated lysine binds between the ZA and BC loops and it is a conserved acetyl-lysine binding domain for histone binding in BDs or KAc domains.^4,5Figure 1 illustrates the solved crystal structure of apabetalone bound to the bromodomains of BRD2.⁶

Figure 1.

Crystal structure of apabetalone bound to the bromodomains of BRD2 (PDB ID 4J1P). (A) Chemical structure of apabetalone. (B) View of the apabetalone binding site with key interacting residues. Red dots represent water molecules. This figure has been obtained from RCSB PDB (PDB ID 4J1P) (https://www.rcsb.org/structure/4j1p).

Of interest, BET proteins have garnered much attention of late as major contributors to the pathogenesis of several diseases such as cancer and inflammatory and autoimmune diseases.¹ Notably, BET proteins detect and bind to acetylated lysine residues on histones located in the promoter or the enhancer region of the gene.^2,4,5,7 Following this binding, the C-terminal domain of BET proteins, mainly presented in the BRD4 family member, recruits the PTEF-b to the transcriptional machinery of genes regulated by BET proteins^2,4,5,7,8 (Figure 2). Indeed, several studies have demonstrated that the BET protein family, particularly the BRD4 protein member, is implicated as an epigenetic regulator of genes involved in maladaptive responses of cell cycle control, cell proliferation, DNA replication, and inflammation, thereby being a critical player in cell growth.⁹⁻¹¹ Thus, it is not surprising that BET/BRD4 has a crucial role in the pathogenesis of various types of cancer;⁹⁻¹¹ therefore, various BET inhibitors have already been proven effective for oncology indications.¹² Additionally, BET proteins have been shown to play a role in autoimmune diseases,¹³ cardiovascular disease,¹⁴⁻¹⁶ inflammation,¹⁷⁻²⁰ and renal disease.²¹ Interestingly, recent studies have also shed light on the involvement of BET proteins in neurological disorders,^22,23 as well as the development and progression of various types of viral infections.^11,24

Figure 2.

Molecular mechanism of action of bromodomain and extra-terminal domain proteins (BET proteins). Tumor necrosis factorα (TNFα), interleukin-6 (IL-6), IL-1β, IL-18, IL12p40, intercellular adhesion molecule 1 (ICAM-1), CCL-2, transforming growth factor-β (TGFβ), alkaline phosphatase (ALP), NADPH oxidase 2 (NOX2). Figure was created with bioRender.com.

In light of the above information, given the multifaceted role of the BET protein family in the pathogenesis of a variety of diseases,^12−14,21 the BET protein family has been investigated as a potential therapeutic target for the treatment of different diseases in recent years.^12,25,26 Thus, there has been an increase in interest in developing drugs that are small-molecule BET ligands using the chemical probes technique.^1,7,27 Notably, while these ligands were initially developed as chemical tools to probe BET function, BET inhibitors are currently investigated for their treatment potential.^12,25 Indeed, nonselective BET inhibitors bind to both BD1 and BD2, and a number of them are already in use or at various stages of a clinical trials for oncology indications, including I-BET762, MK-8628, CPI-0610, TEN-010, ZEN003694, ABBV-075, INCB054329, and INCB057643.^12,25

Although many BET inhibitors have been successfully used for treating different types of cancer,^12,25 not many are in use for non-oncology indications. Indeed, apabetalone, also known as RVX-208 or RVX-000222, is the only BET inhibitor with a selective effect on BD2 that has been granted a breakthrough therapy designation from the FDA outside the area of oncology.²⁶ Thus, the purpose of this review is to present and discuss preclinical and clinical evidence for the beneficial effects and mechanism of action of apabetalone for the treatment of various diseases.

Overview of Apabetalone

Apabetalone is a quinazoline chemical derivative of resveratrol developed by Resverlogix corporation²⁸ (Figure 1A). A pharmacokinetic experiment conducted on cynomolgus monkeys showed that apabetalone demonstrated ∼44% of oral bioavailability with 5 mL/min/kg systemic clearance, 0.81 L/kg volume of distribution, and a half-life of 1.5 h.²⁹ In addition to this, the concentration of apabetalone was higher in the small intestine and liver tissues compared to plasma.²⁹ Importantly, a phase I, open-label, parallel-group trial was performed to examine the pharmacokinetic profile of apabetalone in healthy individuals and chronic kidney disease patients.³⁰ In this study, both healthy individuals (n = 8) and chronic kidney disease patients (n = 8) demonstrated a similar half-life of ∼6 h, time to maximum observed concentration (T_max) of 4 h, maximum observed plasma concentration (C_max) of 360 ng/mL, and area under the curve (AUC_0–last) of ∼2000 h·ng/mL in an open-label, parallel-group study.³⁰ Overall, apabetalone has favorable oral bioavailability and a stable pharmacokinetic profile.

Apabetalone in the Treatment of Cardiovascular Disease

Apabetalone Upregulates the Level of ApoA-I and HDL

Numerous experimental studies have supported the hypothesis that apabetalone is a potent inducer of apolipoprotein A-I (apoA-I).^29,31 For instance, apabetalone significantly increases apoA-I mRNA level and proapoA-I protein secretion in a time- and concentration-dependent manner in human primary hepatocytes.²⁹ The effect of apabetalone on apoA-I has also been confirmed in vivo in the African green monkey model.²⁹ Notably, monkeys treated with apabetalone for 63 days displayed significant improvement in apoA-I levels and ATP-binding cassette transporter (ABCA1)-specific and non-ABCA1-specific cholesterol efflux as well as promoted a shift in high-density lipoprotein (HDL) particle size distribution.²⁹ Given that (i) apoA-I is a major protein component of HDL-particles and is associated with cholesterol efflux from macrophages to HDL-particles³² and (ii) apoA-I is known to play a vital role in mediating the anti-inflammatory and atheroprotective effects of high-density lipoprotein (HDL),³² it is reasonable to assume that apabetalone may exhibit a beneficial effect on the cardiovascular system via upregulation of apoA-I and HDL levels.²⁹ Mechanistically, the process of upregulating the transcription of the apoA-I gene is mediated via the binding of apabetalone to the BET proteins, particularly BD2 of BRD4.⁶ The BD2 domain of BRD4 plays a critical role in recruiting BET proteins to chromatin, thereby altering gene expression.⁶ Thus, by targeting BD2 of BRD4, apabetalone inhibits the activity of BET proteins and their downstream effects on gene expression, including the transcription of apoA-I mRNA.⁶ Overall, previous studies demonstrated that apabetalone may improve lipid profiles via upregulation of the apoA-I/HDL pathway (Table 1).

Table 1. Effect of Apabetalone on Cardiovascular, Renal, and Fabry Diseases, Cancer, HIV, and COVID-19.

disease	study model	treatment	effect	ref
cardiovascular disease	HepG2 cells	concentration up to 60 μM of apabetalone for 48 h	↑ apoA-I	(29)
			↑ HDL
	African green monkeys	apabetalone 15–60 mg/kg/day for 63 days	↑ apoA-I	(29)
			↑ ATP-binding cassette transporter (ABCA1)-specific and non-ABCA1-specific cholesterol efflux
	ApoE(−/−) mouse model of hyperlipidemia and aortic lesion	apabetalone 150 mg/kg BID for 12 weeks	↑ HDL	(87)
			↓ aortic lesion
			↓ circulating adhesion molecules
			↓ cytokines
			↓ haptoglobin
	Western diet fed mouse model of hyperlipidemia and aortic lesion	apabetalone 150 mg/kg BID for 14 weeks	↑ HDL	(87)
			↓ aortic lesion
			↓ CXCL10 and CCL22
	HUVECs and THP-1 cells incubated with TNFα	apabetalone 5 and 20 μM for 2 h	↓ inflammation	(35)
			↓ Adhesion mediators
	cryopreserved hepatocyte or human whole blood from healthy donors	apabetalone 20 μM for 72 h	↓ inflammation	(31)
			↓ thrombotic mediators
	high fat diet mice as a model of obesity-induced aortic inflammation	apabetalone 150 mg/kg for 16 weeks	↓ proinflammatory cytokines and chemokines	(36)
			↓ TNFα signaling
	chimeric mouse with humanized liver	apabetalone 150 mg BID	↓ complement	(38)
	primary human hepatocytes and Huh-7 hepatocellular carcinoma cells incubated with IL-6 and INFγ	apabetalone 20 μM for 24 h	↓ IL-6- and INFγ-driven complement	(38)
			↓ C3, C4 and C5 complement expression
chronic kidney disease	human renal mesangial cells exposed to tissue growth factor β (TGFβ)	apabetalone 1, 5, or 25 μM for 1 h	↓ α-smooth muscle actin	(47)
			↓ collagen production
			↓ inflammatory markers
			↓ fibrotic markers
			↓ ALP
	primary human coronary artery	apabetalone 5 or 25 μM	↓ TNAP expression	(52)
			↓ extracellular calcium deposition
			↓ matrix mineralization markers
			↓ ALP
Fabry disease	peripheral blood mononuclear cells and neutrophils from blood samples of eight Fabry patients incubated with LPS or IFN-γ	apabetalone 1, 5, and 20 μM for 4 h	↓ inflammatory cytokine	(63)
			↓ ROS
cancer	DLD1 and Caco-2 colorectal cancer cell lines	apabetalone 40 μM for up to 90 h	↑ apoA-I	(83)
			↓ ABCA1 expression
			↓ invasiveness
	OVCAR-5, CaOV3, carboplatin-sensitive and -resistant primary HGSOC ovarian cancer cells	apabetalone 80 μM for 72 h	↓ ABCA1 expression	(84)
			↑ sensitivity of ovarian cancer cells to carboplatin
	human xenograft mouse model of rhabdomyosarcoma as well as rhabdomyosarcoma cells	apabetalone 10 μM for 24 h in combination with inhibitors of mammalian target of rapamycin complexes 1 and 2 (mTORC1/2)	↓ BRD4	(85)
			↓ H3K27ac + H4K8ac
			histone modifications
			↑ necroptosis
HIV	j-Lat A2, j-Lat 10.6, U1, and ACH2 cells, as well as primary human CD4+ T cells	apabetalone 10–30 μmol/L for 48 h	reverses latency of HIV reservoir	(66)
			↑ apoptosis of reactivated reservoir cells
	J-Lat C11 cells and A10.6 cells	apabetalone 50 μM for 24–72 h	↑ phosphorylated CDK9	(69)
			reverses latency of HIV reservoir
COVID-19	bronchial epithelial Calu-3 cells and African green monkey kidney epithelial Vero-6 cells as well as hepatic cell lines, HepG2 and Huh-7	apabetalone 1, 5 or 20 μM for 24–96 h	↓ ACE2 expression	(74)
			↓ CD26 expression
			↓ viral host cell entry
			↓ viral replication
	Calu-3 cells stimulated by SARS-CoV-2 RNA	apabetalone 1, 5 or 20 μM for 48 or 72 h	↓ IFN-I signaling pathway	(80)
			↓ inflammatory cytokines

The beneficial effect of apabetalone on the apoA-I/HDL pathway has also been investigated in the apoE(−/−) mouse model of hyperlipidemia and aortic lesion.³³ Treatment of these mice with 150 mg/kg twice daily of oral apabetalone for 12 weeks significantly improved aortic lesions, upregulated HDL levels, and downregulated the level of low-density lipoprotein (LDL).³³ Importantly, the improvement of lipid profiles and aortic lesions by apabetalone in apoE(−/−) mice was associated with a significant reduction of serum proinflammatory cytokines and haptoglobin in addition to adhesion molecules compared to control.³³ The protective effect of apabetalone has also been confirmed in the western-diet-fed mouse model of hyperlipidemia and aortic lesion.³³ These mice were treated with apabetalone or vehicle for 14 weeks.³³ Consistent with the effect obtained in apoE(−/−) mice, apabetalone significantly improved the aortic lesion in western-diet-fed mice.³³ However, no significant changes have been observed in the lipid profiles in western-diet-fed mice.³³ Nevertheless, apabetalone significantly lessened the level of proinflammatory cytokines, such as CXCL10 and CCL22, in these mice.³³ Collectively, these findings suggest that apabetalone may protect against aortic lesions associated with atherosclerosis by improving the lipid profile and reducing inflammation (Table 1).

Apabetalone Reduces Endothelial Dysfunction and Vascular Inflammation

Endothelial dysfunction and vascular inflammation are known contributors to cardiovascular disease.³⁴ Notably, an in vitro study conducted on endothelial cells and monocytes showed that BET proteins are necessary for the induction of inflammation in endothelial cells and adhesion mediator transcripts in monocytes.³⁵ Of interest, apabetalone inhibited BET-dependent transcription, downregulated gene expression of inflammation and adhesion mediators, and reduced adhesion of monocytes to endothelial cells.³⁵ In another study, using microarray analyses, treatment of cryopreserved hepatocyte or human whole blood from healthy donors with apabetalone demonstrated that apabetalone significantly downregulated proinflammatory, pro-atherosclerotic, and pro-thrombotic pathways.³¹ Overall, these findings suggest that apabetalone has a beneficial effect on endothelial dysfunction by reducing inflammation (Table 1).

The protective effect of apabetalone on endothelial dysfunction and vascular inflammation has also been studied in a mouse model of obesity.³⁶ This study utilized high-fat diet fed mice as a model of obesity-induced aortic inflammation.³⁶ These mice were treated twice daily with 150 mg/kg of oral apabetalone or vehicle for 16 weeks.³⁶ Notably, apabetalone treatment significantly reduced the expression of proinflammatory cytokines and chemokines in the aorta of high-fat diet fed mice.³⁶ Mechanistically, using bioinformatics analysis, apabetalone selectively targeted tumor necrosis factor (TNFα) signaling in the aorta of high-fat diet fed mice.³⁶ Furthermore, apabetalone was able to reduce a panel of proinflammatory transcripts by TNFα in the primary human endothelial cells.³⁶ Together, these findings suggest that apabetalone reduces aortic inflammation and endothelial dysfunction by targeting the TNFα signaling pathway (Table 1).

Complement pathway is another important biological process contributing to endothelial dysfunction and cardiovascular diseases such as atherosclerosis.³⁷ Indeed, overactivation of this pathway is linked to plaque development and destabilization.³⁷ Of interest, apabetalone has been shown to reduce the mRNA and protein expression of complements, such as C3, C4, and C5 in primary human hepatocytes and Huh-7 hepatocellular carcinoma cells.³⁸ The effect of apabetalone on complements has also been confirmed in vivo in a model of chimeric mice with humanized liver.³⁸ These mice were treated with 150 mg/kg twice daily of oral apabetalone or vehicle for 3 days.³⁸ Consistent with the effect obtained in hepatocytes, apabetalone significantly downregulated the mRNA expression of human complements in chimeric mice with humanized liver.³⁸ Collectively, these findings indicate that apabetalone is effective in reducing the expression of complement in vitro using hepatic cells and in vivo in a humanized liver.

Given that complements are naturally synthesized in the liver as a result of inflammatory cytokines,³⁸ the study also assessed the effect of apabetalone on the expression of complements induced by cytokines such as interleukin-6 (IL-6) and interferon-γ (INFγ) in liver cells.³⁸ Using primary human hepatocytes and Huh-7 hepatocellular carcinoma cells, apabetalone significantly reduced IL-6- and INFγ-driven mRNA and protein expression of complements.³⁸ Since complements are directly involved in endothelial and vascular dysfunction,³⁷ these results raise the possibility that apabetalone may reduce the risk of cardiovascular disease, partly via downregulating the expression of complements (Table 1).

Clinical Evidence of the Potential Beneficial Effects of Apabetalone on Cardiovascular Diseases

The effect of apabetalone in patients with low levels of HDL has been investigated in the SUSTAIN (Study of Quantitative Serial Trends in Lipids with Apolipoprotein A-I Stimulation) study (SUSTAIN; ClinicalTrials.gov identifier: NCT01423188).³⁹ This randomized phase II clinical trial includes 176 statin-treated patients with low levels of HDL who received either placebo or 100 mg of apabetalone twice daily for 24 weeks.³⁹ Importantly, while the apabetalone-treated group did not show a statistically significant change in atheroma volume compared to the placebo group (0.4% vs 0.3% placebo),³⁹ there was a statistically significant increase in apo-AI level (12.8% vs 10.6% placebo, P <.001) and HDL level (11.1% vs 9.1% placebo, P <.001) compared to the placebo group.³⁹ Overall, this study suggests that apabetalone effectively upregulates apo-AI and HDL levels (Table 2).

Table 2. Clinical Evidence of the Potential Beneficial Effects of Apabetalone in Cardiovascular, Chronic Kidney, and Neurological Diseases.

system	subjects	clinical study	study type	treatment	outcome	ref
cardiovascular disease	299 statin-treated patients with stable coronary artery disease	ASSERT	randomized placebo controlled parallel group study	50, 100, or 150 mg BID for 12 weeks	slight but not significant increase in HDL and apoA-I	(40)
					↑ mean size of HDL particle concentration
	323 angiographic coronary disease patients with low HDL	ASSURE	randomized multicentered placebo controlled parallel group study	100 mg twice daily or placebo	↓ atheroma volume compared to baseline but not placebo	(41)
					↓ adhesion molecule
					↓ metalloproteinases
					↓ cytokines
	176 statin-treated patients with low levels of HDL	SUSTAIN	randomized placebo controlled parallel group study	100 mg apabetalone BID or placebo for 24 weeks	no significant change in atheroma volume	(39)
					↑ apoA-I levels
					↑ HDL
	2425 patients on standard care	BETonMACE	multicenter, event-driven, randomized, double-blind, placebo-controlled trial	100 mg of oral apabetalone twice daily or placebo for about 700 days	no significant effect on MACE	(26)
					↓ first and recurrent hospitalization for heart failure
chronic kidney disease	patients with stage 4 or 5 chronic kidney disease (n = 8) and their matched controls (n = 8)		open-label, parallel group trial	plasma collected after 12 h of single dose apabetalone	↓ proteins associated with inflammation, vascular calcification, cell adhesion, thrombosis, oxidative stress	(30)
					↓ fibrotic markers
	48 patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2	SUSTAIN & ASSURE	post-hoc analysis	100 mg BID of apabetalone or placebo for 24–26 weeks; ALP and eGFR were measured prior to randomization and at final visits	↑ eGFR	(57)
					↓ serum ALP
	288 patients with type 2 diabetes and a recent acute coronary syndrome, with CKD (eGFR < 60 mL/min/1.73 m2)	BETonMACE	multicenter, event-driven, randomized, double-blind, placebo-controlled trial	100 mg of oral apabetalone twice daily or placebo for about 700 days	30% ↓ in MACE	(58)
					↓ heart failure hospitalizations
neurological disorders	464 Alzheimer’s disease and vascular dementia patients (≥70 years) were selected from the BETonMACE trial		placebo-controlled randomized nested analysis	100 mg apabetalone twice daily or placebo for 2 years	↑ total moca Cognitive score	(60)

In addition to the SUSTAIN trial, the ApoA-I Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease (ASSERT) study was designed to assess the efficacy and safety of apabetalone as an adjuvant therapy for the treatment of hyperlipidemia (ASSERT; ClinicalTrials.gov identifier: NCT01058018).⁴⁰ This randomized phase II clinical study evaluated statin-treated patients with stable coronary artery disease.⁴⁰ A total of 299 patients received either 50, 100, or 150 mg apabetalone orally or placebo for 12 weeks.⁴⁰ Notably, while there was a dose-dependent increase in the level of apoA-I and HDL compared to placebo, it was not statistically significant.⁴⁰ In addition, although no changes were observed in the total number of circulating LDL and HDL particles, the mean size of HDL particle concentration was significantly increased (11.1% to 21.1%, P = 0.003) compared to placebo.⁴⁰ Thus, these findings suggest that apabetalone improves lipid parameters in statin-treated patients with stable coronary artery disease. Furthermore, while apabetalone was well-tolerated, 18 patients experienced elevations in liver enzymes.⁴⁰ However, this effect on liver enzymes was reversible and was not associated with an increase in the level of bilirubin.⁴⁰ Overall, this study confirms the potential efficacy and tolerability of apabetalone in statin-treated patients with stable coronary artery disease (Table 2).

ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE) is another important phase II clinical trial that was performed to examine the safety and the efficacy of apabetalone on lipid parameters as well as the progression of coronary atherosclerosis.⁴¹ To test this, a total of 323 angiographic coronary disease patients with low HDL were recruited in a randomized, double-blind, multicenter study (ASSURE; ClinicalTrials.gov identifier: NCT01067820).⁴¹ In this trial, patients received either 200 mg of apabetalone orally or placebo and were assessed at baseline and at 26 weeks.⁴¹ Using intravascular ultrasound imaging, apabetalone did not significantly reduce the atheroma volume compared to placebo.⁴¹ However, patients receiving apabetalone show a statistically significant reduction in the atheroma volume as compared to baseline.⁴¹ Of interest, this effect on the atheroma volume was associated with a significant elevation in apo-AI and HDL and a significant reduction in LDL levels compared to baseline.⁴¹ Adding to this, following analysis of blood samples from the ASSURE study, patients receiving apabetalone demonstrated a significant reduction in circulating adhesion molecules like intracellular adhesion molecule 1 (ICAM-1),metalloproteinases, and cytokines such as TNFα, IL-6, and IL-1β, IL-18, and, IL-12p40, all of which are implicated in coronary artery diseases.^31,35 Thus, these findings suggest that apabetalone may be useful in treating patients with coronary atherosclerosis. Furthermore, although 7.1% of patients in this trial experienced an elevation in hepatic enzymes, the effect was reversible, and apabetalone was well-tolerable overall.⁴¹ Together, this study points toward the potential benefit and safety of apabetalone in patients with coronary atherosclerosis (Table 2). Nevertheless, given the nonsignificant benefits compared to placebo,⁴¹ care should be taken in interpreting the efficacy of apabetalone in treating these patients with coronary atherosclerosis.

In a follow-up analysis of the ASSURE trial,⁴² a coronary atherosclerotic plaque was observed in 31 patients treated with apabetalone and 4 patients who received placebo.⁴² Of interest, coronary atherosclerotic plaque patients who received apabetalone showed a significant reduction in coronary atherosclerotic plaque length, arc, and index compared to baseline.⁴² Importantly, the reduction in coronary atherosclerotic plaque index was inversely correlated with HDL particles in patients who received apabetalone.⁴² Overall, this follow-up study demonstrates that apabetalone has a beneficial effect on coronary atherosclerotic plaques, which could be linked to an increase in HDL particle concentrations.⁴²

Interestingly, analysis of pooled data from the ASSERT and ASSURE phase II clinical trials indicates that apabetalone treatment significantly elevated the plasma level of apoA-I, HDL, and large HDL particles and the average of HDL particle size compared to the placebo group.³¹ Importantly, the post hoc analysis of pooled data from these trials indicates that the upregulation of apoA-I/HDL was associated with a significant reduction of major adverse cardiac events in patients who received apabetalone compared to placebo.³¹ Using SOMscan proteomics on plasma from patients in the ASSERT and ASSURE clinical trials, apabetalone significantly reduced levels of complement proteins and regulators with a 51% reduction in circulating activated fragment C5a, 32% reduction in C3b, and 10% reduction in C5b–C6 compared to placebo, suggesting that apabetalone may reduce the cardiovascular risk in these patients via downregulation of the proinflammatory complement pathways.³⁸

BETonMACE Clinical Trial

Given the promising effect of apabetalone on cardiovascular diseases, the phase III BETonMACE (“Effect of RVX208 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Subjects with Coronary Artery Disease”; ClinicalTrials.gov identifier: NCT02586155) was conducted.⁴³ This randomized, double-blind, placebo-controlled multicenter clinical trial was performed to assess the safety and the efficacy of apabetalone as a therapy to prevent Major Adverse Cardiovascular Events (MACE), including cardiovascular death, nonfatal myocardial infarction, or stroke in patients with type-2 diabetes and a history of recent acute coronary artery syndrome and/or low HDL level.^26,43 In total, 2425 patients on standard care were recruited at 190 sites from 13 different countries and received either 100 mg of oral apabetalone twice daily (n = 1215) or a placebo (n = 1210) for about 700 days.²⁶ Considering MACE as a primary end point, patients receiving apabetalone demonstrated a non-statistically significant reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or stroke compared to patients in the placebo group.²⁶ Furthermore, similar to the previous phase II clinical trial, while apabetalone was well-tolerated, elevation in liver enzymes has been reported in some patients.²⁶ Overall, while apabetalone was tolerable,²⁶ theh BETonMACE study suggested that apabetalone did not significantly reduce the primary MACE outcome in patients with type-2 diabetes and a history of recent acute coronary artery syndrome (Table 2).

The lack of statistically significant reduction in MACE in patients receiving apabetalone might be attributed to some limitations of the BETonMACE study that include a lack of systematic collection of other cardiac functions and biomarkers, the absence of patients with broader cardiovascular disease, as well as a lack of patients already receiving beta-blockers and renin–angiotensin system inhibitors.²⁶ Nevertheless, the BETonMACE study revealed that there was a potential statistically significant synergetic effect of apabetalone when combined with a sodium glucose co-transporter type 2 (SGLT2) inhibitor, particularly empagliflozin, on the prevention of MACE in patients with type-2 diabetes and coronary artery disease.⁴⁴ Adding to this, a prespecified analysis of the BETonMACE clinical trial showed that type-2 diabetes and coronary artery disease patients who received apabetalone demonstrated a significant reduction in initial and recurrent hospitalizations for heart failure compared to patients in the placebo group.⁴⁴ These findings support the notion that apabetalone is a potential therapy for preventing heart failure and MACE especially when combined SGLT2 inhibitor.⁴⁴ Thus, more clinical studies are warranted to address the limitations of the BETonMACE study and confirm secondary end points.

Interestingly, a recent post hoc analysis of the BETonMACE study indicates that apabetalone was associated with a lower incidence of ischemic MACE and hospitalization for heart failure in patients with type-2 diabetes, coronary artery disease, and a moderate-to-high likelihood of advanced nonalcoholic liver fibrosis.⁴⁵ On the other hand, apabetalone had little to no benefit among individuals with a modest likelihood of liver fibrosis.⁴⁵ Nevertheless, patients receiving apabetalone show a significant reduction in the progression of liver fibrosis as compared to placebo over a period of 26.5 months.⁴⁵ An important limitation of this study is that there was no liver histology or imaging to support the hepatic fibrosis score data.⁴⁵ Thus, further research is needed to assess the hepatic and cardiovascular effects of apabetalone in patients with nonalcoholic liver fibrosis.

Another post hoc analysis study used BETonMACE data to investigate the link between insulin use and the risk of MACE in patients with coronary artery disease who received either apabetalone or placebo.⁴⁶ Notably, the rate of MACE in patients who received placebo was higher in insulin-treated individuals than those who had not received insulin suggesting that the use of insulin is linked to an increased risk of MACE.⁴⁶ Of interest, apabetalone reduced the rate of MACE in both insulin-treated and insulin-free subjects.⁴⁶ Overall, given the high risk of MACE in insulin-treated patients, the beneficial effect of apabetalone in these patients needs to be confirmed in a large randomized controlled study.

Apabetalone in the Treatment of Renal Disease

While apabetalone demonstrated cardioprotective effects, some of the most impactful effects of apabetalone appear to occur in chronic kidney disease.³⁰ For instance, in an open-label, parallel-group study, patients with stage 4 or 5 chronic kidney disease (n = 8) and their matched controls (n = 8) received a single dose of apabetalone.³⁰ After 12 h, plasma was collected and analyzed for proteomics profiling.³⁰ Notably, patients with renal disease demonstrated differential expression of 169 proteins, including cystatin C and β2 microglobulin, in the plasma when compared to control at baseline.³⁰ These proteins are critical players in renal impairment including inflammation, vascular calcification, cell adhesion, thrombosis, extracellular matrix remodeling, oxidative stress, and metabolism.³⁰ Interestingly, apabetalone was able to reduce the expression of inflammation markers such as IL-6, downregulate fibrotic markers such as fibronectin, and counteract the activation of most renal disease pathways, clearly indicating a potential of apabetalone for the treatment of chronic kidney disease^30,47 (Table 2). In parallel to the clinical data, another experiment using apabetalone in human renal mesangial cells exposed to tissue growth factor-β (TGFβ) demonstrated that apabetalone prevents upregulation of α-smooth muscle actin, reduces collagen production, and downregulates key inflammatory and fibrotic markers such as IL-6, IL-1β, cyclooxygenase-2, fibronectin, and periostin.⁴⁷ Overall, these findings provide more evidence that apabetalone may help in treating renal dysfunction (Table 1).

From a mechanistic point of view, cardiovascular disease and chronic kidney disease are intrinsically linked partly due to the ability of the latter to contribute to vascular calcification and inflammation, thereby negatively impacting cardiac health.^48,49 Under certain disease states, vascular calcification occurs due to the deposition of calcium phosphate and hydroxyapatite in blood vessels.^50,51 Of importance, BET proteins have been implicated in vascular calcification and stiffness.⁵² Conversely, a BET inhibitor like apabetalone reduces extracellular calcium deposition and matrix mineralization markers in vascular smooth muscle cells⁵² probably by downregulating the mRNA, protein, and enzyme levels of alkaline phosphatase (ALP).⁵² Consistent with this, in human renal mesangial cells, apabetalone also reduced the gene expression and the protein level of ALP induced by TGFβ.⁴⁷ Taken together, these results clearly indicate that apabetalone has a direct effect on the expression of ALP.

Since several studies have suggested a strong correlation between ALP and vascular calcification in chronic kidney disease patients,⁵³⁻⁵⁶ it is possible that apabetalone can reduce cardiovascular risk in chronic kidney disease via reducing ALP.^55,57,58 In support of this, the outcome of the phase II clinical trials SUSTAIN and ASSURE has demonstrated that targeting ALP using apabetalone improves estimated glomerular filtration rate (eGFR)⁵⁷ and reduces cardiovascular risk in these patients with chronic kidney disease.⁵⁷ In a follow-up analysis of the BETonMACE trial, diabetic chronic kidney disease patients (eGFR < 60 at baseline) treated with apabetalone showed a 30% reduction in MACE and heart failure hospitalizations compared to patients in the placebo group, suggesting that the cardioprotective effect of apabetalone excels in patients with renal impairment.⁵⁸ In a manner similar to the previous phase II studies,⁵⁷ the cardioprotective effect of apabetalone in these BETonMACE patients with chronic kidney disease was associated with a prominent reduction of ALP.⁵⁸ Collectively, these findings suggest that apabetalone is a potential novel agent to treat cardiovascular disease in chronic kidney disease patients and prevents progressive kidney function loss possibly via the downregulation of ALP^57,58 (Table 2).

Apabetalone in Neurological Disorders

Apabetalone Improves Cognitive Function

Apabetalone is being investigated for its potential in treating Alzheimer’s disease and vascular dementia.^59,60 In this context, a subset of 464 patients aged 70 years or older were selected from the BETonMACE trial and assigned to receive either 100 mg of apabetalone twice daily or a placebo for 2 years.^59,60 The Montreal Cognitive Assessment (MoCA) was conducted on all patients at the beginning of the trial and annually.^59,60 Participants were then scored as normal performance (MoCA score ≥26), mild cognitive impairment (MoCA score 25–22), or dementia (MoCA score ≤21).^59,60 Notably, treatment with apabetalone for 2 years was associated with an increase in the total MoCA score in patients with moderate to severe cognitive dysfunction.⁶⁰ Specifically, apabetalone improved the recall (memory) and abstraction (conceptual thinking) domains in patients with a baseline of MoCA score of ≤22.⁶⁰ Overall, these findings suggest that inhibition of epigenetic BET proteins by BD2-selective apabetalone led to improved cognition, indicating its potential for the treatment of cognitive dysfunction⁶⁰ (Table 2).

Beneficial Effects of Apabetalone on Fabry Disease

Fabry disease (FD) is a rare genetic X-linked metabolic disorder caused by a defect in the lysosomal enzyme α-galactosidase, leading to the accumulation of globotriaosylceramide (Gb3) in the body.^61,62 Notably, the accumulation of Gb3 triggers systemic inflammation and ultimately leads to damage of multiple organs, such as the heart and kidneys.^61,62 In addition, FD has numerous neurological implications, including burning sensations in hands and feet, paresthesia and Fabry crises, hyperhidrosis, audio-vestibular impairment, stroke, and cerebrovascular disorders.⁶¹ Indeed, neurological manifestations can range from painful small-fiber neuropathy to cerebrovascular disorders and aggressive multifocal forms.⁶² However, while enzyme replacement therapy (ERT) is the standard treatment for FD patients, ERT is less efficacious in the presence of systemic inflammation and organ damage.⁶¹ Thus, limiting the inflammatory responses and reducing heart and renal injuries in FD patients are of paramount importance. Given the potent therapeutic effects of apabetalone in reducing inflammation and cardiovascular, renal, and neurological complications, apabetalone has been investigated for its potential in the treatment of FD patients.⁶³ In a pilot study, peripheral blood mononuclear cells and neutrophils were separated from eight FD patients receiving continuous ERT64 blood samples.⁶³ Importantly, apabetalone treatment of these cells downregulated the gene expression of proinflammatory cytokine secretion, such as IL-6, IL-1β, IL-12, and CCL-2, induced by lipopolysaccharide (LPS) or IFNγ.⁶³ Also, apabetalone significantly reduced the production of reactive oxygen species, possibly by suppressing the transcription of NADPH oxidase 2 (NOX2).⁶³ Furthermore, the study also confirmed the involvement of BET in the beneficial effects of apabetalone in inflammation and oxidative stress associated with FD.⁶³ Together, these results suggest that apabetalone reduces inflammation and oxidative stress in FD through a BET-dependent mechanism⁶³ (Table 1).

Apabetalone in the Treatment of Viral Infections

Efficacy of Apabetalone in the Treatment of HIV Infection

Acquired immunodeficiency syndrome (AIDS) is caused by the incurable viral agent human immunodeficiency virus type-1 (HIV-1).⁶⁴ Restoration of the immune system in AIDS patients has been improved over the past decade due to the administration of a cocktail of antiretroviral agents (ARVs).⁶⁴ However, the therapeutic efficiency of ARVs is eclipsed by the severity of their side effects and the possibility of treatment failure due to the existence of latent viral reservoirs in resting CD4⁺ T cells.⁶⁵⁻⁶⁷ Therefore, there remains a crucial need to identify a new therapy to tackle these challenges associated with ARVs, reactivate latent HIV-1, and reset CD4⁺ T cells.

Of interest, numerous studies have demonstrated the capability of various BET inhibitors, such as OTX015,⁶⁸ PFI-1,⁶⁹ JQ1,^70,71 BMS-986158,⁷² and UMB-13,⁷² to reactivate latent HIV-1 cells in different models of HIV-1 latency cells as well as resting CD4⁺ T cells derived from HIV patients.⁶⁹ However, most of these agents are nonselective and can cause toxicity.⁶⁹ Thus, given the selectivity and safety of apabetalone, it has been tested as a potential therapy for treating HIV-1 infection.⁶⁶ Notably, apabetalone reverses the latency of the HIV reservoir in different HIV-1 latency cell lines, such as j-Lat A2, j-Lat 10.6, U1, and ACH2 cells, as well as primary human CD4⁺ T cells.⁶⁶ Mechanistically, apabetalone dissociates BRD4 from the HIV-1 enhancer site, activates PTEF-b, and recruits Tat to promote latent HIV-1 cells.⁶⁶ In addition, apabetalone induces apoptosis of reactivated reservoir cells by reducing the expression of cyclin D, increasing the expression of p21, and inducing cell cycle arrest at G1/G0 phase.⁶⁶ In light of these findings, it is possible that apabetalone is a potential latency-reversing agent for the eradication of HIV-1 infection (Table 1).

Consistent with the previous finding, another study using apabetalone in HIV latency cell lines, J-Lat C11 cells and A10.6 cells, demonstrated that apabetalone increases the phosphorylation of CDK9, upregulates the expression of PTEF-b, and reactivates HIV transcription that subsequently reverses latency.⁶⁹ Similar results were obtained in resting CD4⁺ T cells derived from ARV-treated patients.⁶⁹ Importantly, apabetalone treatment of these cells neither induced global activation of immune cells nor upregulated cell surface expression of HIV-1 receptors, suggesting that the effect of apabetalone is not associated with a nonspecific immune activation.⁶⁹ Nevertheless, though a high concentration of apabetalone has been used in CD4⁺ T cells derived from ARV-treated patients, the effect of apabetalone on latent HIV was relatively modest.⁶⁹ Thus, while these findings suggest that apabetalone is a potential latency reversing agent (Table 1), further studies are needed to address limitations and confirm these findings.

Apabetalone in the Treatment of COVID-19 and Post-COVID-19 Conditions

The debilitating pandemic caused by the novel coronavirus disease of 2019 (COVID-19) resulted in more than 2 million fatalities globally and remains a significant concern due to mutated variants and the development of post-COVID-19 syndrome.^73,74 From a molecular point of view, the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) disperses through respiratory droplets and aerosols, infecting cells that express the human angiotensin-converting enzyme 2 (ACE2) receptor.⁷³⁻⁷⁵ Thus, therapeutics and vaccines targeting the spike protein–ACE2 interaction have been developed. Of interest, recent evidence suggests that the expression of ACE2 is regulated by epigenetic BET reader proteins.^74,76,77

BET inhibitors such as apabetalone have been shown to reduce ACE2 expression and SARS CoV-2 replication.⁷⁴ Notably, apabetalone downregulates ACE2 gene expression in a variety of cell lines including bronchial epithelial Calu-3 cells, African green monkey kidney epithelial Vero-6 cells as well as hepatic cell lines, HepG2 and Huh-7.⁷⁴ In addition to ACE2, apabetalone reduces the expression of another cell surface receptor, CD26,^78,79 that assists SARS CoV-2 entry into host cells.⁷⁴ This downregulation in CD26 expression, combined with the decreased ACE2 levels, may have a synergistic role in blocking cellular uptake and infection of SARS-CoV-2 by apabetalone.⁷⁴ In support of this, apabetalone attenuates the binding of SARS CoV-2 spike protein receptor binding domain to human lung cells by 80%, suggesting that apabetalone lowers viral association with the host lung cells.^74,80 Intriguingly, when these cells were infected by SARS CoV-2, apabetalone significantly reduced viral replication with comparable efficacy to remdesivir, a viral RNA polymerase inhibitor.⁷⁴ These results collectively imply that apabetalone inhibits viral replication and decreases viral host cell entrance by reducing the binding of SARS CoV-2 spikes to cell surface receptors via downregulating the transcription of ACE2 and CD26⁷⁴ (Table 1).

Following host cell entry, SARS CoV-2 triggers the release of IFN-I that mediates the inflammatory and immunological responses to fight the infection.^77,81 However, the body becomes over-reactive and SARS CoV-2 further releases proinflammatory signals leading to a syndrome known as cytokine storm.^77,81 Importantly, cytokine storm is responsible for the morbidity and mortality in COVID-19 patients during the acute infection and contributes to the development of post-COVID-19 conditions in some patients.^80,82 Of interest, recent evidence points to a strong link between BET/BRD4 and the cytokine storm caused by SARS CoV-2.^77,81 For instance, the group of Kulikowski et al. demonstrated that BET inhibitor apabetalone downregulates the IFN-I signaling pathway as well as inflammatory cytokine storm signals in human lung cells and Calu-3 cell line stimulated by SARS-CoV-2 RNA.⁸⁰ Particularly, cytokines including IL-1, IL-6, CCL2, and CXCL1082 that contribute to post-COVID-19 syndrome were significantly affected by apabetalone.^80,82 Overall, these findings highlight the potential of apabetalone as a pharmacological agent for the treatment of COVID-19 and post-COVID-19 conditions. Of relevance to this, an ongoing clinical trial has already been designed to test if apabetalone can be used of the treatment for COVID-19 and post-COVID-19 conditions (ClinicalTrials.gov Identifier: NCT04894266). Thus, apabetalone may hold promise as a novel treatment for COVID-19 and post-COVID-19 complications (Table 1).

Apabetalone in the Treatment of Cancer

The majority of the BET inhibitor clinical trials address oncology indications, but many face multiple challenges with dose-limiting toxicities due to thrombocytopenia and others, which present some challenges for current and future clinical development.^12,25 While several studies have investigated the effect of apabetalone in multiple disease conditions outside the area of oncology, some recent studies have also shown that apabetalone might be useful for the treatment of some types of cancer.⁸³⁻⁸⁵ Notably, a recent study using apabetalone in ABCA1-overexpressing colorectal cancer cells demonstrated that apabetalone reduces the proliferation and invasive behavior of these cells.⁸³ Importantly, silencing apoA-I abolished the anticancer effect of apabetalone suggesting that the effect of apabetalone on ABCA1-overexpressing colorectal cancer cells appears to be mediated via the upregulation of apoA-I.⁸³ In agreement with this, both exogenous administration of human recombinant apoA-I and endogenous overexpression of apoA-I attenuates the proliferation and aggressiveness of colorectal cancer cells.⁸³ Overall, this finding suggests that apabetalone is beneficial for treating colorectal carcinoma via the upregulation of apoA-I expression (Table 1).

In addition to colorectal carcinoma, apabetalone has also been shown to mitigate cancer resistance associated with chemotherapy.⁸⁴ For instance, apabetalone enhances the sensitivity of carboplatin-resistant ovarian cancer cells to carboplatin by downregulating the protein expression level of ABCA1.⁸⁴ Moreover, apabetalone and inhibitors of mammalian target of rapamycin complexes 1 and 2 (mTORC1/2) synergistically abolished the aggressive growth of rhabdomyosarcoma in vitro and using a human xenograft mouse model.⁸⁵ Mechanistically, the effect of apabetalone appears to be mediated via inducing apoptosis through downregulating the BRD4 signaling pathway.⁸⁵ Overall, these findings suggest that apabetalone is effective in mitigating ovarian cancer and rhabdomyosarcoma resistance (Table 1).

Chemical Derivative of Apabetalone

Aside from apabetalone, RVX-297 is a new 4-quinazolinone derivative, orally bioavailable, and has preferential selectivity for BD2 of BRD2, BRD3, and BRD4.⁸⁶ Given the high selectivity of RVX-297 for BD2, RVX-297 has been investigated for its potential use in various inflammatory and autoimmune disorders.⁸⁷ For example, in human U937 and bone marrow-derived macrophages, mouse primary B cells, THP-1 monocytes, and human peripheral blood mononuclear cells, RVX-297 reduced the expression of IL-6, CCL2, and IL-17 induced by LPS, IL-1β, or T-cell receptor antibody OKT3.⁸⁷ Consistent with this, RVX-297 downregulates the splenic expression of IL-6 and IL-17 as well as the serum levels of a panel of cytokines, such as, IL-6, IL-17, INFγ, and CCL2, in a mouse model of endotoxin-induced sepsis⁸⁷ (Table 3).

Table 3. Beneficial Effects of RVX-297 in Preclinical Models of Acute and Chronic Inflammation.

disease	study model	treatment	effect	ref
acute inflammation	human U937 and bone marrow-derived macrophages, mouse primary B cells, THP-1 monocytes, and human peripheral blood mononuclear cells incubated with LPS, IL-1β or T-cell receptor antibody OKT3	cells received a 1 h pretreatment of RVX-297	↓ IL-6	(87)
			↓ CCL2
			↓ IL-17
			↓ INFγ
rheumatoid arthritis	synovial fibroblasts derived from rheumatoid arthritis patients and stimulated with TNFα	RVX-297 for 24 h	↓ IL-6	(87)
			↓ VCAM-1
	rat collagen-induced arthritis	RVX-297 administered orally BID for 6 days at 25, 50, or 75 mg/kg/dose	↓ swelling	(87)
			↓ cartilage destruction
			↓ bone resorption in joints
			↓ IL-1β
			↓ IL-6
			↓ RANKL
			↓ VCAM-1
	mouse model of collagen-induced arthritis	RVX-297 administered orally at 75 mg/kg 4 h before and at the time of treatment with LPS	↓ cartilage destruction	(87)
			↓ bone resorption
			↑ histopathology scores in knee, paws and joints
			↓ serum level of anticollagen II IgG
multiple sclerosis	mouse model of experimental autoimmune encephalomyelitis	RVX-297 administered orally at 125 mg/kg, FTY720, or vehicle for 18 days	↓ loss of body weight	(87)
			↓ inflammation
			↓ apoptosis
			↓ demyelination in the spinal cord
			↓ IL-1β
			↓ IL-6
			↓ IL-17
			↓ CCL2
			↓ TNFα
			↓ INFγ

Another experiment using RVX-297 in synovial fibroblasts derived from rheumatoid arthritis patients exposed to TNFα demonstrated that RVX-297 reduces the upregulation of IL-6 and vascular cell adhesion protein-1 (VCAM-1) suggesting that RVX-297 may be beneficial in patients with rheumatoid arthritis.⁸⁷ The beneficial effect of RVX-297 has also been investigated in a rat model of collagen-induced arthritis.⁸⁷ Treatment of these rats with twice daily 75 mg/kg of RVX-297 orally significantly improved swelling, cartilage destruction, and bone resorption in the joints of the ankle and knees.⁸⁷ Mechanistically, RVX-297 downregulated the expression of inflammatory cytokines, such as, IL-1β, IL-6, and RANKL, and adhesion molecule VCAM-1 to contribute to the improvement observed in a collagen rat model of rheumatoid arthritis⁸⁷ (Table 3).

The protective effect of RVX-297 has also been confirmed in a mouse model of collagen-induced arthritis.⁸⁷ These mice were treated with RVX-297, dexamethasone (an anti-inflammatory drug used as a positive control), or vehicle.⁸⁷ In a manner similar to dexamethasone, RVX-297 significantly improved the cartilage destruction, bone resorption, and histopathology scores in the knee, paws, and joints as well as reduced the serum level of anti-collagen II IgG compared to mice treated with vehicle.⁸⁷ Overall, the study proposes that RVX-297 is as effective as dexamethasone in the treatment of arthritis (Table 3).

In addition to rheumatoid arthritis, RVX-297 has also shown promise in the treatment of multiple sclerosis.⁸⁷ Notably, an important role of RVX-297 in the treatment of multiple sclerosis has been studied in a mouse model of experimental autoimmune encephalomyelitis.⁸⁷ In this study, mice were treated with 125 mg/kg of RVX-297 orally, FTY720 (an anti-multiple sclerosis agent used as a positive control), or vehicle.⁸⁷ Of interest, similar to FTY720, RVX-297 significantly improved the loss of body weight and abolished inflammation, apoptosis, and demyelination in the spinal cord of experimental autoimmune encephalomyelitis mice.⁸⁷ Importantly, the beneficial effect of RVX-297 was associated with a significant downregulation of the spinal cord expression of inflammatory cytokines, such as, IL-1β, IL-6, IL-17, CCL2, and TNFα, as well as INFγ in CD4⁺ cells compared with the vehicle group.⁸⁷ Overall, this study clearly demonstrated that RVX-297 is as effective as a standard drug, FTY720, in the treatment of multiple sclerosis.⁸⁷ Collectively, the previous findings suggest that the derivative of apabetalone, RVX-297, holds potential for treating various inflammatory and autoimmune diseases, opening up new avenues for epigenetic research (Table 3).

Conclusion

Apabetalone shows promising potential as a therapeutic agent for various diseases, particularly cardiovascular and chronic kidney diseases.^{29−31,33,36,44} By targeting the BD2 of BRDs, apabetalone inhibits the activity of BET proteins at the transcriptional level and thwarts the downstream effects on genes involved in maladaptive responses in inflammation, oxidative stress, and renal and cardiovascular diseases.^31,35,38,58 Notably, apabetalone increases apoA-I and HDL levels, lessens inflammation, reduces ALP and vascular calcification, downregulates the complement pathway, and decreases oxidative stress.^{29−31,33,35,36,38,44,58} As such, apabetalone is the first of its class to instigate such a wide range of therapeutic effects in non-oncological indications. Indeed, preclinical and clinical studies have also demonstrated multiple convincing beneficial effects of apabetalone in cardiovascular, renal, neurological, and viral diseases.^{29−31,33,36,44,60,66,74} Adding to this, a handful of preliminary studies have investigated the potential of apabetalone in several types of cancer such as rhabdomyosarcoma, ovarian cancer, and colorectal cancer.⁸³⁻⁸⁵ With its ability to impact multiple diseases, apabetalone presents itself as a novel therapeutic strategy beyond its primary application in cardiovascular diseases. Considering the broad implications of epigenetic modifications, particularly lysine acetylation, it is conceivable that apabetalone may prove beneficial in treating numerous other disorders using preclinical animal models. Ongoing investigations aim to uncover further therapeutic effects of apabetalone and possible combination therapies that may further enhance the protective role of apabetalone. Given that the drug is novel and is still in clinical trials, further preclinical research and clinical trials are warranted to fully explore the therapeutic potential of apabetalone in a wide range of oncological and non-oncological disease contexts.

This publication was supported by Qatar University Internal Grant No. QUCG-CPH-23/24-209. The findings achieved herein are solely the responsibility of the authors.

The authors declare no competing financial interest.