apabetalone (RVX 208) / Resverlogix - LARVOL DELTA

Apabetalone: evaluating cardiovascular and safety outcomes in meta-analysis (AHA 2024) - "Our meta-analysis highlights the significant impact of apabetalone on certain lipid parameters and adverse events. However, it did not demonstrate significant effects on all-cause mortality or non-fatal MI. Further well-designed and reported RCTs were warranted to elucidate the clinical implications of apabetalone in selected group of patients that might benefit the most from apabetalone that may also improve cardiovascular disease management."

Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction • APOA1

Apabetalone Protects Against Heart Failure with Preserved Ejection Fraction by Suppressing Myocardial Inflammation (AHA 2024) - "Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF."

Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Inflammation • BRD4 • IL1B • TNFA

A Study of Apabetalone in Subjects with Long -COVID (clinicaltrials.gov) - P2/3 | N=200 | Not yet recruiting | Sponsor: Resverlogix Corp

New P2/3 trial • Diabetes • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Type 2 Diabetes Mellitus • CD27 • CD4 • CD8 • IFNG • IL10 • IL12B • IL17A • IL18 • IL1A • IL1B • IL2 • IL33 • IL6 • MIR146A • MMP1 • MMP9 • TNFA

Targeting BRD4-HK2 reverses perivascular adipose tissue meta-inflammation shift and rescues cardiometabolic vascular dysfunction (EASD 2024) - "Materials and We assessed the contribution of BRD4, by acute pharmacological inhibition via the BRD4 inhibitor RVX-208, to ex-vivo microvascular and perivascular adipose tissue (PVAT) function in fat biopsies from healthy volunteers (n=16) and patients with obesity and hypertension (n=16)... We identified BRD4-HK2 interaction at the PVAT level as a novel mediator of cardiometabolic damage. Its targeting rescues vascular dysfunction by reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammation may represent a promising strategy in patients with obesity and hypertension."

Metabolic Disorders • Obesity • BRD4 • HK2 • IL1B

Effects of BET Inhibition on lung micro-environmental changes in obesity-related pulmonary Arterial Hypertension (PAH) (ESC 2024) - "Apabetalone (APA), a selective inhibitor of bromodomain and extra-terminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating gene expression... APA is able to reset the lung micro-envirnment in obesity thus reducing inflammation and senescence. BET inhibitors could represent potential therapeutic approaches in this setting."

Cardiovascular • BRD4 • HIF1A • IL1B • IL6 • NOX4 • RELA • TGFB1 • TNFA

Targeting BRD4-HK2 reverses the meta-inflammatory shift in perivascular adipose tissue and rescues cardiometabolic vascular dysfunction. (ESC 2024) - "We assessed the ex vivo effects of BRD4 inhibition on vascular function by pressure myography in the presence or absence of perivascular adipose tissue (PVAT), at baseline and after incubation with the BRD4 inhibitor RVX-208 or with anti-inflammatory/anti-metabolic drugs... We identified BRD4-HK2 interaction at the PVAT level as a novel mediator of cardiometabolic damage. Its targeting rescues vascular dysfunction by reversing the PVAT meta-inflammatory shift. Epigenetic modulators of meta-inflammation may represent a promising strategy in patients with obesity and hypertension."

Cardiovascular • Hypertension • BRD4 • HK2 • IL1B

The BET inhibitor Apabetalone protects against heart failure with preserved ejection fraction by suppressing myocardial inflammation (ESC 2024) - "Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF."

Cardiovascular • Congestive Heart Failure • Heart Failure • BRD4 • IL1B • TNFA

Epigenetic BET inhibitor apabetalone counters inflammatory and fibrotic processes in activated cardiac fibroblasts providing insight into reduced hospitalizations for heart failure in BETonMACE trial (ESC 2024) - "In vitro, APA treatment reduced proinflammatory crosstalk between monocytes and CFs, resulting in less monocyte migration, monocyte - CF adhesion and CF contraction. APA also reduced signaling by TGF-β1, thus reducing profibrotic and contractile behaviour of CFs responsible for cardiac fibrosis. Since fibrosis contributes to HF, this data provides insight into the observed reduction in hospitalization due to HF in the BETonMACE trial."

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • CCL2 • IFNG • IL1B • POSTN • TGFB1 • TNFA • VCAM1

The BET protein inhibitor apabetalone (RVX-208) prevents doxorubicin-induced endothelial senescence (ESC 2024) - "Targeting BET proteins with RVX-208 may offer a promising therapeutic strategy to prevent endothelial aging in cancer patients undergoing cardiotoxic therapies."

Cardiovascular • BRD4 • CCL2 • CDKN1A • CDKN1C • COL1A2 • CXCL8 • IL6 • TIMP2 • TP53

Correspondence: Reply to commentary on "Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis". (PubMed, Pharmacol Res) - No abstract available

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • PLK1

Exploring the Therapeutic Potential of Apabetalone in Diabetic Kidney Disease: Bridging Preclinical Findings with Clinical Translation. (PubMed, Pharmacol Res) - No abstract available

Journal • Preclinical • Diabetic Nephropathy • Nephrology • Renal Disease

Commentary on "Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis". (PubMed, Pharmacol Res) - No abstract available

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Renal Disease • PLK1

Commentary on "Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis". (PubMed, Pharmacol Res) - No abstract available

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Renal Disease • PLK1

Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis. (PubMed, Pharmacol Res) - "BRD4 regulates the P300/H3K27ac/PLK1 axis, leading to the activation of the NLRP3 inflammasome and subsequent cell pyroptosis, inflammation, and fibrosis. These results may provide new perspectives on DKD treatment."

Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • BRD4 • NLRP3 • PLK1

Combined Inhibition of Histone Deacetylases and Bromodomain Proteins Normalizes Gene Expression and Reverses Sugen/Hypoxia-induced Pulmonary Hypertension (ATS 2024) - "Cells were treated with HDACi (OKI-5) or BRDi (JQ1) or the combination of both. Combination of HDACi and BRDi in low doses is effective in normalizing the persistent activation of PH-Fibs and improving hemodynamics and pulmonary vascular remodeling in Sugen/hypoxia PH rats, offering promise for epigenetic-targeted combination therapies in PAH."

Epigenetic controller • IO biomarker • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • BCL2 • BRD4 • CDKN1A • CXCL12

Apabetalone (RVX-208): A Potential Epigenetic Therapy for the Treatment of Cardiovascular, Renal, Neurological, Viral, and Cancer Disorders. (PubMed, ACS Pharmacol Transl Sci) - "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."

Journal • Review • Cardiovascular • Gene Therapies • Oncology

The BET inhibitor apabetalone decreases neuroendothelial proinflammatory activation in vitro and in a mouse model of systemic inflammation. (PubMed, Transl Neurosci) - "In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation."

Journal • Preclinical • Inflammation • CCL2 • CCR2 • ITGA4 • VCAM1

RVX-208, an inducer of Apolipoprotein A-I, inhibits the particle production of hepatitis B virus through activation of cGAS-STING pathway. (PubMed, Antivir Ther) - "Our study demonstrated that RVX-208, an inducer of ApoA-I, could suppress HBV particle production through activation of cGAS-STING pathway."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • APOA1

Safety and Effect of Oral RVX000222 in Subjects With Fabry Disease (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Resverlogix Corp | N=16 ➔ 0 | Trial completion date: Sep 2020 ➔ Nov 2022 | Unknown status ➔ Withdrawn | Trial primary completion date: Sep 2020 ➔ Nov 2022

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Fabry Disease • Genetic Disorders

An Open-Label Study of Apabetalone in Covid Infection (clinicaltrials.gov) - P2/3 | N=1 | Terminated | Sponsor: Resverlogix Corp | N=100 ➔ 1 | Recruiting ➔ Terminated; Unable to recruit subjects

Biomarker • Enrollment change • Trial termination • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease

Selective BET inhibitor RVX-208 ameliorates periodontal inflammation and bone loss. (PubMed, J Clin Periodontol) - "RVX-208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi-drug' for the prevention of periodontitis."

Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • TRAP

Potentially active compounds that improve PAD through angiogenesis: A review. (PubMed, Biomed Pharmacother) - "This paper focuses on the therapeutic effect of natural products (Salidroside, Astragaloside IV, etc.) and synthetic compounds (Cilostazol, Dapagliflozin, etc.)...Overall, these exogenous compounds have promising therapeutic potential for PAD. This study aims to summarize the potential active compounds, provide a variety of options for the search for drugs for the treatment of PAD, and bring light to the treatment of patients."

Journal • Review • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • Peripheral Arterial Disease

A Two-Part Phase 2a Study of RVX000222 in Patients With End-Stage Renal Disease Treated With Hemodialysis (clinicaltrials.gov) - P1/2 | N=44 | Not yet recruiting | Sponsor: Resverlogix Corp | Phase classification: P2a ➔ P1/2 | Trial completion date: Mar 2021 ➔ Nov 2026 | Trial primary completion date: Mar 2021 ➔ Nov 2026

Phase classification • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

Apabetalone Reduces Fibrotic Inflammatory and Calcific Factors in Renal Cells and Patient Plasma (KIDNEY WEEK 2023) - "Through epigenetic regulation of transcription in MCs, apabetalone suppresses fibrotic, inflammatory and calcific factors associated with CKD. Plasma levels of fibrotic and inflammatory proteins were reduced specifically in CKD subjects. This may, in part, explain reduced MACE risk in the CKD subpopulation receiving apabetalone in BETonMACE, which will be further evaluated in future phase 3 trials."

Clinical • Cardiovascular • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • IL6 • POSTN • TGFB1

Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells. (PubMed, Biomedicines) - "Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4's deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor-and DUX4 transcriptional repressor-losmapimod. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD."

Journal • Muscular Dystrophy • DUX4