Resverlogix Corp. · TSX:RVX
Resverlogix — Technical Presentation (November 2020)
17 slides from Resverlogix's technical presentation, Nov 16, 2020
Slide 1: BET protein inhibitor apabetalone suppresses inflammatory hyper-activation of monocytes
TSX: RVX BET protein inhibitor apabetalone suppresses inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes Sylwia Wasiak, Ph.D. Resverlogix Corp. AHA 2020
Slide 2: Disclosures
Disclosures • This work was financially supported by Resverlogix Corp. and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands, Organization for Health Research and Development and the Royal Netherlands Acade
Slide 3: Epigenetics
Epigenetics The epigenetic code refers to secondary modifications to chromatin components that regulate transcriptional activity Addition, removal or recognition of these modifications is done by proteins called writers, erasers and readers Acetylation of histone lysine residues by writers marks act
Slide 4: Apabetalone is a Small Molecule Inhibitor that Competitively Inhibits BET Bromodomains
Apabetalone (RVX-208) is a Small Molecule Inhibitor that Competitively Inhibits BET Bromodomains BET proteins are part of a superfamily of proteins Each BET protein contains two bromodomains (BD) 1 74-185 345-457 632-710 801 BRD2 BD1 BD2 ET 1 34-145 307-419 562-640 726 BRD3 BD1 BD2 ET 1 58-159 349-4
Slide 5: Apabetalone in Human Clinical Trials
Apabetalone in Human Clinical Trials • Apabetalone/RVX-208/RVX000222 (2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one) was discovered in 2006. • Tested in multiple phase 2 trials in CVD patients (endpoints: HDL, ApoA-I elevation) • Phase 3 cardiovascular event-driven tri
Slide 6: Lowering Monocyte Inflammation In Patients With Type 2 Diabetes and CVD with Apabetalone
Lowering Monocyte Inflammation In Patients With Type 2 Diabetes and CVD with Apabetalone • In diabetes and CVD, microenvironmental factors can trigger pro-inflammatory signaling in monocytes that leads to cytokine production and vascular wall invasion which, in turn, can promote atherosclerosis. • T
Slide 7: Lowering Monocyte Inflammation: Study Design
Lowering Monocyte Inflammation In Patients With Type 2 Diabetes And CVD with Apabetalone 14 Subjects with DM2 and Stable CVD (prior MI, PCI, CABG, unstable angina, TIA, CVA, PAD ≥ 3 months ago) on Statin and/or Insulin Therapy versus 12 Matched Control Subjects Patients versus Controls: Blood Collec
Slide 8: Comparison of Baseline Characteristics of Non-Stimulated DM2+CVD vs. Control Monocytes
Comparison of Baseline Characteristics of Non-Stimulated DM2+CVD vs. CONTROL monocytes • Surface marker expression: Pro-inflammatory pattern recognition receptor TLR2 was expressed at higher levels on the surface of DM2+CVD monocytes vs. controls • Gene expression: Pro-inflammatory genes IL1A, IL1B,
Slide 9: Apabetalone Attenuates Baseline Pro-inflammatory Hyper-Activation in Monocytes (Gene Expression)
Apabetalone Attenuates Baseline Pro-inflammatory “Hyper-Activation” in Monocytes from DM2+CVD Patients on SoC Therapy • Gene expression (1+4h): Apabetalone downregulates genes overexpressed in DM2+CVD monocytes: ↓ IL1A, CXCL8 (IL8), FCAR Fold Difference at Expression in DM2+CVD Gene Name Function Ba
Slide 10: Apabetalone Attenuates Baseline Pro-inflammatory Hyper-Activation (Protein Secretion)
Apabetalone Attenuates Baseline Pro-inflammatory “Hyper-Activation” in Monocytes from DM2+CVD Patients on SoC Therapy • Protein secretion (24h): Apabetalone downregulates secretion of cytokines and chemokines in DM2+CVD monocytes: ↓ IL-8 and GROα (overexpressed in DM2+CVD monocytes) ↓ MCP-1, MCP-3 a
Slide 11: Apabetalone Downregulates Pro-Inflammatory Gene Signatures More Potently in DM2+CVD Monocytes
Apabetalone Downregulates Pro-Inflammatory Gene Signatures More Potently in DM2+CVD Patient Monocytes than in Control Monocytes Apabetalone’s effect on transcriptional signatures in: Control monocytes DM2+CVD monocytes 1. Nanostring Gene Expression Data: IPA® Upstream Regulators IPA® Upstream Regula
Slide 12: IFN Differentiates Monocytes into M1 Classically Activated Pro-Inflammatory Macrophages
IFN Differentiates Monocytes into M1 “Classically Activated” Pro-Inflammatory Tissue Macrophages IFN promotes transcription of genes encoding: • Enzymes • Kinases • Metabolic regulators • Chromatin regulators • Transcription regulators Cellular function • Transcription (IRFs) • Antigen presentatio
Slide 13: Apabetalone Counters Pro-Inflammatory Hyper-Response to IFNγ (Gene Expression)
Apabetalone Counters Pro-Inflammatory Hyper-Response to IFNγ in DM2+CVD Monocytes Gene expression (1+4h): Apabetalone downregulates genes hyper-activated by IFNγ in DM2+CVD monocytes encoding cytokines CCL7, CCL8, TNF and NF-κB signaling proteins RELA and MYD88 Controls DM2+CVD DM2+CVD vs. Control:
Slide 14: Apabetalone Counters Pro-Inflammatory Hyper-Response to IFNγ (Protein Secretion)
Apabetalone Counters Pro-Inflammatory Hyper-Response to IFNγ in DM2+CVD Monocytes Protein secretion (24h): Apabetalone suppressed IFNγ-induced IL-1β and TNFα secretion in DM2+CVD monocytes TNFa DM2+CVD vs. Control: Controls IL-1b DM2+CVD Gene Name Function % Suppression by % Suppression by *** ****
Slide 15: Apabetalone Counters IFN Signaling More Potently in Monocytes from DM2+CVD Patients
Apabetalone Counters IFN Signaling More Potently in Monocytes from DM2+CVD Patients Gene expression: Pathway analysis: IFN transcriptional Apabetalone robustly downregulates IFNγ targets signature is preferentially inhibited by in DM2+CVD monocytes apabetalone in DM2+CVD monocytes Gene IFNγ 4h IFN
Slide 16: Pro-Inflammatory Monocyte Hyper-Activation Is Sensitive to BET Inhibition: Summary
Pro-Inflammatory Monocyte Hyper-Activation Is Sensitive to BET Inhibition: Summary • Monocytes from DM2+CVD patients exhibit pro-inflammatory hyper-activation at baseline. • Monocytes from DM2+CVD patients are hyper-responsive to IFNγ upon ex vivo stimulation. • This pro-inflammatory hyper-activatio
Slide 17: Acknowledgements
Select Publications: • Wasiak 2020 Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Acknowledgements Cardiovascular Disease. Cardiovasc Ther. • Ray 2020 Effect of apabetalone added to standard therapy on major adverse cardiovas