risk & vascular calcification: The clinical perspective for BET - PowerPoint PPT Presentation

Targeting residual cardiovascular risk & vascular calcification: The clinical perspective for BET inhibition Vincent M Brandenburg, MD Würselen, Germany June 15, 2019 - Budapest, Hungary June 15, 2019 - Budapest, Hungary

Budapest, June 15th 2019 Targeting residual cardiovascular risk & vascular calcification The clinical perspective for BET inhibition Vincent Brandenburg Würselen - Germany Prof. Dr. med. Vincent Brandenburg RMK!!!!!!!!!!!! Sektionsleiter Nephrologie Klinik für Kardiologie und Nephrologie Rhein-Maas Klinikum Würselen

Mortality in CKD: the magnitude of the problem Go AS et al.; NEJM 2004 “ exploding “ mortality with CKD In this large, 3-year follow-up study, cardiovascular death rates increased from two per 100 patient-years in those with eGFR>60 ml/min per 1.73 m 2 to 37 per 100 patient-years in those with eGFR<15 ml/min per 1.73 m 2

CKD-PC Risk Models: Chronic Kidney Disease Prognosis Consortium (CKD-PC) is a research group composed of investigators representing cohorts from around the world. For more information, please visit our website, www.ckdpc.org. 4

CKD-PC Risk Models: Chronic Kidney Disease Prognosis Consortium (CKD-PC) is a research group composed of investigators representing cohorts from around the world. For more information, please visit our website, www.ckdpc.org. 5

Consequences of chronic kidney disease-mineral and bone disorder (CKD-MBD) Bone Calcification Disease CVD • Vascular calcification Fractures • Abnormal bone • Soft-tissue calcification morphology Mortality • Arterial stiffness - Turnover - Mineralization - Volume - Linear growth - Strength • Elevated - PTH Laboratory • Decreased - Phosphorus Abnormalities - 1,25(OH) 2 D 3 - FGF-23 - Calcium - Alkaline phosphatase Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD – MBD Work Group. Kidney Int . 2009;76 (Suppl 113):S1 – S130

Cv risk factors in CKD: overview Altered tensile stress Gender Age Altered shear stress Anemia; iron-def. Left ventricular hypertrophy Vascular disease Vitamin K deficiency Vitamin D (high / low) Diabetes Vascular Genetic factors Chronic renal failure Disease Local growth factors/inhibitors FGF23 excess / klotho deficiency Endothelial dysfunction Myocardial Disease Uremic toxins Bone dis. & fractures Inflammation Smoking; oxidative stress Mortality Calcification inhibitors Dyslipidemia Epigenetics  BET inhibition Diminished VDR activation Valvular disease Ca, P, PTH Lipoprotein modifications: oxidation; miRNA glycation, AGE, AOPP NO, ADMA, Uniklinik RWTH Aachen – Titel des Vortrags, homocysteine Datum

Mineralization – Calcification in CKD-MBD Role in (patho-) physiological mineralization and calcification Factor X CVD bone CKD-MBD biochemistry “non - traditional” cv risk factors in CKD → The benefits of traditional cv risk factor control demonstrated in the general population have met with limited success in patients with CKD

Standard cv therapy is less effective in CKD: statins Effects mortality per mmol/L reduction in LDL-C, by baseline renal function Herrington WG et al; Lancet Diabetes Endocrinol. 2016 Oct;4(10):829-39

Calcification is main factor for M&M in CKD Chronic kidney disease – mineral and bone disorder calcification Large arteries Calciphylaxis Heart valve

C. Shanahan JASN 2010 VSMC and calcification: alterations in genetic programming

Epigenetics Regulate Gene Activity • The Epigenetic code refers to secondary modifications to chromatin components that regulate its activity • Transcription is regulated by addition, removal or recognition of these modifications (writers, erasers, readers) • Acetylation is associated with active transcriptional regions of chromatin • BET (Bromodomain and Extraterminal Domain) proteins bind to acetylated lysines on histones and recruit additional transcription factors to turn on gene expression 12

Apabetalone inhibits BET protein binding to chromatin and subsequent gene expression apabetalone (BET inhibitor) Transcription No Transcription BET proteins, such as BRD4, bind acetylated lysine (ac) on histones or transcription factors (TF) via bromodomains (BD), and recruit transcriptional machinery to drive expression of BET sensitive genes. Apabetalone targets bromodomains in BET proteins, causing release from chromatin and downregulation of BET sensitive gene expression. Yellow star size indicates selectivity of apabetalone for bromodomain 2 (BD2).

Apabetalone inhibits BET protein binding to chromatin and subsequent gene expression Kausik K Ray et al, submitted

Apabetalone prevents expression of pro-calcifying genes and osteogenic transdifferentiation of VSMC Gilham D et al. Atherosclerosis. 2019 Jan;280:75-84

Apabetalone downregulates factors and pathways associated with vascular calcification. Gilham D et al. Atherosclerosis. 2019 Jan;280:75-84

BETonMACE CV Outcomes trial testing hypothesis of apabetalone lowering CV events in post-ACS diabetes patients with and without CKD safety follow-up 2,400 + subjects atorvastatin apabetalone 200mg daily + standard of care or • double blinded rosuvastatin • 1-2 week statin run-in placebo + standard of care safety follow-up run-in standard of care includes 20-80 mg atorvastatin or 10-40 mg rosuvastatin 1-2 weeks treatment duration up to 3.5 years 3-5 weeks randomization (1:1) screening end of treatment The study is an event-based trial and continues until 250 narrowly defined MACE events have occurred Study results to be reported H2, 2019 17

BETonMACE CV Outcomes Trial Design Primary Objective Primary Endpoint To evaluate if treatment with apabetalone as Time from randomization to the first compared to placebo increases time to the first occurrence of adjudication-confirmed triple occurrence of triple MACE. Triple MACE is MACE defined as a single composite defined as a single composite endpoint of: 1) CV endpoint of: 1) CV Death or 2) Non-fatal MI death or 2) non-fatal MI or 3) stroke. or 3) Stroke. Secondary Endpoint Time from randomization to the first Key inclusion criteria occurrence of adjudication-confirmed • Type II Diabetes Mellitus MACE including revascularization and o HbA1c > 6.5% or history of diabetes unstable angina medications Changes in apoA-I, apoB, LDL-C, HDL-C, • CAD event 7 days - 90 days prior to screening and TG o Myocardial infarction (MI), unstable angina Changes in HbA1c, fasting glucose, and or percutaneous coronary intervention fasting insulin • HDL < 1.04 for males and < 1.17 for females Changes in ALP and eGFR 18

BETonMACE Blinded Data: A Well Treated SOC Population Baseline Clinical Chemistry Median (min, Parameter N max) Age 2,425 62 (31, 88) Alkaline Phosphatase † , U/L 78 (5, 915) 2,424 HDL-C, mg/dL 33 (14, 47) 2,411 hsCRP † , mg/L 2.8 (0.2, 162.1) 493 Fibrinogen ‡ , mg/L 385 (71, 730) 471 LDL-C, mg/dL 65 (3, 365) 2,393 Apolipoprotein A-I † , mg/dL 118 (58, 179) 483 HbA1c, % 7.3 (4.5, 15.1) 2,367 Platelets, 10 9 / L 249 (6, 989) 2,293 NLR, ratio 2,311 2.6 (0.4, 16.5) MI 74% Males 74.5% As of March 18 th , 2019 Statin Allocation 51% atorvastatin 49% rosuvastatin † results from visit 2/wk 0, whereas all other values are from visit 1/screening At randomization 11% of Patients have CKD with eGFR <60 ml/min/1.73m² 19

Summary CKD potentiates cardiovascular risk beyond “traditional“ risk factors Hence , “traditional“ therapies are less effective (e.g. statins) Vascular calcification is a hallmark of CVD in CKD Epigenetics contribute to CV risk / calcification in CKD Apabetalone = BET inhibitor shows promising experimental evidence Apabetalone is about to finish phase III BETonMACE trial (CV risk reduction in diabetes +/- CKD) with potentially high impact upon future cv therapy in high-risk pts