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

Targeting residual cardiovascular risk & vascular calcification

Vincent Brandenburg

Würselen - Germany

Budapest, June 15th 2019 RMK!!!!!!!!!!!!

• Prof. Dr. med. Vincent Brandenburg

Sektionsleiter Nephrologie Klinik für Kardiologie und Nephrologie Rhein-Maas Klinikum Würselen

The clinical perspective for BET inhibition

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 m2 to 37 per 100 patient-years in those with eGFR<15 ml/min per 1.73 m2

Mortality in CKD: the magnitude of the problem

Go AS et al.; NEJM 2004

“exploding“ mortality with CKD

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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.

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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.

Consequences of chronic kidney disease-mineral and bone disorder (CKD-MBD)

• Abnormal bone

morphology

• Turnover
• Mineralization
• Volume
• Linear growth
• Strength
• Vascular calcification
• Soft-tissue calcification
• Arterial stiffness
• Elevated
• PTH
• Phosphorus
• FGF-23
• Alkaline phosphatase
• Decreased
• 1,25(OH)2D3
• Calcium

CVD Fractures Mortality

Bone Disease Calcification Laboratory Abnormalities

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. Kidney Int. 2009;76 (Suppl 113):S1–S130

Uniklinik RWTH Aachen – Titel des Vortrags, Datum

Cv risk factors in CKD: overview

Endothelial dysfunction Gender

Vascular Disease Myocardial Disease Mortality

Altered shear stress Altered tensile stress Genetic factors Smoking; oxidative stress Local growth factors/inhibitors Lipoprotein modifications: oxidation; glycation, AGE, AOPP Dyslipidemia NO, ADMA, homocysteine Ca, P, PTH Calcification inhibitors Inflammation Anemia; iron-def. Chronic renal failure Diabetes Left ventricular hypertrophy Vascular disease Epigenetics  BET inhibition Diminished VDR activation Bone dis. & fractures Uremic toxins Vitamin D (high / low) Vitamin K deficiency Valvular disease miRNA FGF23 excess / klotho deficiency Age

Mineralization – Calcification in CKD-MBD

bone CVD CKD-MBD biochemistry Factor X

Role in (patho-) physiological mineralization and calcification “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

Calciphylaxis Heart valve Large arteries calcification

Chronic kidney disease – mineral and bone disorder

VSMC and calcification: alterations in genetic programming

• C. Shanahan JASN 2010

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

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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

Apabetalone inhibits BET protein binding to chromatin and subsequent gene expression

Kausik K Ray et al, submitted

Gilham D et al. Atherosclerosis. 2019 Jan;280:75-84

Apabetalone prevents expression of pro-calcifying genes and osteogenic transdifferentiation of VSMC

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

• f apabetalone lowering CV events in post-ACS

diabetes patients with and without CKD

2,400 + subjects

• double blinded
• 1-2 week statin run-in

atorvastatin

• r

rosuvastatin run-in

apabetalone 200mg daily + standard of care placebo + standard of care safety follow-up safety follow-up

standard of care includes 20-80 mg atorvastatin or 10-40 mg rosuvastatin

screening 1-2 weeks treatment duration up to 3.5 years 3-5 weeks randomization (1:1) end of treatment

The study is an event-based trial and continues until 250 narrowly defined MACE events have occurred

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Study results to be reported H2, 2019

Key inclusion criteria

• Type II Diabetes Mellitus
• HbA1c > 6.5% or history of diabetes

medications

• CAD event 7 days - 90 days prior to screening
• Myocardial infarction (MI), unstable angina
• r percutaneous coronary intervention
• HDL < 1.04 for males and < 1.17 for females

Primary Objective To evaluate if treatment with apabetalone as compared to placebo increases time to the first

• ccurrence of triple MACE. Triple MACE is

defined as a single composite endpoint of: 1) CV death or 2) non-fatal MI or 3) stroke. Primary Endpoint Time from randomization to the first

• ccurrence of adjudication-confirmed triple

MACE defined as a single composite endpoint of: 1) CV Death or 2) Non-fatal MI

• r 3) Stroke.

Secondary Endpoint Time from randomization to the first

• ccurrence of adjudication-confirmed

MACE including revascularization and unstable angina Changes in apoA-I, apoB, LDL-C, HDL-C, and TG Changes in HbA1c, fasting glucose, and fasting insulin

Changes in ALP and eGFR

BETonMACE CV Outcomes Trial Design

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BETonMACE Blinded Data: A Well Treated SOC Population

Baseline Clinical Chemistry

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Parameter N Median (min, max) Age 2,425 62 (31, 88) Alkaline Phosphatase†, U/L 2,424 78 (5, 915) HDL-C, mg/dL 2,411 33 (14, 47) hsCRP†, mg/L 493 2.8 (0.2, 162.1) Fibrinogen‡, mg/L 471 385 (71, 730) LDL-C, mg/dL 2,393 65 (3, 365) Apolipoprotein A-I†, mg/dL 483 118 (58, 179) HbA1c, % 2,367 7.3 (4.5, 15.1) Platelets, 109/ L 2,293 249 (6, 989) NLR, ratio 2,311 2.6 (0.4, 16.5) MI Males 74% 74.5% Statin Allocation 51% atorvastatin 49% rosuvastatin

† results from visit 2/wk 0, whereas all other values are from visit 1/screening

As of March 18th, 2019

At randomization 11% of Patients have CKD with eGFR <60 ml/min/1.73m²

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