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 BrandenburgWürselen - Germany

Budapest, June 15th 2019

RMK!!!!!!!!!!!!Prof. Dr. med. Vincent BrandenburgSektionsleiter NephrologieKlinik für Kardiologie und NephrologieRhein-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

CVDFracturesMortality

BoneDiseaseCalcification

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 stressAltered 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 inhibitionDiminished VDR activation

Bone dis. & fracturesUremic 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

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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

(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

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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

2,400 + subjects

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

atorvastatin or

rosuvastatinrun-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

o HbA1c > 6.5% or history of diabetes

medications

• CAD event 7 days - 90 days prior to screening

o Myocardial infarction (MI), unstable angina

or 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

occurrence 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

occurrence of adjudication-confirmed triple

MACE defined as a single composite

endpoint of: 1) CV Death or 2) Non-fatal MI

or 3) Stroke.

Secondary Endpoint

Time from randomization to the first

occurrence 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 PopulationBaseline Clinical Chemistry

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Parameter NMedian (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 impactupon future cv therapy in high-risk pts