targeting residual cardiovascular risk & vascular calcification ......2019/07/03 · targeting...
TRANSCRIPT
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
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
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
VS
MC
an
d c
alc
ific
ati
on
:
alt
era
tio
ns in
gen
eti
c p
rog
ram
min
g
C.
Sh
an
ah
an
JA
SN
20
10
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
Ap
ab
eta
lon
ep
reve
nts
ex
pre
ss
ion
of
pro
-ca
lcif
yin
g
ge
ne
s a
nd
os
teo
ge
nic
tra
ns
dif
fere
nti
ati
on
of
VS
MC
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
17
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
18
BETonMACE Blinded Data: A Well Treated SOC PopulationBaseline Clinical Chemistry
19
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