A Clinical View on BET Inhibition in CKD & CVD: Understanding - - PowerPoint PPT Presentation

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A Clinical View on BET Inhibition in CKD & CVD: Understanding - - PowerPoint PPT Presentation

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A Clinical View on BET Inhibition in CKD & CVD: Understanding Recent Data and Future Perspectives Kam Kalantar-Zadeh, MD, MPH, PhD FACP, FAAP, FAHA, FASN, FNKF Twitter/FB: @KamKalantar Professor of Medicine, Pediatrics and Public Health

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A Clinical View on BET Inhibition in CKD & CVD: Understanding Recent Data and Future Perspectives

Kam Kalantar-Zadeh, MD, MPH, PhD

FACP, FAAP, FAHA, FASN, FNKF Twitter/FB: @KamKalantar Professor of Medicine, Pediatrics and Public Health Chief, Division of Nephrology and Hypertension University of California Irvine, School of Medicine

Veteran Administrations’ Long Beach Healthcare System, Long Beach, CA

Professor of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA

International Steering Committee

World Kidney Day (WKD)

www.WorldKidneyDay.org

Immediate Past President

International Society of Renal Nutrition & Metabolism (ISRNM)

www.RenalNutrition.com

ISN Council Member

International Society of Nephrology (ISN)

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SLIDE 2

Faculty Disclosure: Prof. Kamyar Kalantar-Zadeh, MD, MPH, PhD

I I have received a research grant(s)/ in kind support

A From current sponsor(s) YES NO B From any institution YES NO

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) YES NO B From any institution YES NO

III I have been a consultant/strategic advisor etc

A For current sponsor(s) YES NO B For any institution YES NO

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation YES NO B Not related to presentation YES NO Declaration of financial interests For the last 3 years and the subsequent 12 months:

  • Dr. K. Kalantar-Zadeh has received honoraria and/or support from Abbott,

Abbvie, Alexion, Amgen, ASN (American Society of Nephrology), Astra-Zeneca, Aveo, Chugai, DaVita, Fresenius, Genentech, Haymarket Media, Hofstra Medical School, IFKF (International Federation of Kidney Foundations), ISH (International Society of Hemodialysis), International Society of Renal Nutrition & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, Kabi, Keryx, Novartis, OPKO, NIH (National Institutes of Health), NKF (National Kidney Foundations), Pfizer, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, Shire, Vifor, UpToDate, ZS-Pharma.

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Unmet Need in Diabetes and CKD: Epigenetics and CVD Risk in CKD & Diabetes

  • Patients with diabetes and CKD have far greater risk of CVD death, MI,

Stroke and Heart Failure, leading to shortened life span.

  • Diabetes and CKD patients have highly dysregulated genes and distorted

gene expression and have many genes and proteins that drive CVD risk → Epigenetic Basis of CKD

  • Novel approaches to potentially reduce this high risk are urgently needed
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SLIDE 4

Fontecha-Barriuso M et al. Nephrol Dial Transplant. 2018 Mar 9. doi: 10.1093/ndt/gfy009. [Epub ahead of print]

Key DNA and histone epigenetic modifications. Impact on gene expression DNA: methylation Histones: acetylation methylation crotonylation

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SLIDE 5

Fontecha-Barriuso M et al. Nephrol Dial Transplant. 2018 Mar 9. doi: 10.1093/ndt/gfy009. [Epub ahead of print]

Therapeutic targeting of DNA and histone epigenetic modifications in kidney injury

DNA: methylation Histones: acetylation Histones: methylation Histones: crotonylation BET proteins

Epigenetic reader

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SLIDE 6
  • 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

Epigenetics modulation of distorted genes and gene expression, via novel molecular target Bromodomain and Extraterminal Domain (BET) inhibition, has the potential to regulate key pathways and markers of high risk including calcification and inflammation in diabetes and CKD disease

6

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SLIDE 7

Mechanism of Action of Apabetalone

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 inhibits BET bromodomains, causing release from chromatin and downregulation of BET sensitive gene expression.

Yellow star size: selectivity of apabetalone for BD2

Acknowledgment: Contributions to this figure by Dr. Eric Campeau, Dr. Olesya Kharenko & Dr. Sylwia Wasiak

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SLIDE 8

8

Apabetalone

Mechanism is based on changing the levels of disease causing proteins by regulating their expression at the gene level

Traditional drug therapies

Focus on modifying the activity of one disease protein by using an inhibitor or antibody

CRISPR: genome editing

The mechanism is based on cutting and pasting undesired/desired sequences into or

  • ut of the DNA, thereby altering the gene

sequence and then re-introducing the modified DNA into the body

Apabetalone’s Novel & Unique Mechanism

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Inhibition of BET Proteins with Apabetalone Reduces Mediators of Vascular Calcification In Vitro and in CKD Patients

  • In clinical trials, apabetalone mediated reduction of factors &

pathways associated with vascular calcification (VC).

  • Apabetalone reduced expression of markers of

transdifferentiation & genes that promote calcification of CAVSMCs.

  • Apabetalone reduced the number and size of BRD4-rich

enhancers, consistent with displacement of BRD4 from chromatin.

  • BRD4 ChIP-seq identified 38 unique genes associated with

CAVSMC transdifferentiation and calcification.

  • Involvement of BRD4 in CAVSMC transdifferentiation &

calcification is a novel discovery.

  • The impact of apabetalone on biomarkers, renal function, and

CVD outcomes in patients with impaired kidney function is being evaluated in the phase 3 BETonMACE trial.

Gilham et al, ERA/EDTA 2018

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SLIDE 10

BET inhibition via apabetalone counters extracellular calcium deposition in human CAVSMCs

Dimethyl sulfoxide (DMSO) is a water miscible solvent that is used extensively for osteoblastogenic activation to induce tissue calcium deposition.

Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018

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BET inhibition via apabetalone downregulates expression of genes related to vascular calcification in multiple cell types:

↓↓ expression of Alkaline Phosphatase, Osteopontin, Osteoprotegerin

Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018

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BET inhibition via apabetalone opposes induction of osteogenic markers in human coronary artery vascular smooth muscle cells

Alkaline Phosphatase

Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018

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Apabetalone Downregulates Alkaline Phosphatase (ALP) Expression in Primary Human Hepatocytes

  • Alkaline phosphatase expression is downregulated by apabetalone in PHH
  • Downregulation is consistent with reduced levels in patients receiving apabetalone
  • The mechanism of ALP release into circulation remains unclear

0,0 0,2 0,4 0,6 0,8 1,0 1,2

DMSO 30uM apabetalone 48 hours ALPL

Fold Change relative to DMSO same time point

ALPL mRNA Expression

0,0 0,2 0,4 0,6 0,8 1,0 1,2

20 40 60 80

Fold Change relative to DMSO same time point

Treatment Time (hours) ALPL mRNA Expression 30uM apabetalone 13 Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018

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Alkaline Phosphatase (ALP, AlkPhos)

MW 150 kDa, serum: 20-120 IU/L

  • A hydrolase enzyme responsible for removing phosphate groups from many

types of molecules, including nucleotides, proteins, and alkaloids. (dephosphorylation).

  • ALP is most effective in an alkaline environment.
  • ALP is present in all tissues, particularly concentrated in liver, bone, intestinal

mucosa and placenta→ isozymes:

– bone-specific – liver – tissue-nonspecific – placental

Haarhaus M, Brandenburg V, Kalantar-Zadeh K, Stenvinkel P and Magnusson P . Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol. 2017;13(7):429-442. doi: 10.1038/nrneph.2017.60. PMID: 28502983. URL: https://www.ncbi.nlm.nih.gov/pubmed/28502983 .

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SLIDE 15

Role of Alkaline Phosphatase (ALP) in Tissue & Vascular Mineralization

Haarhaus M, Brandenburg V, Kalantar-Zadeh K, Stenvinkel P and Magnusson P . Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol. 2017;13(7):429-442. doi: 10.1038/nrneph.2017.60. PMID: 28502983.

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  • Recent studies have shown that higher levels of serum alkaline phosphatase are associated with

increased mortality in the general population and in survivors of myocardial infarction, and chronic kidney disease patients

Tonelli M, et al. 2009 Circulation 2009;120(18):1784-1792, Beddhu S, et al., 2009. Clin J Am Soc Nephrol. 2009;4(11)1805-1810, Blayney MJ, et al 2008 Kidney Int. 2008;75(5):655-663, Kalantar-Zadeh K, et al., 2006 Am J Kidney Dis.2006;48(1):59-68. Lee GH et al., 2007 J Ren Nutr. 2007;17(1):38-44, Regidor DL, et al 2008 J Am Soc Nephrol. 2008;19(11):2193-2203.

  • The highest quartile of serum alkaline phosphatase was associated with higher prevalence of

myocardial infarction, stroke, congestive heart failure, and diabetes. High serum alkaline phosphatase levels are strongly associated with increased prevalence of metabolic syndrome and subsequent increase in all-cause mortality (retrospective observational study of 15,234 adult participants in the National Health and Nutrition Examination Survey III.

Krishnamurthy VR et al., 2011 The American Journal of Medicine (2011) 124, 566.e1-566.e7)

  • Serum alkaline phosphatase has a critical role in calcification and has been used as a marker and

therapeutic target of vascular calcification, BAP (bone derived alkaline phosphatase) has been proposed to link insulin resistance with vascular calcification, cardiovascular diseases, or even mortality

Cheung CL et al., 2013 J Clin Endocrinol Metab. 2013 Sep;98(9):3856-63.

Alkaline Phosphatase (ALP) is a Prognostic Biomarker

ALP linked to Mortality, Cardiovascular Disease and Diabetes

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SLIDE 17

unadjusted

Higher Alkaline Phosphatase (ALP) is Associated with Increased Mortality in ESRD Patients

Fixed-covariate model with baseline values

All-Cause Death Hazard Ratio 0.7 1.5 2 3 1 Alkaline Phosphatase (U/L) <50 50 to 69.9 70 to 89.9 90 to 109.9 110 to 129.9 130 to 19.49 150 to 169.9 170 to 189.9 190 to 209.9 210

Frequency

2000 4000 6000 8000 10000 12000 14000 16000 case-mix & labs case-mix

Source: Kalantar-Zadeh et al, Kidney Int, 2006

Prospective Mortality in 58,058 Hemodialysis Patients: 2001-2003

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Elevated Alkaline Phosphatase (ALP) is Associated with Mortality in General Population

Source: Tonelli et al, Circulation 2009

Notes: N= 4,115, median follow-up 5 years; adjusted for age, sex, race, phosphate, alcohol use, FBG, medication use, proteinuria, eGFR, SBP, albumin, RDW, hemoglobin, HDL-C, calcium, bilirubin, AST, ALT, GGTP

p=0.02 p=0.06 p=0.051 p=0.6

death CHD, MI CVA or CHF CHF MI CHD death

<80 IU/l 80 – 99 IU/l > 99

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Vascular Calcification is a Strong Predictor of Death in CKD

Coronary Artery Calcification Score (CAC)

Source: Shantouf … Kalantar-Zadeh, Am J Nephrol 2010

1-100 101-400 >400

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Alkaline Phosphatase (ALP) >120 IU/L is Associated with Coronary Calcification in CKD5 Patients

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of LAD lesions <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of LAD lesions <120 ≥120 <120 ≥120

200 400 600 800 1 2

Serum Alkaline Phosphatase (IU/L) LAD calcification score <120 ≥120

200 400 600 800 1 2

Serum Alkaline Phosphatase (IU/L) LAD calcification score <120 ≥120 <120 ≥120

0.4 0.5 0.6 0.7 0.8 0.9 1 2

Serum Alkaline Phosphatase (IU/L) Number of LM lesions <120 ≥120

0.4 0.5 0.6 0.7 0.8 0.9 1 2

Serum Alkaline Phosphatase (IU/L) Number of LM lesions <120 ≥120 <120 ≥120

10 20 30 40 50 60 70 1 2

Serum Alkaline Phosphatase (IU/L) LM calcification score <120 ≥120

10 20 30 40 50 60 70 1 2

Serum Alkaline Phosphatase (IU/L) LM calcification score <120 ≥120 <120 ≥120

200 300 400 500 600 1 2

Serum Alkaline Phosphatase (IU/L) RCA calcification score <120 ≥120

200 300 400 500 600 1 2

Serum Alkaline Phosphatase (IU/L) RCA calcification score <120 ≥120 <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of RCA lesions <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of RCA lesions <120 ≥120 <120 ≥120

2 3 4 5 6 7 1 2

Serum Alkaline Phosphatase (IU/L) Number of circumflex lesions <120 ≥120

2 3 4 5 6 7 1 2

Serum Alkaline Phosphatase (IU/L) Number of circumflex lesions <120 ≥120 <120 ≥120

100 200 300 400 500 600 700 1 2

Serum Alkaline Phosphatase (IU/L) Circumflex calcification score <120 ≥120

100 200 300 400 500 600 700 1 2

Serum Alkaline Phosphatase (IU/L) Circumflex calcification score <120 ≥120 <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of LAD lesions <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of LAD lesions <120 ≥120 <120 ≥120

200 400 600 800 1 2

Serum Alkaline Phosphatase (IU/L) LAD calcification score <120 ≥120

200 400 600 800 1 2

Serum Alkaline Phosphatase (IU/L) LAD calcification score <120 ≥120 <120 ≥120

0.4 0.5 0.6 0.7 0.8 0.9 1 2

Serum Alkaline Phosphatase (IU/L) Number of LM lesions <120 ≥120

0.4 0.5 0.6 0.7 0.8 0.9 1 2

Serum Alkaline Phosphatase (IU/L) Number of LM lesions <120 ≥120 <120 ≥120

10 20 30 40 50 60 70 1 2

Serum Alkaline Phosphatase (IU/L) LM calcification score <120 ≥120

10 20 30 40 50 60 70 1 2

Serum Alkaline Phosphatase (IU/L) LM calcification score <120 ≥120 <120 ≥120

200 300 400 500 600 1 2

Serum Alkaline Phosphatase (IU/L) RCA calcification score <120 ≥120

200 300 400 500 600 1 2

Serum Alkaline Phosphatase (IU/L) RCA calcification score <120 ≥120 <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of RCA lesions <120 ≥120

5 6 7 8 9 10 1 2

Serum Alkaline Phosphatase (IU/L) Number of RCA lesions <120 ≥120 <120 ≥120

2 3 4 5 6 7 1 2

Serum Alkaline Phosphatase (IU/L) Number of circumflex lesions <120 ≥120

2 3 4 5 6 7 1 2

Serum Alkaline Phosphatase (IU/L) Number of circumflex lesions <120 ≥120 <120 ≥120

100 200 300 400 500 600 700 1 2

Serum Alkaline Phosphatase (IU/L) Circumflex calcification score <120 ≥120

100 200 300 400 500 600 700 1 2

Serum Alkaline Phosphatase (IU/L) Circumflex calcification score <120 ≥120 <120 ≥120

* * * * * *

Source: Shantouf … Kalantar-Zadeh, Clin J Am Soc Nephrol 2009

LAD LM RCA Cx . . .

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SLIDE 21

Alkaline phosphatase (ALP) and Outcomes in CKD:

Supportive & Consistent Literature

Strong independent literature on link between ALP and CKD outcomes and mortality Large population studies demonstrating link between ALP and CKD

22

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SLIDE 22
  • Is there an intervention to lower serum ALP in both the non-

CKD and CKD patients?

  • Is a proactive decrease in ALP associated with improved

cardiovascular outcomes?

Can Alkaline Phosphatase (ALP) activity be modulated in vivo?

23

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SLIDE 23

Apabetalone (RVX-208) Early Impact on MACE (Major Averse Cardiac Events)

Gilham et al. Atherosclerosis 2016, Johansson et al. European Heart Journal (2014); 35 (Abstract Supplement), Puri et al. J Am Coll Cardiol. (2014); 63(12_S)

Note: Patients were censored at 30 days after the last dose of study medication. Log- Rank test for between group comparison

MACE: Major Adverse Cardiac

Events including: death, myocardial infarction, stroke, coronary revascularization, hospitalization for acute coronary syndrome or heart failure

0% 3% 6% 9% 12% 15% 18% 21% 30 60 90 120 150 180 210

Cumulative Event Rate (%) Days Since Randomization 69% RRR p = 0.007 RVX-208 hsCRP>2 mg/L (n=179) Placebo hsCRP>2 mg/L (n=104)

0% 3% 6% 9% 12% 15% 18% 21% 30 60 90 120 150 180 210

Cumulative Event Rate (%) Days Since Randomization RVX-208 DM (n=127) Placebo, DM (n=65) 77% RRR p = 0.01

0% 3% 6% 9% 12% 15% 18% 21% 30 60 90 120 150 180 210

Cumulative Event Rate (%) Days Since Randomization 55% RRR p = 0.02 RVX-208 (n=331) Placebo (n=168)

ASSURE and SUSTAIN Studies

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SLIDE 24

3,2% 3,8% 5,3% 9,1% R² = 0,8686 0,0% 2,0% 4,0% 6,0% 8,0% 10,0% Quartile 1 Quartile 2 Quartile 3 Quartile 4 n = 186 n = 210 n = 190 n = 209 median = 52 median = 66 median = 78 median = 97 # of MACE = 6 # of MACE = 8 # of MACE = 10 # of MACE = 19 Percentage of MACE Events (%)

Phase 2 Studies of Apabetalone:

Alkaline Phosphatase (ALP) Quartiles and MACE (Major Adverse Cardiac Events) in Human Participants

Adapted from Kalantar-Zadeh et al Poster ASN 2015

Quartile analysis of baseline ALP measurements indicate that: higher ALP was associated with higher MACE rates

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Phase 2 Analysis MACE patients illustrated higher baseline ALP

Phase 2, Placebo Controlled, Double Blinded Trials: Subjects with Cardiovascular Disease on Standard of Care

Kalantar-Zadeh et al , ASN 2015, San Diego

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SLIDE 26

60 65 70 75 80 85 Baseline Wk 12 Wk 24/ET Median ALP (U/L)

RVX-208 200mg (n=88) Placebo (n=88)

60 65 70 75 80 85 Baseline Wk 14 Wk 26 Median ALP (U/L)

RVX-208 200mg (n=243) Placebo (n=80)

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BET inhibition via apabetalone (RVX-208) induced lowering of serum Alkaline Phosphatase (ALP) is maintained for at least 6 months in Phase II Trials

Wilcoxon signed-rank test for change from baseline vs. placebo Error bars reflect standard error of the mean (SEM)

SUSTAIN (Phase II)

† p < 0.001 vs placebo † p < 0.001 vs placebo

† † † †

ASSURE (Phase II)

Kalantar-Zadeh et al , Poster ASN 2015, San Diego

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SLIDE 27

Apabetalone decreases circulating levels of proteins associated with Vascular Calcification in patients with cardiovascular disease

Phase 2, Placebo Controlled, Double Blinded Trials: Subjects with Cardiovascular Disease on Standard of Care

Alkaline Phosphatase Osteoprotegerin Osteopontin Adapted from: Kulikowski et al. ERA-EDTA 2017 Gilham et al. ERA-EDTA 2018 Nicholls et al Am J Cardiovasc Drugs 2018

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Apabetalone Phase II trials:

Rank-ordered changes in Calcification, Lipid and Inflammation Markers in Participants

Rank

Biomarker Apabetalone (n=331) Placebo (n=166)

p value vs placebo Change from baseline (%▲) p value vs. baseline Change from baseline (%▲) p value vs. baseline 1

Alkaline phosphatase (U/L)

  • 8.0 (-11.0)

<0.0001

  • 2.0 (-3.2)

0.03

<0.0001

2

HDL-C (mg/dL) +3.0 (+7.69)

<0.0001

0.0 (0.0)

0.59

0.0003

3

ApoA-I (mg/dL) +12.3 (+10.3)

<0.0001

+4.8 (+3.8)

0.0003

0.005

4

Glucose† (mmol/L)

  • 0.3 (-4.69)

0.25

+0.9 (+10.3)

0.06

0.008

5

Large HDL particles (mol/L)

+0.8 (+30.7) <0.0001 +0.1 (+4.11) 0.02

0.03

6

HDL particle size (nm)

+0.1 (+1.16) <0.0001 0.0 (0.0) 0.30

0.049

7

Total HDL particles (mol/L)

+1.9 (+6.51) <0.0001 +0.1 (+0.40) 0.61

0.07

8

hsCRP (mg/L)

  • 0.36 (-28.4)

<0.0001

  • 0.33 (-22.4)

0.0002

0.67

Results expressed as expressed as median percentage change from baseline † Significance vs placebo observed in diabetes population with baseline HDL<40 mg/dL

Nicholls SJ, Ray KK, Johansson JO, Gordon A, Sweeney M, Halliday C, Kulikowski E, Wong N, Kim SW and Schwartz GG. Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease. Am J Cardiovasc Drugs. 2018;18(2):109-115. doi: 10.1007/s40256-017-0250-3. PubMed PMID: 29027131. URL: https://www.ncbi.nlm.nih.gov/pubmed/29027131 .

Ranking based on statistical significance vs placebo

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SLIDE 29

Endothelial Dysfunction

Inflammation & Oxidative Stress

Pyrophosphate Inhibition Vasodilation Abnormalities Atherosclerotic Changes Cytokine Activation Vascular Calcification Cardiovascular Risks Chronic Kidney Disease

Thromboembolic & Cardiovascular Events

Mortality Hospitalization

Bone Disease Genetic Factors

Alkaline Phosphatase Expression/Activatio n

Selective BET Inhibition

Selective BET Inhibition

Potential Pathways in CKD

Haarhaus M, Brandenburg V, Kalantar-Zadeh K, Stenvinkel P and Magnusson P . Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD. Nat Rev Nephrol. 2017;13(7):429-442. doi: 10.1038/nrneph.2017.60. PMID: 28502983.

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Benefit of Apabetalone on Plasma Proteins in Renal Disease

  • We studied the impact
  • f apabetalone on the

plasma proteome in patients with impaired kidney function

  • The phase I apabetalone

pharmacokinetic study

  • consisted of 2 cohorts of 8 subjects each who received a single 100-mg oral dose of apabetalone

– Cohort 1: Subjects with CKD stage 4 or 5 not on dialysis, with an eGFR of <30 mL/min per 1.73 m2 – Cohort 2: Control subjects matched to CKD subjects in age, weight, sex, but eGFR ≥60 mL/min per 1.73 m2

  • Blood samples for determination of plasma concentration of apabetalone were collected at the

following time points: baseline and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 34, and 48 hours post-dose

  • Safety assessments included monitoring of adverse events, vital signs, clinical laboratory findings, 12-

lead electrocardiograms &, an physical examination

Wasiak S, Tsujikawa LM, Halliday C, C Stotz S, Gilham D, Jahagirdar R, Kalantar-Zadeh K, Robson R, Sweeney M, Johansson JO, Wong NC and Kulikowski

  • E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018 [not pubmed yet];3(3):711-721 Epub 2017/12/8. doi. PubMed
  • PMID. URL: http://www.kireports.org/article/S2468-0249%2817%2930457-6/abstract#.WjVMjYsJg7c.facebook

April 2018

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Phase I Apabetalone in non-dialysis CKD 4-5 Study: Baseline Characteristics

Characteristics Cohort 1 CKD 4-5 (n = 8) Cohort 2 controls (n = 8)

Age (yrs) 55.9 ± 16.5 52.6 ± 16.5 Male sex 5 (63) 5 (63) White race 8 (100) 8 (100) Ethnicity Non-Hispanic or Non-Latino 8 (100) 8 (100) BMI (kg/m2) 28.1 ± 5.1 25.5 ± 3.0 Median clinical chemistry measures Albumin (g/L) 36.0 ± 4.1 39.8 ± 3.1 Alkaline Phosphatase (U/L) 113.1 ± 60.4 73.0 ± 16.2 CKD-EPI (mL/min per 1.73 m2) 18.8 ± 5.9 78.4 ± 10.6 Serum creatinine (μmol/L) 305.3 ± 104.9 87.9 ± 10.3 Blood urea nitrogen (mmol/L) 21.9 ± 10.5 6.1 ± 1.9 Blood Pressure Systloic (mm Hg) 132.8 ± 26.4 129.0 ± 21.7 Diastolic (mm Hg) 67.4 ± 14.8 71.5 ± 12.7 Comorbidities Hypertension 5 3 Hypo/hyperthyroidism 2 Diabetes 1 Hyperlipidemia 1 Peripheral vascular disease 1 Allergy 1 1 Autoimmune 1 1 Genetic Disorder 1 Gastrointestinal 1

Wasiak S, … Kalantar-Zadeh K, … Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018

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SOMA Scan Analysis of Plasma Proteome:

non-dialysis CKD 4-5 Study: Baseline Characteristics

33

Figure 1. SOMAscan analysis of the plasma proteome. Study design flowchart (a). Proteins differentially expressed in the CKD cohort are plotted according to their fold enrichment (b). The degree of significance is color coded (see legend). Note that p values tend to be highly significant for highly enriched proteins. Fold enrichment as a function of protein molecular weight (c). Note that the majority of enriched proteins have a molecular weight of <45 kDa. Protein enrichment also tends to be greater for proteins with molecular weight <45 kDa.

Wasiak S, … Kalantar-Zadeh K, … Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018

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SLIDE 33
  • A total of 169 proteins (adjusted p <0.05) were identified as differentially

expressed in plasma from control vs. CKD patients, including cystatin C and β2 microglobulin, which correlate with renal function.

  • Significant activations of 42 pathways were found that control immunity

and inflammation, oxidative stress, endothelial dysfunction, vascular calcification, and coagulation

  • Many of the proteins upregulated in the CKD cohort are directly or indirectly linked to

inflammation

  • Essential components of the innate and adaptive immune system were among the top

upregulated pathways in the CKD cohort

  • Multiple APR proteins were upregulated in plasma from the CKD cohort, with APR

signaling pathway being ranked the sixth most activated pathway in CKD plasma

Overview of SOMA Scan Findings:

Phase I Apabetalone in non-dialysis CKD 4-5 Study

34

Wasiak S, … Kalantar-Zadeh K, … Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018

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SLIDE 34

Ingenuity Pathway Analysis CKD vs control: baseline

CKD apabetalone

z score P value z score P value

Dendritic cell maturation 3.46α <0.0001 –4.12b <0.0001 IL-6 signaling 3.21α <0.0001 –3.46b <0.0001 Th1 pathway 3.16α <0.0001 –3.32b <0.0001 Colorectal cancer metastasis signaling 3.13α <0.0001 –3.50b <0.0001 NF-kB signaling 3.05α <0.0001 –3.46b <0.0001 Acute phase response signaling 2.89α <0.0001 –3.46b <0.0001 HMGB1 signaling 2.84α <0.0001 –3.50b <0.0001 IL-17A signaling in airway cells 2.83α <0.0001 –2.33b <0.0001 Type I diabetes mellitus signaling 2.83α <0.0001 –2.65b <0.0001 Role of NFAT in cardiac hypertrophy 2.83α 0.004 <0.0001 Death receptor signaling 2.83α <0.0001 –2.12b <0.0001 p38 MAPK signaling 2.65α 0.0008 –3.32b <0.0001 STAT3 Pathway 2.53α <0.0001 –1.63 0.0002 Production of nitric oxide and reactive oxygen species in macrophages 2.50α <0.0001 –3.16b 0.0001 VEGF family ligand-receptor interactions 2.45α 0.001 –3.16b <0.0001 VEGF signaling 2.45α 0.003 –2.33b <0.0001 Nitric oxide signaling in the cardiovascular system 2.45α 0.006 –3.00b <0.0001 Induction of apoptosis by HIV1 2.45α 0.0001 –1.63 <0.0001 PAK signaling 2.45α 0.002 –2.65b 0.0002 CNTF signaling 2.45α 0.0002 –2.00b 0.006 Oncostatin M signaling 2.45α <0.0001 0.007 Pancreatic adenocarcinoma signaling 2.33α <0.0001 –2.53b <0.0001 ILK signaling 2.33α 0.001 –2.89b <0.0001

Ingenuity Pathway Analysis – Canonical Pathways: CKD 4-5 vs Control Slide 1 of 2

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Table 4. Ingenuity Pathway Analysis canonical pathway analysis of proteins enriched in the CKD cohort and the impact of apabetalone in the CKD cohort at 12 hours post-dose versus baseline Wasiak S, … Kalantar-Zadeh K, … Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018

Ingenuity Pathway Analysis CKD vs control: baseline CKD apabetalone z score P value z score P value Renin-angiotensin signaling 2.33α <0.0001 –2.83 0.0001 Cardiac hypertrophy signaling 2.33α 0.004 –3.16 0.0006 Role of pattern recognition receptors in recognition of bacteria and viruses 2.24α 0.0004 –2.45 <0.0001 IL-22 signaling 2.24α <0.0001 –1.63 <0.0001 Tec kinase signaling 2.24α 0.02 –3.16 <0.0001 Role of NANOG in mammalian embryonic stem cell pluripotency 2.24α 0.001 –2.45 <0.0001 Coagulation system 2.24α <0.0001 –0.45 <0.0001 Type 2 diabetes mellitus signaling 2.24α 0.04 –3.00 <0.0001 NGF signaling 2.24α 0.02 –2.65 0.0006 Melanocyte development and pigmentation signaling 2.24α 0.008 –2.24 0.005 Corticotropin releasing hormone signaling 2.24α 0.0009 –2.00 0.01 Notch signaling 2.24α 0.0001 0.07 BMP signaling pathway 2.12α <0.0001 –2.45 0.0003 IL-8 signaling 2.11α <0.0001 –3.74 <0.0001 PEDF signaling 2.00α 0.004 –2.53 <0.0001 GM-CSF signaling 2.00α 0.02 –3.00 <0.0001 Role of PI3K/AKT signaling in the pathogenesis of influenza 2.00α 0.02 –2.83 <0.0001 Role of IL-17F in allergic inflammatory airway diseases 2.00α <0.0001 0.0002 Ephrin B signaling 2.00α 0.003 0.6 PPAR signaling –2.12b <0.0001 2.24 0.005 Antioxidant action of vitamin C –2.24b 0.01 2.45 0.0003

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SLIDE 35
  • Analysis of plasma from CKD patients revealed that a single dose of apabetalone at 12 hours

rapidly downregulated multiple CKD and CVD protein markers, as well as associated molecular pathways, and reduced the abundance of disease markers, including interleukin-6, plasminogen activator inhibitor-1 (PAI-1), and osteopontin.

– Apabetalone reduced the plasma protein levels of multiple cytokines & chemokines: IL-6, IL-12, IL-17, and IL-23 – Apabetalone was predicted to counter the CKD-associated upregulation of cytokine pathways: IL-6, IL-8, and IL-17 – Apabetalone had a significant impact on the innate and adaptive immune system, including the dendritic cell maturation and the Th1 signaling pathways – The Acute Phase Reactant (APR) pathway was robustly downregulated by apabetalone – Apabetalone significantly decreased markers of the fibrinolysis pathway (including plasminogen activator inhibitor-1, urokinase-like plasminogen activator, and tissuetype plasminogen activator), which are associated with disturbances in hemostasis and atherosclerosis in CKD patients – Apabetalone reduced the plasma concentration of activated C3 fragments and of the anaphylatoxin C5a, a marker that has been correlated with CVD outcomes – Apabetalone downregulated the abundance of multiple NF-kB target proteins in plasma from the CKD cohort, including IL-6, IL-1a, IL-12, IL-23, MMP-3, and plasminogen activator inhibitor-1 – Apabetalone also decreased the predicted activation of the NF-kB signaling pathway

Summary and Conclusions: Phase I Apabetalone in non-dialysis CKD 4-5 Study

36

Wasiak S, … Kalantar-Zadeh K, … Kulikowski E. Benefit of Apabetalone on Plasma Proteins in Renal Disease. Kidney Int Rep. 2018

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SLIDE 36
  • What is the effect of Apabetalone in CKD patients?

Real Word Evidence: Apabetalone in Patients with CKD

37

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SLIDE 37

The first report on CKD effects of pharmacologic epigenetic modulation of novel selective BET inhibition Apabetalone

Kidney Blood Pressure Research 2018: This is the first report on the effects of pharmacologic epigenetic modulation via novel selective BET inhibition in form of an

  • ral small molecule BET inhibitor,

apabetalone, on levels of alkaline phosphatase (ALP) and kidney function in CKD patients

Kulikowski E, Halliday C, Johansson J, Sweeney M, Lebioda K, Wong N, Haarhaus M, Brandenburg V, Beddhu S, Tonelli M, Zoccali C and Kalantar-Zadeh K. Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney

  • Disease. Kidney Blood Press Res. 2018;43(2):449-457. doi: 10.1159/000488257. PubMed PMID: 29566379. URL:

https://www.ncbi.nlm.nih.gov/pubmed/29566379

Apr 2018

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SLIDE 38

Phase II patients eligible for post-hoc CKD Subgroup Analysis

39

  • 499 subjects received either 100mg b.i.d. of apabetalone (n=331) or placebo (n=168) in SUSTAIN and ASSURE studies
  • SUSTAIN study: 28 patients had baseline eGFR<60 mL/min/1.73 m2,
  • 18 randomized to the apabetalone group and 10 to the placebo group
  • ASSURE study: 20 patients had baseline eGFR<60 mL/min/1.73 m2,
  • 17 randomized to the apabetalone group and 3 to the placebo group
  • A total of 48 patients were included in this post-hoc analysis

Nicholls SJ, Ray KK, Johansson JO, Gordon A, Sweeney M, Halliday C, Kulikowski E, Wong N, Kim SW and Schwartz GG. Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease. Am J Cardiovasc Drugs. 2018;18(2):109-115. doi: 10.1007/s40256-017- 0250-3. PubMed PMID: 29027131. URL: https://www.ncbi.nlm.nih.gov/pubmed/29027131 .

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SLIDE 39

Phase II Apabetalone CKD Substudy: Baseline Characteristics

Table 1. Patient demographics, concomitant medications, and baseline laboratory values in placebo- and apabetalone treated patients with baseline eGFR<60 mL/min/1.73 m2 from the pooled SUSTAIN and ASSURE studies

Categorical variables are summarized using frequencies N(%), while laboratory parameters are reported as median (min, max); eGFR estimated glomerular filtration rate, hsCRP high- sensitivity C-reactive protein, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol

Parameter All (n=48) Placebo (n=13) Apabetalone(n=35) p-value Age, yrs. 67.5 (43 – 83) 68 (55 – 83) 67 (43 – 81) 0.2 Male 31 (64.6) 4 (30.8) 27 (77.1) 0.006 Caucasian 36 (75.0) 10 (76.9) 26 (74.3) 1.0 Body mass index, kg/m2 29.5 (17.3 – 49.4) 29.8 (20.0 – 48.1) 29.4 (17.3 – 49.4) 0.8 Hypertension 42 (87.5) 12 (92.3) 30 (85.7) 1.0 Hyperlipidemia 29 (60.4) 6 (46.2) 23 (65.7) 0.3 Cardiovascular Disease History 46 (95.8) 13 (100.0) 33 (94.3) 1.0 Diabetes 24 (50.0) 6 (46.2) 18 (51.4) 1.0 Smoker 8 (16.7) 3 (23.1) 5 (14.3) 0.7 Statin Use Atorvastatin 16 (33.3) 8 (61.5) 8 (22.9) 0.02 Rosuvastatin 32 (66.7) 5 (38.5) 27 (77.1) 0.02 Concomitant Medications ACE Inhibitors 20 (41.7) 4 (30.8) 16 (45.7) 0.5 Beta Blockers 28 (58.3) 10 (76.9) 18 (51.4) 0.2 Anticoagulants 39 (81.3) 9 (69.2) 30 (85.7) 0.2 Diabetes Medications 24 (50.0) 6 (46.2) 18 (51.4) 1.0 Baseline Chemistry Alkaline Phosphatase, U/L 76 (39 – 156) 70 (59 – 156) 77 (39 – 134) 0.4 eGFR, mL/min per 1.73 m2 53.6 (40.0 – 59.7) 53.0 (42.0 – 59.7) 54.4 (40.0 – 59.1) 0.7 Creatinine, mg/dL 1.3 (1.0 – 1.6) 1.1 (1.0 – 1.5) 1.3 (1.0 – 1.6) 0.002 hsCRP, mg/L 2.1 (0.4 – 22.5) 2.3 (0.9 – 22.5) 1.8 (0.4 – 11.3) 0.06 HDL-C, mg/dL 39.0 (23.0 – 56.0) 44.0 (31.0 – 56.0) 38.5 (23.0 – 54.0) 0.09 Apolipoprotein A-I, mg/dL 121.5 (79.8 – 168.7) 134.8 (90.1 – 168.7) 121.4 (79.8 – 159.3) 0.3 LDL-C, mg/dL 91.5 (42.0 – 190.3) 98.1 (51.4 – 151.0) 89.6 (42.0 – 190.3) 0.3

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457.

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SLIDE 40

Parameter Placebo (n=13) Apabetalone (n=35) p-value between groups Percent Change p-value vs. baseline Percent Change p-value vs. baseline

Alkaline Phosphatase, U/L

  • 6.3

0.9

  • 14.0

<0.0001 0.02

eGFR, mL/min per 1.73 m2

  • 5.8

0.6 +3.4 0.04 0.3

Effects of Apabetalone on Alkaline Phosphatase (ALP) and eGFR in CKD

41

Table 2. Effects of Apabetalone on ALP and eGFR in the subgroup of patients with baseline eGFR<60 mL/min/1.73 m2 from the pooled SUSTAIN and ASSURE studies

Mann-Whitney test was used to examine the differences in biochemical parameters between treatment groups at baseline; median percent change from baseline to 24/26 weeks in the renal parameters was analyzed using a 2-sided Van Elteren test of apabetalone vs placebo, stratified by study in the safety population

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457.

Apabetalone

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SLIDE 41

Effects of Apabetalone on Alkaline Phosphatase (ALP) and eGFR in CKD

42

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457.

eGFR was calculated using the CKD-EPI formula. Wilcoxon signed-rank test for change vs. baseline * p<0.05 Apabetalone

6 Month eGFR Data

Parameter Placebo (n=13) Apabetalone (n=35) p-value between groups Percent Change p-value vs. baseline Percent Change p-value vs. baseline

Alkaline Phosphatase, U/L

  • 6.3

0.9

  • 14.0

<0.0001 0.02

eGFR, mL/min per 1.73 m2

  • 5.8

0.6 +3.4 0.04 0.3

Table 2. Effects of Apabetalone on ALP and eGFR in the subgroup of patients with baseline eGFR<60 mL/min/1.73 m2 from the pooled SUSTAIN and ASSURE studies

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SLIDE 42

System Organ Class/Preferred Term All (N=48) Placebo (N=13) Apabetalone (N=35) p-value Number of Subjects with at least one SAE 7 (14.6) 2 (15.4) 5 (14.3) Cardiac disorders 2 (4.2) 2 (5.7) 1.0 Angina Pectoris 2 (4.2) 2 (5.7) 1.0 General disorders and administration site conditions 1 (2.1) 1 (7.7) 0.3 Death 1 (2.1) 1 (7.7) 0.3 Hepatobiliary disorders 1 (2.1) 1 (2.9) 1.0 Cholecystitis Acute 1 (2.1) 1 (2.9) 1.0 Infections and infestations 1 (2.1) 1 (2.9) 1.0 Infectious Mononucleosis 1 (2.1) 1 (2.9) 1.0 Nervous system disorders 1 (2.1) 1 (7.7) 0.3 Syncope 1 (2.1) 1 (7.7) 0.3 Skin and subcutaneous tissue disorders 1 (2.1) 1 (2.9) 1.0 Angioedema 1 (2.1) 1 (2.9) 1.0 Vascular disorders 1 (2.1) 1 (2.9) 1.0 Peripheral Vascular Disorder 1 (2.1) 1 (2.9) 1.0

Rx-Emergent Adverse Events: Apabetalone was well tolerated

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Table 3. Treatment-emergent Serious Adverse Events (SAEs)

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457.

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SLIDE 43

Hypothetical Model: Biologically plausible links among ALP, selective BET Inhibition via oral Apabetalone, and CKD and CVD Outcomes

Elevated Alkaline Phosphatase (ALP) is associated with increased CVD mortality In the general population and in CKD patients

Elevated ALP is associated with increased vascular calcification vascular calcification is associated with increased mortality (and faster CKD progression?) Clinical studies have shown apabetalone lowers ALP and improves CKD progression dose-dependent & time-dependent

44

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457.

ALP: Serum Alkaline Phosphatase

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SLIDE 44

Conclusions:

CKD subgroup study of apabetalone phase II trials

  • This post-hoc analysis demonstrated favorable effects of

apabetalone on ALP and eGFR in both diabetic patients with CVD and the subgroup of CKD patients.

  • Generated the hypothesis is that epigenetic modulation

by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients

  • This data supports further renal function and MACE

research and provides rationale for a pre-specified CKD patient subgroup in the phase 3 BETonMACE study

  • Apabetalone is being evaluated in BETonMACE, a trial

enrolling high risk post-acute coronary syndrome patients with diabetes, of which approximately 10-15% will have stage III CKD. Key clinical endpoints will include MACE reduction, renal function, and changes in CKD markers in the CKD patients in the trial.

Kulikowski E, … Kalantar-Zadeh K. Kidney Blood Press Res. 2018;43(2):449-457. MACE: Major Averse Cardiac Events

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SLIDE 45

BETonMACE Phase III RCT

Commenced November 2015

BELGIUM CROATIA TAIWAN MEXICO CROATIA

BETonMACE is an ongoing pivotal Phase 3 trial designed to confirm if BET inhibitor apabetalone can prevent CVD events in post-ACS patients with T2DM and low HDL cholesterol

The details of the trial can be found at www.clinicaltrials.gov

HUNGARY POLAND SERBIA ISRAEL SLOVAKIA ARGENTINA GERMANY BULGARIA

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SLIDE 46

BETonMACE CV Outcomes Study Design: 2015-2019

2,400 + subjects

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

atorvastatin or rosuvastatin run-in apabetalone 200mg/ day + 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 >24 weeks 4-16 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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SLIDE 47

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 or

percutaneous coronary intervention

  • HDL < 1.04 (40) in males and < 1.17 (45) 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 or 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 Study Design: 2015-2019

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SLIDE 48
  • Pre-specified subgroup analyses for the primary endpoint include:

– Rosuvastatin/Atorvastatin – < 30 days/> 30 days post-acute coronary syndrome – LDL/HDL/TG’s above and below median – HbA1c above and below median – eGFR >60 mL/min and < 60 mL/min

  • Also change in eGFR for all patients with eGFR <60 mL/min

BETonMACE Subgroups:

2015-2019

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SLIDE 49

PROBLEM: CKD is a Multifactorial Disease:

  • a. inflammation & oxidative stress, complement activation
  • b. platelet activation, endothelial dysfunction & vascular calcification

Epigenetic gene regulation governed by BET proteins is central to pathways that drive CVD & CKD risk In diabetic and CKD patients

50

POTENTIAL SOLUTION: Epigenetic Modulation

BET-Inhibition: A Multifactorial Mechanism

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SLIDE 50

Conclusions: BET Inhibition via Apabetalone in CKD and CVD

  • CVD and CKD are multifactorial diseases driven by dysregulated genes and

pathways, such as inflammation and calcification

  • BET proteins (epigenetic “readers”) appear to regulate the genes and pathways

underlying these pathologies.

  • Apabetalone inhibits BET proteins and is the only BET clinical candidate in a

Phase 3 CVD outcomes trial in high-risk diabetes and CKD: BET on MACE, 2015- 2019

  • The BETonMACE trial is 100% enrolled (mid 2018) and is designed to reconfirm

marked MACE reductions and improved renal function observed in previous trials (by 2019)