Academic Medical Center / University of Amsterdam The Netherlands - - PowerPoint PPT Presentation

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Academic Medical Center / University of Amsterdam The Netherlands - - PowerPoint PPT Presentation

Nov 25, 2022 28 likes •208 views

Prof. John J.P. Kastelein, MD PhD FESC Dept. of Vascular Medicine Academic Medical Center / University of Amsterdam The Netherlands Disclosures Dr. Kastelein consults with and speaks for biotechnological as well as pharmaceutical companies

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SLIDE 1
  • Prof. John J.P. Kastelein, MD PhD FESC
  • Dept. of Vascular Medicine

Academic Medical Center / University of Amsterdam The Netherlands

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SLIDE 2

2

Disclosures

  • Dr. Kastelein consults with and speaks for biotechnological

as well as pharmaceutical companies that develop molecules that influence lipoprotein metabolism and / or inflammation to prevent CVD, including Regeneron, Sanofi, Amgen, Pfizer, Eli Lilly, Iosis, AstraZeneca, CSL Behring, Cerenis, Esperion, The Medicines Company, Kowa, Affiris, UniQure, Madrigal Pharmaceuticals, Akcea Therapeutics, Staten Biotech, Akarna, Corvidia and Gemphire

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SLIDE 3

BET Protein Guides Basal Transcription Complex Along Gene

Confidential 3

BRD4 BET Protein 4 (BRD4)

Nature Reviews Molecular Cell Biology 13, 543-547

28 Aug 2016

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SLIDE 4

Apabetalone Is A Selective Inhibitor of BET Proteins

1 58-159 349-461 600-678 1362

BD1 BD2 ET

2 bromodomains (BD1 & BD2) are present in each BET protein to read acetylated lysine Apabetalone (RVX-208)

Core Histones Histone Tail BET Protein Acetylated Lysine

A Nucleosome Apabetalone selectively inhibits BD2

Confidential 4 28 Aug 2016

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SLIDE 5

Effects on Gene Activity: Apabetalone (selective)

  • vs. JQ-1 (pan) BET inhibitors

5

(+)-JQ1

PNAS, 2013 110 (49):19754-9.

JQ-1 PAN Dose 1 RVX208 PAN Dose 2 RVX208 BD2

Regulated genes

BD2 specific gene expression differs from pan inhibitor

Confidential 28 Aug 2016

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SLIDE 6

Beneficial Effects of Apabetalone on Inflammation

0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,01 0,1 1 10 100 Fold Change (relative to DMSO) Apabetalone (uM) MCP-1 VCAM 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 0,01 0,1 1 10 100 Fold Change (relative to DMSO) Apabetalone (uM) IL-6

Apabetalone Treatment of HAEC* (TNFα 3h) Apabetalone Treatment of Macrophage Cell Line (LPS 3h)

Confidential 6 28 Aug 2016

*Human Aortic Endothelial Cells

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SLIDE 7

Apabetalone Reduces Atheroma in Aorta

  • f ApoE-/- Mice

7 WK 8

HF Diet

WK 19 High Fat (42% kcal) Diet Animal Arrival

Necropsy

WK 9 Chow Chow: TD 2016 +/- apabetalone WK 33

Chow Diet

Placebo Apabetalone (150 mg/kg)

 of -40% (p<0.045)

Plaque/whole area (%) +/- SE

20 15 10 5

15.081-608-519 11.081-607-040

Whole aorta Apabetalone Placebo

16.040-776-379 8.092-895-111

Aortic sinus Whole aorta

Placebo Apabetalone (150 mg/kg)

 of -31% (p<0.016)

Aortic sinus

Jahagirdar et al, Atherosclerosis 2015

Confidential 28 Aug 2016

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SLIDE 8

Downregulation of Pathways Important for Atherosclerotic CV Disease

8

Microarrays were performed on Primary Human Hepatocytes (PHH) treated with apabetalone at and analyzed for genes (20,000+) and pathways (1,000+) affected.

Blue: genes that are downregulated Black: genes not affected Yellow: genes that are upregulated Gilham et al Atherosclerosis 2016

Confidential 28 Aug 2016

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SLIDE 9

Apabetalone in the Clinic

9

  • 985 subjects have participated in completed trials
  • 706 received treatment with apabetalone including 576

patients with CAD and/or dyslipidemia on top of standard of care therapy

  • Three Phase 2 studies in patients with CAD have been

completed:

  • 12-week (ASSERT) enrolled 299 patients
  • 24-week (SUSTAIN) enrolled 176 patients
  • 26-week (ASSURE) enrolled 323 patients
  • On going Phase 3 CVOT (BETonMACE) currently has ~ 600

patients

Confidential 28 Aug 2016

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SLIDE 10

Combined Phase 2 Six Month Studies Patient Demographics

Parameter Placebo (n=168) apabetalone (n=331) Age, (years) 57.2 58.7 Male, n (%) 113 (67.3) 249 (75.2) Hypertension, n (%) 136 (81.0) 260 (78.5) Diabetes, n (%) 65 (38.7) 127 (38.4) Prior myocardial infarction, n (%) 44 (26.1) 117 (35.3) Concomitant Medication Use Prior statin use, n (%) 116 (69.0) 268 (81.0) Aspirin, n (%) 125 (74.4) 263 (79.5) Beta blocker, n (%) 90 (53.6) 227 (68.6) ACE inhibitor, n (%) 71 (42.3) 131 (39.6)

Source: RVX data on file – ASSURE and SUSTAIN SAFETY Population. Confidential 10 28 Aug 2016

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Protein Name Gene Symbol

Placebo (n=47) Apabetalone 200mg (n=47) Treatment Difference p-value vs placebo

C-reactive protein CRP

  • 22.3
  • 43.6
  • 21.3

0.02

Tumor necrosis factor receptor superfamily TNFRSF11B

7.8

  • 6.2
  • 14.0

0.003

Vascular cell adhesion protein 1 VCAM1

5.7

  • 6.4
  • 12.2

0.005

Interleukin-6 receptor subunit alpha IL6R

  • 0.1
  • 9.3
  • 9.1

0.01

Fibronectin FN1

  • 19.8

14.3 34.1 0.04

Patients treated with apabetalone experienced reductions in inflammatory biomarkers, consistent with preclinical observations

Clinical Analysis of Vascular Inflammation in CVD Patients in ASSURE Study (n=94)

Confidential 11 28 Aug 2016

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Protein Name Gene Symbol Placebo (n=47) Apabetalone 200mg (n=47) Treatment Difference p-value vs placebo

C5a anaphylatoxin C5

22.7

  • 28.7
  • 51.4

0.0001

Complement component C6 C6

0.9

  • 15.3
  • 16.1

0.002

Complement C2 C2

4.2

  • 6.7
  • 10.9

0.0002

Complement C5 C5

  • 0.9
  • 11.7
  • 10.8

0.0001

Apabetalone Reduces Levels of Complement and Coagulation Components in ASSURE Patients (n=94)

Confidential 12

Complement

Patients treated with apabetalone experienced reductions in complement and coagulation proteins. No increase in the incidence of infections, infestations or bleeding events has been observed. Coagulation factor Xa F10

7.4

  • 1.0
  • 8.5

0.005

Coagulation Factor XI F11

4.1 0.1

  • 4.0

0.03

Thrombin F2

  • 17.6
  • 3.0

14.6 0.02

Coagulation Factor V F5

4.6

  • 0.9
  • 5.6

0.08 Coagulation

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Apabetalone Biomarker Changes Accompanied by MACE Reduction in Phase 2 Studies

13

Source: RVX data on file – ASSURE and SUSTAIN Safety Population. Log-Rank test for between group comparison Note: Patients were censored at 30 days after the last dose of study medication.

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

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Apabetalone Adverse Events

14

  • Across the three studies (ASSERT/SUSTAIN/ASSURE) most

common AEs were similar to placebo:

  • gastrointestinal disorders (nausea, diarrhea, and

constipation)

  • infections (upper respiratory tract infection, sinusitis, and

bronchitis)

  • With few exceptions these findings were mild and moderate in

severity

  • Most clinically significant adverse event is raised hepatic

transaminases

Confidential 28 Aug 2016

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Hepatic Adverse Events

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  • Hepatic profile of apabetalone evaluated in detail
  • Incidence of transaminases >3X ULN 7-8%
  • No cases of Hy’s law or serious hepatic injury to date in >1000

subjects

  • Raised transaminases resolve rapidly (approx 15 days for 5X

to <ULN)

  • More data to be obtained from BETonMACE study to further

delineate both early and long term hepatic safety

Confidential 28 Aug 2016

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2,400 + subjects with T2DM

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

atorvastatin and 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

  • r 10-40 mg rosuvastatin

screening 1-2 weeks treatment duration up to 104 weeks 4-16 weeks randomization (1:1) end of treatment The study is an event-based trial and continues until 250 events have occurred.

BETonMACE CV Outcomes Study Design

Confidential 16 28 Aug 2016

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Key inclusion criteria

  • T2DM
  • HbA1c > 6.5% or history of diabetes

medications

  • CAD event 7 days - 90 days prior to Visit 1
  • MI, UA or PCI
  • 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 composite endpoint of CV death, non-fatal MI, and stroke. Primary Endpoint Time from randomization to the first

  • ccurrence of adjudication-confirmed triple

MACE defined as a composite endpoint of CV Death, Non-fatal MI, and Stroke. Secondary Endpoint Time from randomization to the first

  • ccurrence of adjudication-confirmed MACE

including revascularization and UA 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

Confidential 17 28 Aug 2016

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SLIDE 18

Apabetalone and BETonMACE Summary

  • Apabetalone is a first in class BET-inhibitor that regulates

genes and pathways that underlie development of CVD

  • In phase 2 clinical trials, CVD event reductions were found

which were most pronounced in patients with diabetes mellitus

  • r increased inflammation
  • BETonMACE is an ongoing pivotal phase 3 trial designed to

confirm if apabetalone can prevent CVD events in post-ACS patients with T2DM and low HDL cholesterol

  • Current recruitment ~ 600 patients

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

Confidential 18 28 Aug 2016