Clinical

In 2015, Resverlogix initiated a global Phase 3 clinical trial – BETonMACE – with the most advanced epigenetic drug outside of oncology – apabetalone. The study has focused enrollment on high-risk cardiovascular disease patients with type 2 diabetes mellitus and low levels of high-density lipoprotein (HDL), where the effect of apabetalone is expected to be the greatest.

The primary endpoint in BETonMACE – the outcome we are measuring that will deem the trial a success – is the time to first occurrence of Major Adverse Cardiac Events (MACE). In addition, BETonMACE will test for kidney function in a subset of patients with chronic kidney disease (CKD). Patients over the age of 70 will also be assessed for neurological function with the Montreal Congitive Assessment (MoCA).

BETonMACE was fully enrolled in March of 2018, with over 2,400 patients participating.

The following information summarizes the BETonMACE clinical trial. Follow this link to view the full trial protocol.


PHASE 3 BETonMACE CLINICAL TRIAL

Primary Objective

To evaluate if treatment with apabetalone as compared to placebo increases time to the first occurrence of a Major Adverse Cardiac Event (MACE). MACE is defined as a single composite endpoint of: 1) Cardiovascular death, or 2) Non-fatal myocardial infarction, or 3) Stroke.

Key Inclusion Criteria
  • Type 2 Diabetes Mellitus
  • Coronary Artery Disease event 7 days - 90 days prior to screening
    • Myocardial infarction (MI) or unstable angina with or without percutaneous coronary intervention to manage ACS
  • High-density lipoprotein cholesterol (HDL-C) < 40 mg/dL for males and < 45 mg/dL for females
Primary Endpoint

Time from randomization to the first occurrence of adjudication-confirmed Major Adverse Cardiac Event (MACE) defined as a single composite endpoint of: 1) Cardiovascular death, or 2) Non-fatal myocardial infarction, or 3) Stroke.

Secondary Endpoint

The key secondary endpoints will be:

1. Time from randomization to the first occurrence of adjudication-confirmed MACE broadly defined between treatment groups. Broadly defined MACE is the occurrence of any of the following events:

  • CV death
  • Non-fatal myocardial infarction (MI)
  • Hospitalization for CVD events which include:
    • Unstable angina AND evidence of new or presumed new progressive obstructive coronary disease, OR
    • Emergency revascularization procedures at any time and urgent revascularization procedures ≥30 days after the index events prior to randomization
  • Stroke

2. Total incidence of Narrow MACE
3. Time from randomization to CV Death or Non-fatal MI
4. Time from randomization to coronary heart disease death or Non-fatal MI
5. Time from randomization to Non-fatal MI
6. Time from randomization to CV Death
7. Time from randomization to Stroke
8. All-cause mortality
9. Incidence of hospitalization for congestive heart failure

Other secondary and exploratory endpoints include:

  • Changes from baseline in kidney function in subgroup population with estimated glomerular filtration rate <60 mL/min/1.7m2 within and between treatment groups
  • Change in MoCA score in all and those with baseline MoCA <26 within and between treatment groups 


BETonMACE CLINICAL INDICATIONS

  • Cardiovascular Disease
  • Diabetes Mellitus
  • Chronic Kidney Disease
  • Neurodegenerative diseases

There is a direct link between heart disease, diabetes and chronic kidney disease. Adults with diabetes are 2 to 4 times more likely to die from cardiovascular disease than those without diabetes. High blood pressure and diabetes are the main causes of chronic kidney disease. About half of people with chronic kidney disease also have diabetes as well as cardiovascular disease. These patients remain at high-risk for having a heart attack, stroke or cardio-related death, despite taking currently approved standard of care therapies.

Large scale studies of proteins – proteomics – in high-risk cardiovascular disease patients have revealed links between inflammation, lipid transport, calcification, and cognition. Moreover, both diabetes and cardiovascular disease have been associated with higher levels of dementia and neurocognitive problems.


Clinical Trial History of Apabetalone
 

Indications In R&D

Chronic Kidney Disease

There is a direct link between heart disease, diabetes and chronic kidney disease. High blood pressure and diabetes are the main causes of chronic kidney disease. Findings from a groundbreaking Phase 1 study (Benefit of Apabetalone on Plasma Proteins in Renal Disease - Kidney International Reports, Wasiak et al., 2017) demonstrated plasma proteome dysregulation in patients with impaired kidney function and the beneficial impact of apabetalone on proteins and pathways linked to chronic kidney disease and its cardiovascular complications.

Apabetalone continues to be evaluated for the treatment of patients with chronic kidney disease. Estimated glomerular filtration rate (eGFR) will be measured for BETonMACE patients, and a predefined subset of the patients with low baseline eGFR will be evaluated for improvements in renal function versus placebo. A Phase 2a program is also underway for CKD patients on dialysis, which will examine safety and key risk biomarkers.

Fabry Disease

Resverlogix has received approval from Health Canada, Therapeutic Products Directorate, to proceed with a clinical trial of apabetalone in patients with Fabry disease. This is an open-label, exploratory clinical study that will last up to 16 weeks. The study population will consist of two cohorts:

  • Cohort 1: Patients with Fabry disease receiving enzyme replacement therapy (ERT)
  • Cohort 2: Patients with Fabry disease not receiving ERT

The primary objective of the study is to evaluate the safety and tolerability of apabetalone in patients with Fabry disease. Secondary objectives include evaluating the effect of apabetalone on key biomarkers including alkaline phosphatase (ALP), high-sensitivity C-reactive protein (hs-CRP), and other well-known markers of chronic kidney disease and CVD. In addition, an ex vivo study of apabetalone treated Fabry disease patient blood is underway.

Pulmonary Arterial Hypertension

Due to the positive effects of apabetalone treatment on primary lung smooth muscle cells (SMCs) and in animal models, a clinical trial of the effect of apabetalone on top of standard of care in pulmonary arterial hypertension has been planned.

Vascular Cognitive Dementia

Both diabetes and CVD have been associated with higher levels of dementia and neurocognitive problems. Moreover, multiple proteomics assessments have revealed significant overlap between processes associated with CVD – vascular inflammation and calcification – and the biological pathways that drive cognitive risk. Our Phase 3 trial, BETonMACE, includes a pre-specified analysis of cognition scores in patients over the age of 70, utilizing the MoCA assessment.

Changes in MoCA scores for patients undergoing apabetalone treatment will be compared with the placebo arm of two separate groups: those with a baseline MoCA score of 26 or higher (normal cognitive function), and those with 25 and below (mild to moderate cognitive function). An improvement in MoCA scores with apabetalone treatment could signal its efficacy in the treatment of neurodegenerative disorders such as dementia and vascular cognitive impairment. Additional studies are being planned following trial completion.

Facio Scapulo Humeral Muscular Dystrophy (FSHD)

Apabetalone has been shown to inhibit the expression of DUX4, the protein identified as the primary cause of FSHD, in human skeletal muscle cells. Strategic partnerships are currently being pursued to support testing apabetalone in FSHD animal models. At the same time, development of a topically-administered formulation of apabetalone is in progress, to improve muscle-specific delivery of the drug.


Clinical Steering & Advisory Boards

Our appointed committee members hold the highest levels of expertise in a multitude of medical fields.

BETonMACE

Clinical Steering Committee (CSC)

Professor Kausik K. Ray

BSc (hons), MBChB, MD, MPhil (Cantab), FACC, FAHA, FESC, FRCP
Chairman

Professor Ray’s research interests focus on the prevention of cardiovascular disease using observational methods and intervention studies including large trials.

  • Professor of Public Heath, Department of Primary Care and Public Health, School of Public Health, Imperial College London, UK
  • Established the Familial Hypercholesterolaemia (FH) Studies Collaboration (FHSC)
  • Principal Investigator for the TOGETHER study
Dr. Henry N. Ginsberg

MD, FAHA
Member

Dr. Ginsberg’s research focuses on the regulation of lipoprotein metabolism, particularly in relation to insulin resistance and diabetes.

  • Irving Professor of Medicine at Columbia University College of Physicians and Surgeons
  • Associate Dean for Clinical and Translational Research
  • Director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center
  • Principal Investigator in the landmark ACCORD Lipid Trial
Dr. Kamyar Kalantar-Zadeh

MD, MPH, PhD, FAAP, FACP, FASN, FAHA, FNKF
Member

Dr. Kalantar’s research focuses on kidney disease outcomes and cardiovascular risks in CKD and diabetes. Dr. Kalantar has authored or coauthored over 400 peer reviewed research articles and scientific papers and 15 book chapters.

  • Professor of Medicine, Pediatrics, Public Health and Epidemiology
  • Chief of the Division of Nephrology and Hypertension at UC Irvine School of Medicine
  • President Elect of the International Society of Renal Nutrition and Metabolism
  • Associate Editor of several journals including the American Journal of Kidney Diseases and Nephrology Dialysis Transplantation
Dr. Stephen J. Nicholls

MBBS, PhD
Member

  • Professor of Cardiology at the University of Adelaide
  • Deputy Director at the South Australian Health and Medical Research Institute
  • Principal Investigator of the SATURN, AQUARIUS, ACCELERATE, STRENGTH and GLAGOV trials
  • Fellow of the Royal Australasian College of Physicians and American College of Cardiology
  • Member of the American Heart Association
Dr. Gregory G. Schwartz

MD, PhD
Member

  • Professor of Medicine in the Division of Cardiology of the University of Colorado Denver
  • Lead investigator in MIRACL (atorvastatin), dAL-OUTCOMES (dalcetrapib), and ODYSSEY Outcomes (alirocumab) trials
  • Fellow of the American Heart Association and the American College of Cardiology
  • Member of the American Physiological Society and the International Society for Heart Research
Dr. Peter P. Toth

MD, PhD, FAAFP, FICA, FAHA, FNLA, FCCP, FACC
Member

  • Chief of Medicine for CGH Medical Center
  • Clinical Professor at the University of Illinois School of Medicine
  • Associate Professor of Medicine at Johns Hopkins University School of Medicine
  • Member of the American College of Cardiology Foundation Council on Cardiovascular Disease Prevention
  • Member of the American Heart Association’s Council on Lipoproteins, Lipid Metabolism, and Thrombosis
BETonRENAL

Renal Clinical Advisory Board (RCAB)

Dr. Kamyar Kalantar-Zadeh

MD, MPH, PhD
Chairman

  • Professor and Chief, Division of Nephrology and Hypertension at University of California, Irvine
  • Founder and Director of the Harold Simmons Center for Kidney Disease Research and Epidemiology
  • Associate Editor of several peer-reviewed journals including Nephrology Dialysis Transplantation (NDT), American Journal of Kidney Diseases (AJKD), Cardiorenal Medicine (CRM), Seminars in Dialysis, Journal of Cachexia, Sarcopenia and Muscle (JCSM)
  • Member of the editorial board of Kidney International (KI), Journal of American Society Nephrology (JASN), Nature Reviews Nephrology, American Journal of Nephrology (AJN)
Dr. Srinivasan Beddhu

MD
Member

Dr. Beddhu’s clinical and research interests include hypertension, chronic kidney disease progression and complications and end-stage renal disease.

  • Professor of Medicine at the University of Utah School of Medicine
  • Board Certified in Internal Medicine and Nephrology
  • Served on several national committees including NIH panels, American Society of Nephrology Research Committee and NKF Clinical Practice Guidelines Committee
Dr. Vincent Brandenburg

MD
Member

Dr. Brandenburg's primary focus is on chronic kidney disease – mineral and bone disorder, cardiorenal syndrome, and calciphylaxis.

  • Nephrologist, Associate Professor and Senior Consultant at the Department of Cardiology, Intensive Care Medicine and Vascular Medicine, University Hospital of the RWTH Aachen, Germany
  • Leader of the German Calciphylaxis Registry
  • Board member of the ERA-EDTA Scientific Working Group Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD)
  • Member of the German and European Societies of Nephrology and the Societies of Cardiology
Dr. Mathias Haarhaus

MD, PhD
Member

Dr. Haarhaus’s research at the Division of Renal Medicine, Karolinska Institutet, focuses on the link between skeletal disorders and cardiovascular complications in chronic kidney disease, with a special focus on alkaline phosphatase.

  • Consultant Nephrologist at the Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden where he is head of the Bone and Mineral Program
  • Member of the Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD) Working Group of the European Renal Association – European Dialysis and Transplantation Association (ERA-EDTA)
  • Member of the Guidelines Committee of the Swedish Society of Nephrology
Dr. Marcello Tonelli

MD, SM, FRCPC
Member

Dr. Tonelli was named a “Highly Cited” researcher in 2015 by Thomson-Reuters, corresponding to a rank in the top 1% by citations of all researchers worldwide for field and publication year.

  • Associate Vice-President (Research) at the University of Calgary
  • Fellow of the Canadian Academy of Health Sciences
  • Member of the American Society for Clinical Investigation in 2014
Dr. Carmine Zoccali

MD, FASN, FNKF, FERA
Member

Dr. Zoccali is a specialist in Renal Diseases (Pisa University) and Hypertension.

  • Director, Division of Nephrology, Hypertension and Renal Transplantation, Ospedali Riuniti, Reggio Cal, Italy
  • Chief, CNR-IBIM Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension
  • Professor, Postgraduate Schools of Nephrology, Palermo, Catania and Messina Universities
  • Editor in Chief, Nephrology Dialysis and Transplantation
  • Academic Editor, (Nephrology) PlosOne
  • Editorial Board member, Journal of the American Society of Nephrology (JASN)
  • Editorial Board member, Clinical Journal of the American Society of Nephrology (cJASN)
  • Editorial Board member, Kidney International (KI)
NEURODEGENERATIVE

Neurodegenerative Clinical & Scientific Advisory Board (NCSAB)

Dr. Bengt Winblad

MD, PhD
Chairman

Dr. Winblad’s research interests focus on the basic mechanisms behind, as well as treatment of, Alzheimer’s disease.

  • Professor at the Karolinska Institutet Alzheimer Disease Research Center in Huddinge, Sweden
  • Chief Physician at Karolinska University in Huddinge
  • Guest professor at the Department of Psychiatry in Frankfurt
  • Honorary professor at Beijing University, Wuhan University and Shanghai University in China
  • Member of the Advisory Committee for the Medical Research Council
  • Co-chair of the European Alzheimer’s Disease Consortium (EADC)
  • Chair of the Medical Scientific Advisory Panel of Alzheimer’s Disease International (ADI)
Dr. Jeffrey L. Cummings

MD, ScD
Member

Dr. Cummings is an experienced clinical trialist with expertise in clinical trial design and analysis, global trial implementation, and trial outcome measures.

  • Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada and Cleveland, Ohio
  • Camille and Larry Ruvo Chair of the Neurological Institute of Cleveland Clinic
  • Author of the Neuropsychiatric Inventory (NPI)
  • Former Professor of Neurology and Psychiatry at UCLA, Director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, and Director of the Deane F. Johnson Center for Neurotherapeutics at UCLA
Dr. Rada Koldamova

MD, PhD
Member

Dr. Koldamova’s current research is concentrated on the role of lipoproteins in AD pathogenesis using transgenic mice expressing human ApoE isoforms.

  • Associate Professor at the University of Pittsburgh, Pittsburgh, PA
Dr. Henrik Zetterberg

MD, PhD
Member

Dr. Zetterberg is has spent the last 10 years focusing on the development of biomarkers for Alzheimer’s disease and other brain disorders.

  • Developed new diagnostic tests for Alzheimer’s disease, as well as new preclinical models
  • Professor of neurochemistry at the University of Gothenburg