Clinical

In 2015, Resverlogix initiated a global Phase 3 clinical trial called BETonMACE with the most advanced epigenetic drug called apabetalone (also known as RVX-208) for the reduction of Major Adverse Cardiac Events (MACE) in high-risk cardiovascular disease patients with type 2 diabetes mellitus and low high-density lipoprotein (HDL). The primary endpoint is the time to first occurrence of MACE. In addition, BETonMACE will test for renal function in a subset population of chronic kidney disease (CKD) patients. Patients over the age of 70 will also be assessed for neurological function with the Montreal Congitive Assessment (MoCA).

Apabetalone has been tested in over 1,700 patients in 18 countries

 

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, unstable angina or percutaneous coronary intervention
  • 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
  • Time to first occurrence of adjudication-confirmed broadly defined MACE: CV death, non-fatal MI, hospitalization for CVD events, or stroke
  • Percent change in concentration over time within and between treatment groups of the following: apoA-I, apoB, LDL-C, HDL-C, TG, HbA1c, fasting glucose, fasting insulin, ALP, and hsCRP
  • Change in kidney function in population baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.7m2
  • Percent change in fibrinogen within and between treatment groups
  • Transcription (messenger RNA [mRNA]) change in whole blood
  • Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L

 

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 2-4 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. 50% of people with chronic kidney disease also have diabetes and cardiovascular disease. Tragically, these patients remain at high-risk for having a Major Adverse Cardiac Event (MACE), which essentially means: heart attack, stroke or cardio-related death. This is happening at an alarming rate despite these patients taking current therapies. Over 2,200 Americans die of CVD each day, an average of 1 death every 40 seconds (Mozaffarian, Benjamin et al. 2016). Multiple proteomics assessments in high risk CVD patients have revealed links between markers connected with inflammation and other biological pathways and cognition. Moreover, both diabetes and CVD have been associated with higher levels of dementia and neurocognitive problems.

Clinical Trial History of Apabetalone

View Protocol

 

Indications In R&D

Fabry Disease

Resverlogix has received approval from Health Canada, Therapeutic Products Directorate, to proceed with a clinical trial with apabetalone in patients with Fabry disease.This is an open-label, exploratory clinical study to assess the patient safety and effect on key biomarkers of apabetalone in subjects with Fabry disease for 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 in subjects with Fabry disease as determined by change in key biomarkers including alkaline phosphatase (ALP), high-sensitivity C-reactive protein (hs-CRP), and other well-known markers for chronic kidney disease. In addition, an ex vivo study of apabetalone treated Fabry Disease blood is planned.

Muscular Dystrophy/Facio Scapulo Humeral Dystrophy

We have tested apabetalone and a variety of other RVX compounds for target and biomarker engagement in muscle cells, we are also analyzing human muscle biopsies from patients treated with apabetalone. Additional work is ongoing.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Due to positive data on the effect of apabetalone on the complement cascade, plans to start a safety/efficacy trial have been initiated.

Neuroinflammation

Direct effects of apabetalone demonstrate reduced inflammation and microglial activation with drug treatment and no detrimental effects on neurons. Additional work is ongoing.

Calcification

Treatment of vascular smooth muscle cells with apabetalone has demonstrated favorable effects on reducing osteogenic gene expression and calcium deposition, in vitro. Work is ongoing.

Pulmonary Arterial Hypertension

Due to the positive effects of apabetalone treatment on primary lung smooth muscle cells (SMCs), an animal study of the effect of apabetalone on top of standard of care in pulmonary arterial hypertension is ongoing.

Malignant Peripheral Nerve Sheath Tumors (MPNST)

Studies examining the effect of apabetalone in vitro and in vivo on MPNST are ongoing.