There is a paradigm shift coming in cardiovascular disease (CVD) research and drug development. Soon atherosclerosis will not just be managed, but can ultimately be eliminated. Biomarkers such as apolipoprotein A-1 (ApoA-1), high density lipoprotein (HDL) cholesterol, and large HDL particles are key indicators of reverse cholesterol transport (RCT). RCT is a biological pathway by which accumulated cholesterol is transported from the arterial wall to the liver for excretion. This is important news for the more than 80 million US adults (1 in 3) who currently have CVD.
Cardiovascular disease is the leading cause of death in the US and other developed nations1 costing the American health care system $448.5 billion in 2008.2 The underlying cause of CVD is atherosclerosis, a build-up of plaque in the arteries often referred to as “hardening of the arteries.”3 Statin therapies—the current standard of care—only prevent the disease from progressing. The development of new cardiovascular therapeutics that can reverse atherosclerosis is essential for further disease risk reduction and lower costs.
Epidemiology studies have shown that the incidence of cardiovascular events correlate directly with a decreased level of plasma HDL4,5 and its primary protein, ApoA-1.6-8 Biotechnology company, Resverlogix Corp. in Calgary, Canada, is developing a first-in-class small-molecule oral drug, RVX-208, to clear plaque out of arteries, something that leading drugs in the $35 billion cholesterol market have so far failed to do. Two clinical trials have illustrated RVX-208’s ability to increase the body’s production of ApoA-1 (the main protein of HDL cholesterol) and other key reverse cholesterol transport markers.
Resverlogix reported data from a successful Phase 1b/2a double-blind safety and tolerability study in September and is now embarking on an ambitious Phase 2 clinical plan. The studies will be guided under the steering committee direction of Cleveland Clinic Department of Cardiovascular Medicine chairman, Dr. Steven Nissen, with Dr. Steve Nicholls as principal investigator.
Different HDL approaches: CETP inhibitors
Other drugs attempting to target HDL have used the cholesteryl ester transfer protein (CETP) pathway. The Phase 3 trial of Pfizer’s CETP drug, Torcetrapib, was terminated because of side effects, including blood pressure elevation. It is currently unclear if the blood pressure side effect is the result of the Torcetrapib molecule or if the CETP target itself is flawed. CETP inhibition raises HDL cholesterol by interfering with the removal of cholesterol from plasma. In contrast, RCT drugs cause a flux of cholesterol from the arterial wall to the liver. No other company is currently working on the same approach as Resverlogix, a small molecule drug that increases the production of ApoA-1 by the body.
RVX-208 mechanism of action
RVX-208 works by increasing serum levels of ApoA-1, a key cardioprotective protein that makes up 70% of HDL cholesterol. RVX-208 creates more serum HDL particles to function as reverse cholesterol transporters away from the atherosclerotic plaques. The drug molecule turns on the gene that makes ApoA-1 by signaling to a target protein in the cytoplasm. This target then signals to the nucleus, leading to increased ApoA-1 transcription and subsequent protein synthesis. The ApoA-1 protein is then secreted from the liver and small intestines to plasma as lipid poor disk-formed particles.
These lipid-poor, cholesterol-empty ApoA-1 particles interact with the ABCA-1 transporter on the macrophages. Cholesterol is removed from the macrophages, in effect stabilizing the plaque. In this process the disc-formed particles bind the cholesterol and become spherical ?-HDL particles. With RVX-208, more new empty, pre-?-HDL discs flow through the atherosclerotic plaques thereby filling up with cholesterol becoming mature ?-HDL particles. The ?-HDL particles transport the cholesterol to the liver, where they release the cholesterol through the scavenger receptor B-1 which is then flushed out of the body. The RVX-208 molecule raises the number of these “functional HDLs”, which is a different mechanism of increasing HDL levels than CETP inhibitors, where the net effect is a stagnation of cholesterol in plasma and in the existing number of HDL particles.
Pharmacoeconomic analysis of atherosclerosis regression
Leading pharmaceutical industry consultants Destum Partners conducted a detailed pharmacoeconomic analysis of the potential health system cost savings with atherosclerosis regression. The study clearly illustrates that over and above current standard-of-care drugs, such as statins, a 1% regression to 5% regression could save the American health system $22.9 to $76.8 billion annually. These types of savings represent an unprecedented potential for future cardiovascular and health system management.
RVX-208 phase 2 parallel study plans
Two phase 2 clinical studies are to proceed in parallel. All patients in both studies will be on standard therapy for more than 10 weeks beforehand. The first is a three-month lipid-dose response study in 280 stable patients with cardiovascular disease on standard-of-care therapy including statins. The second study is a pilot-IVUS (intravascular ultrasound) study with two doses in 120 acute coronary syndrome patients, to examine early lipid effects and atheroma plaque characterization of the coronary vessel wall. Both studies will commence Q1 2010, and be headed by the Cleveland Clinic. IVUS images are designed to show the degree of atheroma- volume burden and changes in this volume. Exploratory examination of plaque composition characterizes will also be performed as well. It is hoped that plaque characterization will be successful in demonstrating trends of plaque stabilization and plaque regression.
RVX-208 phase 1b/2A study results
The completed double-blind safety and tolerance Phase 1b/2a study tested RVX-208 in 72 subjects for 28 days in three 24-subject dosing arms: low dose, dose-escalation and a high dose. Half of the subjects had low levels of baseline HDL, and treatment effects for them were equally good to that of subjects with normal HDL. In all subjects in all doses, plasma ApoA-1 increased compared to placebo from 5.1% to 10.4% at days 8 and 28 respectively. At the lowest dose of 1 mg/kg twice daily, subjects with low levels of HDL-cholesterol/plasma ApoA-1 had statistically significant increases of 5.7% (p<0.05) at day 8 and 7.8% (p<0.05) at day 28.
In addition to the primary endpoint of increased production of plasma ApoA-1, the study looked at additional markers for reverse cholesterol transport, such as ApoA-1, HDL-c, pre-β-HDL and α-HDL subparticles. A critical RCT functionality marker, α1- HDL particles, showed high statistical significance, with an increase of 46.7% (p<0.004), in all subjects, and 57.2% (p<0.02) in the low-dose arm over placebo at day 28.
RVX-208 secondary indication: Alzheimer’s disease
Resverlogix is also researching RVX-208 for disorders that effect cognitive function such as Alzheimer’s disease. Epidemiological and mechanistic evidence indicates that there exists a link between low ApoA-1/HDL and neurodegenerative disease such as Alzheimer’s.
References
1. National Center for Health Statistics Health, United States, 2008 With Chartbook Hyattsville, MD: 2009.
2. AHA 2008 Heart Disease & Stroke Statistics Update Report: 2005 data.
3. American Heart Association Heart and Stroke Facts.
4. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707-14.
5. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996 Jul;124 Suppl:S11-20
6. Von Eckardstein A, Fischer F, Schulte H, Tataru M, Köhler E, Assmann G. Association of serum apolipoprotein A-I (but not high-density lipoprotein cholesterol) with healed myocardial infarction in men independent of serum insulin and C-peptide. Am J Cardiol. 2001 Oct 1;88(7):723-6.
7. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001 Dec 15;358(9298):2026-33.
8. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52.
Filed Under: Drug Discovery
