World Diabetes Day

On the 14th of November every year, the International Diabetes Federation (IDF) celebrates World Diabetes Day (WDD). WDD is a worldwide campaign established in 1991 by the IDF and the World Health Organization. The campaign was developed to engage the IDF and its members to raise awareness about the growing economic and healthcare burden that diabetes represents. This year’s WDD campaign focused on establishing and strengthening public health education and to encourage lifestyle changes to prevent Type-2 diabetes. In 2015, the IDF distributed its “Framework for Action on Sugar”. This initiative targeted policies to reduce the consumption of sugar and aid in the production and availability of healthier foods. Excess sugar consumption is one of the most important contributors to the risk of developing Type-2 diabetes.

In conjunction with the WDD and the upcoming World Diabetes Congress in Vancouver on December 1st, the IDF released new epidemiological estimates for the prevalence and growth of diabetes worldwide. In 2015, it is estimated that 415 million people worldwide have one type of diabetes and this number is expected to increase to 642 million people worldwide by 2040 (IDF Diabetes Atlas 2015). Based on these staggering numbers, an estimated one in 11 adults have diabetes worldwide (IDF Diabetes Atlas 2015).  Regional estimates suggest that the Western Pacific region has the highest number of individuals with diabetes, 153 million, however North America has the highest prevalence per capita with one in 8 adults suffering from the disease (IDF Diabetes Atlas 2015). On a per country basis, China has the largest diabetic population and the second highest diabetes-related health care expenditure (IDF Diabetes Atlas 2015).

One of the most severe consequences of diabetes is that it is a major risk factor for the development of cardiovascular disease (CVD). Diabetes and its associated complications, such as CVD, are leading causes of death in most countries. In some modernized and developed countries, CVD is responsible for 50% of deaths due to diabetes (IDF Diabetes Atlas 2015). According to the IDF, an estimated 5 million adults died from diabetes in 2015, which is equivalent to an astonishing one death every six seconds. From 2011 through 2013, the estimates of mortality due to diabetes increased by 11% which is in contrast to all other non-communicable diseases worldwide which illustrated declining mortality rates (IDF Atlas 2015). The mortality of diabetes reflects a larger burden compared to other high profile public health concerns such HIV/AIDS, tuberculosis and malaria.

In the recently commenced phase 3 BETonMACE clinical trial, Resverlogix is exploring the potential benefit of apabetalone (RVX-208) on the reduction of major adverse cardiac events (MACE) in patients with type 2 diabetes mellitus. This study and ongoing laboratory research will aid in establishing the emerging role of BET inhibition in high-risk vascular disease and especially in those with diabetes.

The Complement System: Part 2

Complement Mediated Diseases

As discussed in part 1 of this blog series, the complement system is a network of tightly regulated proteins which are a key part of the innate immune response. The complement system is initiated by the identification of a pathogen or antibody by complement proteins which trigger a cascade that results in cleavage of inactive proteins by a series of proteases, culminating in inflammation, phagocytosis and the assembly of the membrane attack complex (MAC). This protein complex assembles on the surface of target cells, creating a pore that results in the lysis or bursting of the specific cell. When activated, the complement system promotes inflammatory response and mediates lysis and clearance of microbial invaders or diseased host cells. Because of its central role in immune response, complement is a target for immune evasion and a contributor to many disease states. Several mechanisms regulate complement activation and deactivation. In a pathological state, inappropriate initiation of the complement cascade or deficiencies in specific factors or regulators can result in aberrant activation leading to host tissue damage. This blog will explore two diseases that develop as a result of abnormal activity of the complement system: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS).

PNH is an acquired rare disease that occurs as a result of a mutation in hematopoietic stem cells (cells that give rise to blood cells). The disease manifests itself in the complement-mediated destruction of red blood cells (RBCs), a process known as hemolysis with potentially fatal consequences. In healthy individuals, RBCs and other blood cell types have specific cell surface proteins that function to inhibit the complement system and ultimately protect cells against formation of the MAC. The root cause of this disorder lies in specific protein anchors, which act as tethers for proteins responsible for protecting blood cells from the activity of the complement system. CD59 and complement decay-accelerating factor (DAF) function as such inhibitors by impeding the activity of the enzymes that activate C3 and C5, respectively. These regulators are membrane-bound via a glycophosphatidyinositol (GPI) anchor. Due to the acquired mutation in their hematopoietic stem cells, patients with PNH do not express these host proteins and their RBCs become subject to complement-mediated destruction. A direct link exists between excessive complement activation and the clinical manifestation of PNH. The resultant excessive RBC lysis causes transfusion dependence in these patients. Symptoms of PNH include extreme fatigue, abdominal pain, anemia and hemoglobinuria (the release of free hemoglobin into the urine), which can lead to renal failure.

A life threatening complication of PNH is repeated thrombosis (blood clot formation) which is the leading cause of death in PNH, accounting for at least 40% of PNH mortality. PNH has an estimated annual incidence rate of 1-5 cases per million in the general population. A UK study found that approximately one-third of patients diagnosed with PNH died within 5 years of diagnosis despite receiving the current standard of care. Historically, the median survival has been 10 to 15 years from the time of diagnosis.

aHUS is a severe kidney disease associated with genetic alterations of complement components, modulators and inhibitors that result in excessive activation of the complement cascade. Genetic defects cause excessive cleavage and activation of complement components. Regulatory proteins such as factor H, factor B, membrane cofactor protein (MCP), factor I or thrombomodulin as well as the enzymes that activate C3 and C3 itself have all been implicated in the manifestation of aHUS. The identified genetic defects incur an amplified generation of C3 and C5, main components in the cascade, resulting in increased MAC formation at the endothelial cell surface. This results in damage to cells that line blood vessel walls, resulting in exposure of the underlying matrix and thrombus formation. Abnormal blood clot formation in the small blood vessels in the kidneys eventually leads to kidney failure. A direct link exists between excessive complement activation and the clinical manifestation of aHUS.

The estimated annual incidence rate for aHUS is 2 cases per million in the general population. Genetic mutations in at least 10 different complement regulatory genes and complement components have been identified in aHUS patients; however mutations are not identified in 30-50% of diagnosed patients. Children and adults alike are susceptible to developing the disease. During the first year after diagnosis, outcomes include permanent kidney damage requiring dialysis or death despite currently available transfusion therapies.

Despite current therapies for the treatment of both PNH and aHUS, a significant unmet need remains. Given the organization of the complement system, there are multiple points for therapeutic intervention which would attenuate the activity of this system in diseases where over activation is the driver of the pathology. Our final blog to this series will address Current Treatments for Complement-Mediated Diseases.



The Complement System: Part 1

On September 24, 2015, Resverlogix announced the commencement of an orphan disease program specific for complement-mediated diseases. Apabetalone (RVX-208) has been shown to modulate the complement pathway, which has known roles in cardiovascular disease and a variety of orphan indications. Based on these findings, Resverlogix plans to pursue proof-of-concept trials in complement mediated diseases, with the first clinical trial targeting Paroxysmal Nocturnal Hemoglobinuria (PNH).

Over the next few weeks, we will be detailing a series of blog posts highlighting the complement system, complement-mediated diseases and current therapeutic treatments for patients suffering from such diseases. The series will include three blog posts:

  • What is the complement system?
  • Complement-mediated diseases (examples include atypical hemolytic-uremic syndrome (aHUS) and PNH)
  • Current treatment for complement-mediated disease

What is the Complement System?

The immune system is made up of special cells, proteins, tissues and organs, which work in concert to defend the human body against germs and microorganisms. It is the body’s defense against foreign pathogens (biological entity that causes disease or illness) as well as abnormal cells that are derived from host tissues. This system is composed of two main parts, the innate immune response and the adaptive immune response. Several molecular components, such as complement proteins, cytokines and acute phase proteins, act in both the innate and adaptive immune responses.

The complement system represents one of the major effector mechanisms of the innate immune response, and comprises more than 30 blood soluble or membrane-associated proteins, the majority of which are synthesized by the liver. Most complement proteins circulate as pro-proteins (inactive until acted upon by specific enzymes) and the complement system remains inactive until triggered. Recognition of an antigen on the surface of a pathogen or a diseased cell activates the cascade that allows for conversion of complement pro-proteins into active components. The end-result of this activation is in the massive amplification of the response and in the generation of the membrane attack complex (MAC) on cell surfaces. The MAC forms a pore that spans the membrane of the target cell, resulting in cell lysis. Specific complement protein cleavage products generated during cascade amplification can also act as inflammatory mediators (C3a and C5a) or recognition molecules that allow for clearance of damaged cells (C3b and C4b) (see figure).



In general, the activation of the complement cascade results in the enhanced clearance of antigens (phagocytosis), the enhanced recruitment of macrophages and neutrophils into the area (inflammation), the cell lysis of foreign and abnormal cells and the enhanced agglutination or the clustering and binding of pathogens. Complement activation occurs through three principal pathways: classical, alternative and lectin (see figure). Though various factors can initiate complement activation (including MBL, C1q, C3), all three main pathways converge at the cleavage of C3, the most abundant complement protein in blood. Several mechanisms regulate complement activity including enzymes such as plasma carboxypeptidases and proteases.

Excessive complement activity is associated with several inflammatory, autoimmune, neurodegenerative and infectious diseases. The involvement of complement in the pathology of such diseases may be a result of either inappropriate initiation of the complement cascade or deficiencies in specific factors or regulators of the various pathways resulting in aberrant activation. Examples of such diseases include PNH and aHUS.  Current therapies for complement disorders do not adequately treat the disorder are prohibitively costly.  Combined, there is significant unmet need for individuals and families that are coping with the challenges of these disorders. Our next blog post will discuss complement-mediated diseases in more detail.

Resverlogix presents at the 2015 EASD annual meeting in Stockholm, Sweden

Today Dr. Norman Wong, Chief Scientific Officer of Resverlogix presented an oral abstract entitled ‘RVX-208 acts via an epigenetic mechanism to lower major adverse cardiovascular events (MACE) in patients with atherosclerosis and especially in those with diabetes mellitus’ at the annual meeting of the EASD held in Stockholm, Sweden.

The contents of the presentation detailed the continued efforts to understand the beneficial effects of RVX-208 (recently named apabetalone) on top of standard of care therapy in lowering MACE when given to patients with established cardiovascular disease (CVD). In previously completed Phase 2b clinical trials (SUSTAIN and ASSURE), post-hoc analyses showed that RVX-208 markedly reduced the combined MACE.

Our interest to understand the mechanisms by which RVX-208 reduces MACE in the trials comprised of patients with CVD and low levels of high-density lipoproteins (HDL) underlies the studies presented at the EASD. The data presented clearly showed the ability of RVX-208 to raise ApoA-I/HDL by enhancing production, but this effect of the compound was not sufficient to explain the observed reduction in MACE.  Therefore, several studies were undertaken to further explore the actions of RVX-208 in lowering CVD risk. Results of new studies involving the use of micro-array technology to survey gene expression in both liver cells and whole blood showed a number of pathways were affected by exposing them in vitro to RVX-208. These studies revealed that the compound affected specific pathways known to be important contributors to CVD risks including; complement, coagulation, inflammation, diabetes pathways, cholesterol synthesis and fatty acid synthesis. These pathways were not only acted upon by RVX-208 in a beneficial fashion but they were amongst the pathways most affected by the actions of the compound.  Of particular relevance to the EASD was the finding that in patients who had diabetes mellitus with established CVD and low HDL, RVX-208 use was associated with a serum glucose that was -0.3 mmol/L (n=76) lower while placebo was +0.9 mmol/L (n=43).  The absolute difference between the two groups was 1.2 mmol/L and this was significant with a p<0.01.

The results arising from our findings opened our eyes to the benefits of RVX-208, the first selective bromodomain extra-terminal (BET) protein inhibitor being tested for CVD risk reduction. The significance of the data is that this selective BET inhibitor has effects beyond its ability to enhance HDL production.  These unexpected actions of RVX-208 on several pathways that impact CVD risk provide potential biologic plausibility to why this compound may reduce MACE in the SUSTAIN and ASSURE trials.

New video of President & CEO Donald McCaffrey

At the recent Rodman & Renshaw 17th Annual Global Investment Conference, Donald McCaffrey, President & CEO had the opportunity to speak with Stock News Now (SNN). The video interview can be accessed here: Resverlogix also webcast from Rodman & Renshaw. The archived presentation can be accessed here:

Resverlogix is developing RVX-208 also named ‘apabetalone,’ a first-in-class, small molecule that is a selective BET bromodomain inhibitor. BET bromodomain inhibition is an epigenetic mechanism that can regulate disease-causing genes. Apabetalone is the first and only BET inhibitor selective for the second bromodomain (BD2) within the BET protein called BRD4. This selective inhibition of apabetalone on BD2 produces a specific set of biological effects with potentially important benefits for patients with diseases such as cardiovascular disease (CVD), diabetes mellitus (DM), Alzheimer’s disease, peripheral artery disease, and chronic kidney disease while maintaining an excellent safety profile. Apabetalone is the only selective BET bromodomain inhibitor in human clinical trials. Resverlogix’s Phase 3 clinical trial BETonMACE in high-risk CVD patients with DM and low HDL is planned to commence in the fall of 2015. Resverlogix’s common shares trade on the Toronto Stock Exchange (TSX: RVX). For further information please visit We can also be followed on Twitter @Resverlogix_RVX

Resverlogix featured in The Life Sciences Report

Resverlogix is featured in today’s issue of The Life Sciences Report: “Disrupting Treatment of Cardiovascular Disease with Epigenetics: Resverlogix CEO Donald McCaffrey.” The full article can be accessed here:

Updated Resverlogix Website

We are pleased to share that Resverlogix has updated sections to the corporate website. Please look for updates to the Programs section as well as Presentations & Publications at

Please note that Resverlogix can also be followed on Twitter @Resverlogix_RVX and LinkedIn.

Resverlogix in The Life Sciences Report with Marcel Wijma

On Wednesday, July 1, Marcel Wijma, chief research analyst at Van Leeuwenhoeck Institute discussed Resverlogix and RVX-208 with Gail Dutton of The Life Sciences Report in Probe Biotech’s Diverse Subsectors For Strong, Undervalued Companies: Van Leeuwenhoeck’s Marcel Wijma.

Here is an excerpt from the article:

“The current, more innovative thinking is to reduce the risk of actually experiencing a heart attack. This new tactic, using epigenetics, is getting more emphasis from scientists and cardio specialists. The approach being developed by Resverlogix is a small molecule that can uncover the involved environmental and individual aspects of lifestyle that directly interact with the genome to influence epigenetic change in the DNA of a person. The company is targeting patients who have diabetes mellitus or chronic kidney failure who are at high risk for cardiovascular disease.

Resverlogix seems to have an interesting new way to deal with cardiovascular disease. With RVX-208, a first-in-class, small molecule, selective BET inhibitor, Resverlogix may have the answer to developing a new generation of cardio drugs.”

You can read the full article here: utm_source=delivra&utm_medium=email&utm_campaign=TLSR+Final+7-1-15

European Biopharmaceutical Review (EBR) Publication

Resverlogix’s Dr. Ewelina Kulikowski has written and published an article for the summer 2015 issue of the European Biopharmaceutical Review (EBR) titled, “New Direction.” The article focuses on how BET inhibition has an impact on multiple biologies with the potential to treat a variety of conditions such as cancer, inflammatory, neurodegenerative, metabolic and cardiovascular disorders.

Dr. Ewelina Kulikowski has been with Resverlogix for over 10 years and was recently appointed to Vice President of Scientific Development.

You can read “New Direction,” by Dr. Kulikowski here:

Here is a link to the full EBR Summer 2015 issue:

We can also be followed on Twitter @Resverlogix_RVX

Highlights from the ADA 75th Scientific Sessions 2015

Resverlogix’s scientists were in attendance at the American Diabetes Association (ADA): 75th Scientific Sessions June 5-9 in Boston. At the meeting there were major announcements in regards to diabetes mellitus (DM) and cardiovascular disease (CVD) in the late breaking trials section. Most people who suffer from DM die of CVD (68% over the age of 65). These two diseases are closely linked and the medical community is recognizing the significance and complexity of this relationship. In line with this connection, in 2008, the FDA provided a document called: “Guidance for Industry, Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.”  The guidance requires that, since DM and CVD are so closely linked, any new drugs being developed for DM must undergo clinical trials to determine their effects in cardiovascular disease outcomes.

At the ADA there were two major sessions detailing recent clinical trials intended to ensure that new drugs on the market for treating DM were not raising CVD risks. Two trials called ELIXA and TECOS tested two members of the incretin class of drugs used to lower glucose in patients with DM. While ELIXA studied lixisenatide, an injected GLP-1 agonist being developed by Sanofi, the TECOS trial dealt with the actions of an oral dipeptidyl peptidase-4 inhibitor (DDP-IV) inhibitor saxagliptin from Merck. Both trials enrolled patients with DM and CVD to determine whether the addition of either of these agents on top of standard of care was better or worse in terms of CVD events.

The results of both trials were similar in that there was not an increase nor a decrease in major CVD events in response to lixisenatide or saxagliptin treatment on top of standard of care. This means that the treatments may be cardiovascular-safe in that they don’t increase the risk of cardiovascular events however they didn’t lower the rate of cardiac events either. The results point to the growing body of evidence revealing that drugs capable of effectively lowering glucose levels in patients with diabetes do not seem to be capable of lowering CVD risks.