By: Dr. Norman C.W. Wong, M.D., FRCPC

Dr. Wong is Chief Scientific Officer at Resverlogix

A full Bio can be found at:

http://www.resverlogix.com/corporate_profile/senior_management

Resverlogix’s RVX-208 vs. CETP Inhibitors

The field of High Density Lipoprotein (HDL) therapy has attracted immense interest and many companies including Resverlogix are attempting to harness the beneficial actions of this class of lipoproteins. This document is divided into two parts. The first deals with the field of HDL therapies and details why Resverlogix feels their lead drug RVX-208 is superior to that of competing CETP technologies. This part also explains why the production of new HDL particles by RVX-208 constitutes a much more viable approach for regressing atherosclerosis in treating cardiovascular disease. The second part of the report will review data from abstracts presented at the European Society of Cardiology (ESC) Congress 2011 to support Resverlogix’s position taken in part 1 of the report.

RVX-208

RVX-208 is a novel small molecule that stimulates endogenous Apolipoprotein A-I (ApoA-I) production to trigger the formation of new HDL particles. The use of this approach aligns with the body’s natural protection against atherosclerosis using functional HDL. To appreciate how RVX-208 is unique requires an understanding of HDL biology. HDL is the smallest class of lipoproteins and ApoA-I is the major protein component of HDL.  The main role of HDL particles is to mediate a normal physiologic process called Reverse Cholesterol Transport (RCT).  In this process, HDL removes cholesterol from cells (i.e. macrophage foam cells within the atherosclerotic plaques of the arterial wall), and carry the cholesterol in plasma to the liver for processing into bile salts. Enhanced activity of RCT decreases the cholesterol content in the macrophage foam cells. In so doing, HDL clears cholesterol from atherosclerotic plaques leading to stabilization and regression of atherosclerosis.

Two concepts that are key to recognizing the benefits of HDL are: (i) their function and (ii) levels of HDL particles in blood. (i) HDL function reflects the ability of the particles to remove cholesterol from macrophage foam cells. Increased functionality, as shown recently by Dr. D. Rader’s group in The New England Journal of Medicine article (January 13, 2011), was the best parameter in correlating inversely with the risk of atherosclerotic disease. (ii) HDL levels are dependent on the synthesis and degradation of HDL. Many experts in the field believe that HDL functionality is key to reducing atherosclerosis and that HDL functionality goes hand in hand with the generation of new HDL particles. The first step in the formation of functional HDL particle is the production of ApoA-I protein in the liver.

CETP Inhibitors

CETP is an enzyme that is critical in facilitating the redistribution of cholesterol from HDL to apoB containing lipoproteins such as, Low-Density Lipoprotein (LDL) and Very-Low-Density Lipoprotein (VLDL) in exchange for triglyceride. When CETP is inhibited, it blocks the flow of cholesterol from HDL to the other lipoproteins resulting in elevated plasma HDL cholesterol. But the elevated HDL due to CETP inhibition yields particles that are passed their prime and can no longer mediate RCT. In contrast, the younger, more functional and new synthesized HDL arising from the production of ApoA-I have high capacity for RCT.

Another important point is that the levels of HDL following CETP inhibition treatment do not portray the more important feature of HDL functionality. This lesson was learned from the studies of Torcetrapib (Pfizer), a CETP inhibitor that caused a 60% increase in HDL levels but functionality of HDL as measured by RCT was not affected. Torcetrapib failed in late stages of phase 3 studies because treated subjects had a 61% increase in mortality. The inability of CETP inhibitors to alter HDL functionality is likely due to the fact that blockage of CETP activity prevents degradation of HDL particles. These particles are old and inefficient in cholesterol removal from atherosclerosis plaques. In our opinion, CETP inhibition blocks activity of an enzyme of critical importance for RCT and HDL function. These two processes are essential in not only reducing but also regressing atherosclerosis.

ESC Congress 2011, Paris, France

Several presentations on HDL modulating therapies and their effects on risk factors for atherosclerosis and cardiovascular disease incidence were featured at the ESC Congress 2011 held this past August in Paris, France, including RVX-208 and Dalcetrapib.

Two abstracts on RVX-208 co-authored by members of Resverlogix’s Clinical Steering Committee were presented at the Congress. The first abstract described a dose-response lowering of hs-CRP (high sensitive C-reactive Protein) of up to 22% by RVX-208 by 12 weeks treatment. The increase of this vascular inflammation marker was significantly correlated with the treatment induced plasma levels of ApoA-I, HDL cholesterol, as well as large HDL particles. This correlation suggests that the elevations of HDL result in a decrease in vascular inflammation which overtime may cause stabilization and regression of atherosclerosis plaque.

In Resverlogix’s second abstract, Dr. Steven Nicholls of the Cleveland Clinic presented how two HDL subclass methods, NMR (Nuclear Magnetic Resonance) and 2D-PAGGE (Two-dimensional Polyacrylamid gradient gel electrophoresis) were consistent in showing that treatment with RVX-208 results in elevations of large HDL particles. This finding provides additional support for the improved functionality of HDL in response to treatment with RVX-208. The rise in the large HDL is due to newly synthesized HDL particles picking up cholesterol leading to their growth in size. RVX-208 does not affect CETP so the cholesterol transport to LDL and VLDL remains unaltered. These new data provide an opportunity for the company to examine new biomarkers and companion diagnostics for its RVX-208 program.

Roche made two announcements at the Congress regarding Dalcetrapib stemming from data collected in the dal-VESSEL and dal-PLAQUE trials. Dalcetrapib is a member of a family of CETP inhibitors. Dalcetrapib increases HDL cholesterol levels in plasma by preventing the transport of HDL cholesterol to VLDL/LDL. The effect is that each HDL cholesterol particle assumes a longer residence time in plasma following Dalcetrapib treatment. However, the HDL cholesterol level as mentioned above is a poor assessment of HDL functionality.

The goal of dal-VESSEL was to assess two parameters: flow mediated dilation (FMD) and blood pressure (BP) in subjects treated with Dalcetrapib 600 mg per day. The results showed that both parameters remained unchanged in subjects receiving Dalcetrapib vs. placebo. These findings indicated that Dalcetrapib had neither positive nor adverse effects on dilation of the blood vessels or BP, respectively. These findings contrast with those of the previous CETP inhibitor Torcetrapib, which had adverse effects on FMD and increased BP. The differences between the two CETP inhibitors are to be expected because the molecular scaffold from which Dalcetrapib was derived is not the same as that of other CETP inhibitors (Anacetrapib or Torcetrapib). The neutral (as opposed to adverse) data from the dal-VESSEL study on FMD and BP enable other studies initiated on this compound by Roche to continue.

The dal-PLAQUE study had 6 or more primary endpoint including: Total Atheroma Volume (TAV), wall area, and wall thickness at 12 months as determined using Magnetic Resonance Imaging (MRI). One of the endpoints, MRI at 24 months, showed a regression of atherosclerosis (p=0.04) prior to adjustment of multiple comparisons (Lancet, 12 September 2011). However, none of the measurements of these parameters were statistically significant at 12 months according to the topline information presented in a poster at the Congress. While these findings appear to be interesting, the report received much criticism. Top amongst the concerns, was the analysis of the dal-PLAQUE data could represent a classical type 1 error in statistical analysis, meaning that it could be a false positive finding. The rationale is that when there are so many primary endpoints (at least 6 primary endpoints), statistical formulae for corrections need to be applied in the final analysis to exclude this type of error. However, none appeared to have been used. The primary endpoint stated in the poster was TAV at 12 months but the authors only spoke about the results at 24 months. Observers await the publication of the full data set from dal-PLAQUE. From an initial assessment of the poster presentation, it would seem that there are many ways to interpret the data. However, a specific piece of data presented in the poster clearly illustrates that Dalcetrapib at a dose of 600 mg daily for 24 months did not regress atherosclerosis, it merely kept this parameter unchanged. It would seem that Dalcetrapib merely stabilized progression of atherosclerosis, thus actions of this drug appear to mimic that of a Statin.

RVX-208 vs. CETP Inhibitors

CETP inhibition does not affect the production of ApoA-I/HDL. As seen with the failure of Torcetrapib, functionality of HDL was not affected by this drug and the treated subjects had a 61% increase in mortality. Data from the dal-VESSEL and dal-PLAQUE studies are not clear as to whether Dalcetrapib will have any impact on CVD risk reduction. The dal-OUTCOMES trial will measure CVD events, which is projected to be completed in 2013-14.

The actions of RVX-208, namely increasing ApoA-I production to affect HDL function and its levels, represent a novel approach to HDL therapeutics. In the eyes of many, this is the most logical way to harness the benefits of HDL activity, which ultimately leads to atherosclerosis regression. RVX-208’s ability to increase ApoA-I production and thereby augment RCT makes it highly differentiated from all other HDL therapies. RVX-208 is therefore positioned to be one of the most promising new drugs in HDL therapy. RVX-208 is moving forward in two Phase 2b clinical trials led by Cleveland Clinic. Top line data will be available in 2012.

Thank you for reading Issue 1 of Experts Corner

Questions and Comments can be sent to expertscorner@resverlogix.com