A-MACE-Ing RVX-208: What Have We Heard About Heart Disease And RVX-208?

| About: Resverlogix Corp. (RVXCF)
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RVX-208 is a BET inhibitor that may reduce the risk of major adverse cardiac events (MACE) in a high risk patient population.

Post hoc analysis of two Phase II clinical trials showed that patients with low HDL and chronic low-grade inflammation as indicated by elevated hsCRP respond extremely well to RVX-208.

In a recent press release, Resverlogix revealed that also patients suffering from diabetes mellitus responded very well to RVX-208, resulting in a statistically significant reduction of MACE.

The connection between BET inhibition, inflammation and diabetes is discussed in the light of a recent trial with RVX-208 being used to treat pre-diabetic patients.

This article also summarizes the data on MACE reduction in various subpopulations of patients in two Phase II clinical trials.

On July 23rd, Resverlogix (OTCPK:RVXCF and RVX.TO) announced that patients with diabetes mellitus responded unexpectedly well to RVX-208. According to the press release, there was a greater than 65% relative risk reduction in major adverse cardiac events (MACE) in the subpopulation of the ASSURE trial patients who suffered from diabetes. Moreover, when further dissecting the results from the diabetes patients, it was found that a general trend (in the diabetics subpopulation receiving RVX-208) towards reduced blood sugar concentration turned out to be a statistically significant reduction for the subgroup of diabetes patients with low HDL. Before returning to the analysis of MACE, I would like to discuss the connection between BET inhibitors (such as RVX-208, please see my previous articles in Seeking Alpha) and diabetes.

Diabetes and RVX-208

Diabetes has a very important element of inflammation to it, as discussed in the excellent review by Donath (2014) in Nature Reviews Drug Discovery. A key marker of inflammation is CRP, a protein signaling that the immune system is on the alert - which is not a good thing when it is a chronic condition. CRP is also one of the markers used by Resverlogix to identify responders to RVX-208, and there is decent experimental evidence supporting that RVX-208 reduces CRP. CRP, or to be more precise, hsCRP (high sensitivity CRP) is an established marker of increased risk of developing diabetes, as discussed by Ridker (2003). Thus, RVX-208, being an hsCRP reducing drug, could very well have a use in preventing or treating diabetes. This may have been the kind of thinking that went into designing the very small (23 patients) clinical trial in which RVX-208 was used to reduce blood sugar concentration in pre-diabetic patients (the Australian study mentioned in the July 23rd press release). However, things take time, and the patients were only treated for 30 days or so before being tested, which may not have been enough to see an effect, particularly not with such a small number of patients. While no details were included in the press release, it was clear that the diabetes study did not meet the primary endpoint, an all too familiar situation for faithful Resverlogix investors! That being said, Resverlogix also reported that in the ASSURE trial, the reduction in blood sugar concentrations was not detectable before the patients had been treated with RVX-208 for 12 weeks, which is much longer than the treatment time in the diabetes study. I tend to think that the diabetes study included too few patients treated for a too short time for an effect of RVX-208 to be evident. Moreover, I firmly believe that RVX-208 reduces inflammation, and that - a process that is likely to take some time - is the key to understanding the mode of action of RVX-208 and the effect RVX-208 has on diabetes.

A compilation of MACE data

The July 23rd press release contained yet another post hoc analysis of the clinical trial data from the ASSURE and the SUSTAIN data - this time the data were sliced along the diabetes axis, so to speak. This is not the first time a post hoc analysis has been presented, and while I think the news was very positive, the market seemed to be somewhat immune to more post hoc analyses, as the share price actually went down on the day Resverlogix came out with the press release. However, as I don't think that we are going to hear about more post hoc analyses in the near future, it is worth summarizing the data we have seen so far. The table below contains the essence of MACE data from the September 3rd 2013 presentation, the February 2014 presentation and the July 23rd presentation (no new MACE data were presented at the September 10th, 2013 presentation). In the table, RRR stands for Relative Risk Reduction, indicating the RVX-208 treatment associated reduction in risk of heart attack, etc.

Table 1. MACE data as reported by Resverlogix.

Clinical trial


Frequency of MACE, Placebo

Frequency of MACE, RVX-208



September 2014



13.75%, n=80

7.4%, n=243




Below median HDL, received Rosuvastatin

17.4%, n=23

1.6%, n=62




6.82%, n=88

1.14%, n=88





10.1%, n=168

5.7%, n=331



February 2014


hsCRP>2 mg/dL

20.53%, n=104

6.42%, n=179



July 2014


Diabetes Mellitus

n=apprx. 23

n=apprx. 69




Low HDL and Diabetes Mellitus

n=apprx. 65

n=apprx. 130



Where indicated by "apprx," the July 2014 data are estimated based on the comments and numbers that were revealed in the press release.

While I think the numbers speak for themselves, one can summarize the various post hoc analyses by saying that the ideal RVX-208 responding patient should have low to very low HDL, high hsCRP, suffer from diabetes and accept being treated with a combination of RVX-208 and rosuvastatin (rosuvastatin, sold as Crestor, is a cholesterol lowering drug). It should be mentioned that there is a great deal of overlap between diabetes and high hsCRP, i.e. elevated hsCRP is associated with diabetes as mentioned in one of the articles mentioned above. Moreover, HDL is known to have an anti-inflammatory effect, which again could suggest that low HDL and high hsCRP might be associated, although this last association is pure speculation on my part. It is, however, not necessary to combine the effects from the subgroups to be impressed, as several of the subgroups benefit so much from RVX-208 that the p-values - in spite of the small number of patients in the subgroups - are very low. This, of course, makes one speculate how a population of "ideal" patients would respond to RVX-208, and I guess that this is what Resverlogix intends to answer in their next clinical trial.

All of the above analyses are based on post hoc analyses, which - never to be ignored - are at the very best hypothesis generating, and the results should be treated that way. However, the analyses are intriguing, and the fact that recent scientific publications provide a growing body of evidence supporting the proposed mode of action of BET inhibitors in general and RVX-208 in particular, suggests to me that RVX-208 has a decent chance of becoming a blockbuster drug.

Final comments

Resverlogix has secured funds for running a new trial with RVX-208, a trial that we are soon going to hear more about. There is a special meeting of the shareholders of Resverlogix on August 13, 2014, where the only point on the agenda is to approve a loan agreement that allows Resverlogix to borrow an additional $30 million, enough to run a trial with 1000 patients. Such a trial takes time, patients and patience, and it will certainly be a make it or break it trial for Resverlogix.

Disclaimer: This is not investment advice. Please talk to a suitably certified advisor before making an investment in Resverlogix, as such an investment is extremely risky.

Disclosure: The author is long RVXCF. The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it (other than from Seeking Alpha). The author has no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: I am long RVX.TO, i.e. Resverlogix traded on the Toronto stock exchange

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