Bjarke Krysel Christensen
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Resverlogix: Analysis Of The Science Behind RVX-208
Apr. 8, 2015 9:25 AM ET | About: Resverlogix Corp. (RVXCF), Includes: AZN
Disclosure: The author is long RVXCF. (More...)
Summary
Post hoc analysis of data from two Phase 2 clinical trials with RVX-208 showed a 77% reduction of major adverse cardiac events (MACE) in patients with diabetes mellitus.
Reduced inflammation resulting in reduced arterial plaque formation is one way that RVX-208 reduces the risk of MACE.
Access to the second bromodomain of Brd4 is necessary for the transcription factor activity of p53, a protein that is implicated in a number of age related diseases.
RVX-208, known to block the second bromodomain of Brd4, is proposed to reduce the cardiovascular risk associated with hyperactive p53.
Supported by links to peer reviewed scientific papers, this article gives an overview of the science behind RVX-208 and explains why RVX-208 and Crestor (but not Lipitor) may work synergistically.
With 23.7 million new prescriptions or refills in the past 12 months and annual sales in the US exceeding $5 billion, AstraZeneca's (NYSE:AZN) Crestor is currently the most prescribed drug in the US. Crestor (generic name is rosuvastatin) is a so-called statin, which is a class of drugs that reduces the risk of heart attacks by reducing the amount of "bad cholesterol" - known as LDL - in plasma. In contrast to LDL, high levels of high density lipoprotein, also known as HDL or "good cholesterol", are associated with reduced risk of atherosclerosis, a major cause of heart attacks. While there are several LDL lowering drugs on the market, development of drugs aimed at increasing HDL has proven difficult. A prominent example of this is the failure of Torcetrapib, a CETP-inhibitor developed by Pfizer (NYSE
FE). In clinical trials, Torcetrapib successfully increased HDL levels, but the drug was associated with increased cardiac risk. The complete failure of Torcetrapib dashed the hope that Torcetrapib would become "one of the most important compounds of our generation", as Pfizer's CEO at that time was quoted as saying. Another CETP-inhibitor, Dalcetrapib, has proven to be as ineffective as Torcetrapib, casting doubt on the mechanism of CETP-inhibitors. Notwithstanding the unsuccessful CETP-inhibitor trials, the inverse relationship between risk of heart attacks and HDL levels in plasma remains a fact. However, as was recently pointed out in an article in The New England Journal of Medicine (Rohatgi et al., 2014), HDL levels alone are not necessarily a good indicator of cardiac risk. The lead author of the paper was quoted as saying that "The hypothesis has changed from an HDL-cholesterol hypothesis to an HDL-function hypothesis to better capture cardiovascular risk and provide a better target for therapy to reduce that risk." The HDL-function referred to by the authors is the so-called cholesterol efflux capacity, i.e. the ability of HDL to remove cholesterol from macrophages in arterial plaque.
Besides cholesterol, HDL consists of a protein called apolipoprotein A1 (apoA1), and there is some clinical data suggesting that boosting HDL by increasing apoA1 plasma levels reduces atherosclerosis. Thus, in 2003, Esperion Therapeutics (NASDAQ:ESPR) successfully showed that intravenous administration of a variant of apoA1, called apoA1-Milano, reduced atherosclerosis, but for various reasons, the drug (ETC-216) was never commercialized. Esperion Therapeutics was subsequently acquired by Pfizer for $1.3 billion. The success of Esperion Therapeutics may have been one of the reasons that Resverlogix (OTCPK:RVXCF), a small Canadian biotech company, directed its research towards identifying small molecule drugs that increase the expression of apoA1. The effort led to the identification of RVX-208, a compound that was shown to be able to increase apoA1 levels in hepatic cells in vitro. Interestingly, the compound was also shown to increase cholesterol efflux (Bailey et al., 2010), the very property of HDL that was recently shown to be crucial for preventing atherosclerotic cardiovascular disease. However, an increased level of apoA1 is only a small part of the RVX-208 story, as will be described in the following.
RVX-208 is a BET inhibitor
In 2012 - well into the clinical trial program with RVX-208 - Resverlogix announced that RVX-208 is an inhibitor of bromodomain and extraterminal domain (BET) proteins. The significance of this finding was underscored by a recent publication by a team from Harvard Medical School, where it was reported that BET inhibition reduces atherosclerosis in a mouse model. It has also been reported that BET inhibition suppresses pathologic cardiac remodeling in vivo (Anand et al., 2013), a condition associated with heart failure. As the scientific community is becoming increasingly aware of the pharmaceutical potential of BET inhibitors for treating cardiovascular disease, Resverlogix has already completed Phase 2 trials with its BET inhibitor, RVX-208, and a Phase 3 study with RVX-208 is expected to start enrolling patients in the first half of 2015.
In the following, I will give an overview of the most recent RVX-208 clinical trial results, followed by an introduction to the biology in which BET proteins work. I will also try to account for the complex science behind RVX-208, as well as try to explain why patients with diabetes mellitus are likely to benefit the most from RVX-208. I will also give some reasons for why there may be some synergy between RVX-208 and Crestor.
Overview of MACE data in RVX-208 clinical trials
The pooled results from two recent Phase 2 clinical trials (named ASSURE and SUSTAIN) with RVX-208 indicated that RVX-208 treatment resulted in a drastic and statistically significant reduction of major adverse cardiac events - also known as MACE - in a patient population with established atherosclerosis. A reduction in MACE is exactly what RVX-208 was supposed to show, but MACE was not the primary endpoint and pooling the results from SUSTAIN and ASSURE was not pre-specified. Had MACE reduction been the primary endpoint and had the statistical analysis method of the data been pre-specified, the company would have been worth orders of magnitude more than is the case today. Alas, the endpoint for the most recent Phase 2 trial (the ASSURE trial) was arterial plaque regression, an endpoint that showed a positive trend without reaching statistical significance. The choice of endpoint, i.e. plaque regression, appeared to be inspired by the skyrocketing share price of Esperion Therapeutics, whose drug (ETC-216) a decade ago demonstrated that it could remove plaque from the arteries. While plaque regression in the intent-to-treat (ITT) population in the ASSURE trial did not come out as statistically significant, a subgroup analysis of patients who were given RVX-208 in combination with Crestor (rosuvastatin) showed a statistically significant degree of plaque regression, but again, it was not pre-specified that the Crestor-treated patients should be analyzed separately.
Not meeting the pre-defined endpoint and relying on post hoc analyses of non-pre-defined subpopulations are good reasons to be skeptical about the value of RVX-208. Thus, while presenting an interesting case for RVX-208, the post hoc analysis comes with the following important reservations:
The combination of Crestor and RVX-208 was not pre-specified.
MACE was not the primary endpoint.
Combining the two most recent Phase 2 trials was not pre-specified.
The statistical method was not pre-specified.
Interestingly, another result from the post hoc analysis of the two most recent Phase 2 trials was that it appeared as if the entire reduction in MACE could be ascribed to the subpopulation of patients who suffered from diabetes mellitus, making the MACE reduction in this subpopulation reach a staggering 77% - a reduction that comes on top of the effect of the current standard of care.
Listed chronologically, the various analyses of the MACE data for the SUSTAIN and ASSURE trials are summarized in Table 1. It should be mentioned that when asked why the October 2014 analysis of the pooled results of ASSURE and SUSTAIN differed from the September 2013 analysis, the company explained that the September 2013 analysis was carried out by Resverlogix staff, using 30, 90, 180 days and end of study data. The October 2014 analysis was done by an expert third party life science statistician who used 15-day intervals and censored patients who dropped out of the study 30 days after their last dose, thus the difference in p-values.
Table 1
Clinical trial
Subpopulation
Frequency of MACE, Placebo
Frequency of MACE, RVX-208
RRR
p-value
September 2013
ASSURE
All
13.75%, n=80
7.4%, n=243
46%
0.088
ASSURE
Below median HDL, received Rosuvastatin
17.4%, n=23
1.6%, n=62
0.006
SUSTAIN
All
6.82%, n=88
1.14%, n=88
83%
0.09
ASSURE+SUSTAIN
All
10.1%, n=168
5.7%, n=331
43%
0.09
February 2014
ASSURE+SUSTAIN
hsCRP>2 mg/dL
20.53%, n=104
6.42%, n=179
69%
0.007
July 2014
ASSURE
Diabetes Mellitus
n=apprx. 23
n=apprx. 69
>65%
65%
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Resverlogix: Analysis Of The Science Behind RVX-208
Apr. 8, 2015 9:25 AM ET | About: Resverlogix Corp. (RVXCF), Includes: AZN
Disclosure: The author is long RVXCF. (More...)
Summary
Post hoc analysis of data from two Phase 2 clinical trials with RVX-208 showed a 77% reduction of major adverse cardiac events (MACE) in patients with diabetes mellitus.
Reduced inflammation resulting in reduced arterial plaque formation is one way that RVX-208 reduces the risk of MACE.
Access to the second bromodomain of Brd4 is necessary for the transcription factor activity of p53, a protein that is implicated in a number of age related diseases.
RVX-208, known to block the second bromodomain of Brd4, is proposed to reduce the cardiovascular risk associated with hyperactive p53.
Supported by links to peer reviewed scientific papers, this article gives an overview of the science behind RVX-208 and explains why RVX-208 and Crestor (but not Lipitor) may work synergistically.
With 23.7 million new prescriptions or refills in the past 12 months and annual sales in the US exceeding $5 billion, AstraZeneca's (NYSE:AZN) Crestor is currently the most prescribed drug in the US. Crestor (generic name is rosuvastatin) is a so-called statin, which is a class of drugs that reduces the risk of heart attacks by reducing the amount of "bad cholesterol" - known as LDL - in plasma. In contrast to LDL, high levels of high density lipoprotein, also known as HDL or "good cholesterol", are associated with reduced risk of atherosclerosis, a major cause of heart attacks. While there are several LDL lowering drugs on the market, development of drugs aimed at increasing HDL has proven difficult. A prominent example of this is the failure of Torcetrapib, a CETP-inhibitor developed by Pfizer (NYSE
FE). In clinical trials, Torcetrapib successfully increased HDL levels, but the drug was associated with increased cardiac risk. The complete failure of Torcetrapib dashed the hope that Torcetrapib would become "one of the most important compounds of our generation", as Pfizer's CEO at that time was quoted as saying. Another CETP-inhibitor, Dalcetrapib, has proven to be as ineffective as Torcetrapib, casting doubt on the mechanism of CETP-inhibitors. Notwithstanding the unsuccessful CETP-inhibitor trials, the inverse relationship between risk of heart attacks and HDL levels in plasma remains a fact. However, as was recently pointed out in an article in The New England Journal of Medicine (Rohatgi et al., 2014), HDL levels alone are not necessarily a good indicator of cardiac risk. The lead author of the paper was quoted as saying that "The hypothesis has changed from an HDL-cholesterol hypothesis to an HDL-function hypothesis to better capture cardiovascular risk and provide a better target for therapy to reduce that risk." The HDL-function referred to by the authors is the so-called cholesterol efflux capacity, i.e. the ability of HDL to remove cholesterol from macrophages in arterial plaque.Besides cholesterol, HDL consists of a protein called apolipoprotein A1 (apoA1), and there is some clinical data suggesting that boosting HDL by increasing apoA1 plasma levels reduces atherosclerosis. Thus, in 2003, Esperion Therapeutics (NASDAQ:ESPR) successfully showed that intravenous administration of a variant of apoA1, called apoA1-Milano, reduced atherosclerosis, but for various reasons, the drug (ETC-216) was never commercialized. Esperion Therapeutics was subsequently acquired by Pfizer for $1.3 billion. The success of Esperion Therapeutics may have been one of the reasons that Resverlogix (OTCPK:RVXCF), a small Canadian biotech company, directed its research towards identifying small molecule drugs that increase the expression of apoA1. The effort led to the identification of RVX-208, a compound that was shown to be able to increase apoA1 levels in hepatic cells in vitro. Interestingly, the compound was also shown to increase cholesterol efflux (Bailey et al., 2010), the very property of HDL that was recently shown to be crucial for preventing atherosclerotic cardiovascular disease. However, an increased level of apoA1 is only a small part of the RVX-208 story, as will be described in the following.
RVX-208 is a BET inhibitor
In 2012 - well into the clinical trial program with RVX-208 - Resverlogix announced that RVX-208 is an inhibitor of bromodomain and extraterminal domain (BET) proteins. The significance of this finding was underscored by a recent publication by a team from Harvard Medical School, where it was reported that BET inhibition reduces atherosclerosis in a mouse model. It has also been reported that BET inhibition suppresses pathologic cardiac remodeling in vivo (Anand et al., 2013), a condition associated with heart failure. As the scientific community is becoming increasingly aware of the pharmaceutical potential of BET inhibitors for treating cardiovascular disease, Resverlogix has already completed Phase 2 trials with its BET inhibitor, RVX-208, and a Phase 3 study with RVX-208 is expected to start enrolling patients in the first half of 2015.
In the following, I will give an overview of the most recent RVX-208 clinical trial results, followed by an introduction to the biology in which BET proteins work. I will also try to account for the complex science behind RVX-208, as well as try to explain why patients with diabetes mellitus are likely to benefit the most from RVX-208. I will also give some reasons for why there may be some synergy between RVX-208 and Crestor.
Overview of MACE data in RVX-208 clinical trials
The pooled results from two recent Phase 2 clinical trials (named ASSURE and SUSTAIN) with RVX-208 indicated that RVX-208 treatment resulted in a drastic and statistically significant reduction of major adverse cardiac events - also known as MACE - in a patient population with established atherosclerosis. A reduction in MACE is exactly what RVX-208 was supposed to show, but MACE was not the primary endpoint and pooling the results from SUSTAIN and ASSURE was not pre-specified. Had MACE reduction been the primary endpoint and had the statistical analysis method of the data been pre-specified, the company would have been worth orders of magnitude more than is the case today. Alas, the endpoint for the most recent Phase 2 trial (the ASSURE trial) was arterial plaque regression, an endpoint that showed a positive trend without reaching statistical significance. The choice of endpoint, i.e. plaque regression, appeared to be inspired by the skyrocketing share price of Esperion Therapeutics, whose drug (ETC-216) a decade ago demonstrated that it could remove plaque from the arteries. While plaque regression in the intent-to-treat (ITT) population in the ASSURE trial did not come out as statistically significant, a subgroup analysis of patients who were given RVX-208 in combination with Crestor (rosuvastatin) showed a statistically significant degree of plaque regression, but again, it was not pre-specified that the Crestor-treated patients should be analyzed separately.
Not meeting the pre-defined endpoint and relying on post hoc analyses of non-pre-defined subpopulations are good reasons to be skeptical about the value of RVX-208. Thus, while presenting an interesting case for RVX-208, the post hoc analysis comes with the following important reservations:
The combination of Crestor and RVX-208 was not pre-specified.
MACE was not the primary endpoint.
Combining the two most recent Phase 2 trials was not pre-specified.
The statistical method was not pre-specified.
Interestingly, another result from the post hoc analysis of the two most recent Phase 2 trials was that it appeared as if the entire reduction in MACE could be ascribed to the subpopulation of patients who suffered from diabetes mellitus, making the MACE reduction in this subpopulation reach a staggering 77% - a reduction that comes on top of the effect of the current standard of care.
Listed chronologically, the various analyses of the MACE data for the SUSTAIN and ASSURE trials are summarized in Table 1. It should be mentioned that when asked why the October 2014 analysis of the pooled results of ASSURE and SUSTAIN differed from the September 2013 analysis, the company explained that the September 2013 analysis was carried out by Resverlogix staff, using 30, 90, 180 days and end of study data. The October 2014 analysis was done by an expert third party life science statistician who used 15-day intervals and censored patients who dropped out of the study 30 days after their last dose, thus the difference in p-values.
Table 1
Clinical trial
Subpopulation
Frequency of MACE, Placebo
Frequency of MACE, RVX-208
RRR
p-value
September 2013
ASSURE
All
13.75%, n=80
7.4%, n=243
46%
0.088
ASSURE
Below median HDL, received Rosuvastatin
17.4%, n=23
1.6%, n=62
0.006
SUSTAIN
All
6.82%, n=88
1.14%, n=88
83%
0.09
ASSURE+SUSTAIN
All
10.1%, n=168
5.7%, n=331
43%
0.09
February 2014
ASSURE+SUSTAIN
hsCRP>2 mg/dL
20.53%, n=104
6.42%, n=179
69%
0.007
July 2014
ASSURE
Diabetes Mellitus
n=apprx. 23
n=apprx. 69
>65%
65%
