When the structure of the BET bromodomain inhibitor, JQ1, was published in an article Nature in 2010, the scientists behind JQ1 not only revealed the structure of JQ1, they also made the compound available to scientists at other universities. Thus, since 2011, JQ1 has been shipped to virtually hundreds of research groups around the world, propelling research in BET bromodomain inhibitors forward at a staggering speed.
JQ1 itself has a very short half-life, preventing therapeutic use. However, for research purposes, JQ1 has paved the way for bromodomain inhibition as a therapeutic target. The pre-clinical results are impressive, suggesting potential in anything from atherosclerosis and diabetes to inflammatory renal diseases, autoimmune diseases and alzheimers.
RVX-208, a small molecule developed by a Canadian company called Resverlogix (OTCPK:RVXCF), is one such BET bromodomain inhibitor, but in contrast to JQ1, RVX-208 (also called Apabetalone) has made it through phase I and phase II clinical trials and is currently in clinical phase III. The primary endpoint of the clinical trial is a reduction in incidence of major adverse cardiovascular events (MACE), i.e. heart attack, stroke and cardiovascular death in a diabetes (type 2) patient population with coronary artery disease.
From an investment point of view, the substantial body of scientific literature on JQ1-based BET-inhibition - combined with data from clinical trials with RVX-208 - draws an unusually detailed picture of what to expect from the phase III study with RVX-208. The following provides an update on the science behind RVX-208 based on results from recently published scientific articles; links to the original sources are provided throughout the text.
Atherosclerosis, ageing and Cellular Senescence
Atherosclerosis, a condition where the arteries become hardened and narrow, is a leading cause of heart attack and stroke. Despite a popular belief that arteries get clogged by cholesterol building up, somewhat resembling the clogging of a drain pipe, the narrowing of the arteries is primarily driven by immune cells invading the arterial wall. These immune cells attempt to remove irritants, e.g. oxidized cholesterol, from the arterial wall.
Ideally, the immune cells are eliminated after having done their job, but if the immune cells are not eliminated, the immune cells themselves may become irritants, prompting more immune cells to arrive at the site, potentially starting a vicious cycle. The precise mechanisms for how this works are not known, but less than a year ago, an article in Science - one of the most respected scientific journals in the world - came up with an interesting result (quote): "...senescent cells drive atherosclerosis at all stages..." (Childs et al., 2016).
An open access source describing the salient features of the Science paper is found here. Senescent cells are cells that have been stressed to a point where they have permanently lost their ability to divide. Senescence inducing stress may arise from nutrient excess - e.g. excess glucose (diabetes) or cholesterol (dyslipidemia) - but factors such a obesity and physical inactivity can also result in cellular senescence.
According to the Science paper, senescent cells drive atherosclerosis by secreting a wide range of pro-inflammatory proteins, resulting in a so-called senescence associated secretory phenotype (SASP), a response that favors the onset of many chronic age-related diseases, atherosclerosis being one of them; chronic kidney disease being another.
In a recent review with the title, "Cellular senescence in renal ageing and disease", the authors point out that "...accumulation of senescent cells over time in mice shortens lifespan, promotes tissue deterioration and impairs the function of several organs, including the heart, vasculature, adipose tissue, and kidney" (Sturmlechner et al., 2016).
An article in another article top journal, this time in Nature, described how removal of senescent cells from mice (mice that were genetically modified to allow such removal) resulted in "...attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat..." (Baker et al., 2016). The same authors go on to suggest that "therapeutic removal [of senescent cells] may be an attractive approach to extend healthy lifespan".
To summarize, reviews and articles in top journals strongly indicate:
that senescent cells accumulate over time, leading to tissue and organ deterioration,
that the elimination of senescent cells causes no apparent side effects, but may instead extend healthy lifespan
that a pro-inflammatory response called senescence associated secretory phenotype (SASP) is heavily involved in the deteriorating effects of senescent cells and that SASP is directly linked to atherosclerosis
It is not obvious why senescent cells would be involved in the mode of action of RVX-208, but that is nevertheless the case I will make in the following.
BRD4 is required for SASP
In June 2016, Tasdemir et al., 2016 published some remarkable results coupling SASP and BRD4, one of four different human BET proteins. The authors found that JQ1 mediated inhibition of BRD4 significantly reduces SASP - or as the authors put it "...genetic or pharmacologic suppression of BRD4 collapses SASP gene expression...".
Tasdemir et al. (2016) do not make the claim that BRD4 inhibition ameliorates atherosclerosis, but combining the following quote from the final sentence in the Science paper by Childs et al., 2016 (note: "paracrine activity" refers to SASP):
"...senescent cells drive atherosclerosis at all stages through paracrine activity..." (Childs et al., 2016)
with the following quote from Tasdemir et al., 2016:
"...BRD4 is required for paracrine senescence..." (Tasdemir et al., 2016),
a compelling link between atherosclerosis and BRD4 inhibition is made, strongly suggesting that BRD4-inhibition has therapeutic potential in atherosclerosis.
Moreover, in a commentary to the article by Tasdemir et al., 2016, a link between BRD4 inhibition and ageing related diseases is suggested (Senescence can be BETter without the SASP? Vizioli and Adams, 2016), which is very much aligned with the conclusions from my previous Seeking Alpha article about a year ago. Readers of my previous Seeking Alpha article may appreciate a comment made by Tasdemir et al. (2016) who noted that - "NFkB [is] a bona fide SASP regulator" (Tasdemir et al., 2016).
To put the above into the context of RVX-208:
SASP is directly involved in all stages of atherosclerosis,
SASP is inhibited by BET bromodomain inhibitors, and
RVX-208 is a BET bromodomain inhibitor.
The logical next question is to ask if RVX-208 actually SASP.
RVX-208 and SASP
There are four BET proteins, BRD2, BRD3, BRD4 and BRDT. Each of these four BET proteins has two bromodomains, BD1 and BD2. The BET bromodomain inhibitors in the literature I have cited up until this point have all been so-called pan-BET inhibitors, i.e. they inhibit both BD1 and BD2 in all four BET proteins. RVX-208 is different in this aspect, as it preferentially inhibits the BD2 domains, leaving the BD1 domains much less affected.
As I have discussed in previous Seeking Alpha articles, the preference for BD2 most likely makes for a drug with much milder side effects, but it also leaves us with the key question if the research on JQ1 and other BET inhibitors applies to RVX-208. For obvious reasons, it is difficult to study the effect of RVX-208 on senescent cells if the cells being studied are not in a senescent state.
I have not come across good pre-clinical results from experiments in which senescent cells were exposed to RVX-208, and the lack of such studies makes it difficult to say with certainty that the BD2-specific BET bromodomain inhibition of RVX-208 inhibits SASP in the same way as has been reported for pan-BET inhibition.
However, on January 23rd, 2017, Resverlogix announced that they had analyzed the plasma protein patterns in a phase I study with RVX-208 in patients with chronic kidney disease, finding that interleukin 6 and osteopontin where among the proteins that were down regulated (or as the press release read: "... interleukin 6 (IL6) and osteopontin, were regulated positively with respect to disease severity and progression").
Interleukin 6 is the most dominant SASP component - a so-called canonical SASP component - and osteopontin is also a prominent component of SASP (Pazolli et al., 2012). Since SASP beyond any reasonable doubt plays a role in the chronic kidney disease patients enrolled in the phase I study with RVX-208, the results from this phase I study can be seen as clinical evidence that RVX-208 does indeed inhibit two prominent components in the SASP response.
It should also be noted that while RVX-208 is a BD2-specific BET-inhibitor, blocking either BD1 or BD2 has been shown to inhibit NF-kB, a masterregulator of SASP (Chien et al., 2011). It is therefore reasonable to expect that RVX-208 at least partially inhibits NF-kB, resulting in a blunted SASP. The question of inhibition of BD1 vs. inhibition of BD2 being responsible for the anti-inflammatory effect was addressed recently by Zhao et al., 2017 who compared a BD1 specific BET bromodomain inhibitor, olinone, with RVX-208 (BD2 specific), finding that in contrast to olinone, RVX-208 reduced the expression of inflammatory cytokines - such as MCP-1, IL-1b and IL-6 - in microglial cells. Thus, there is both clinical and pre-clinical evidence supporting the anti-inflammatory and SASP reducing properties of RVX-208.
Sound skepticism towards the hypothesis that RVX-208 has a positive effect on atherosclerosis could be based on the fact that atherosclerotic plaque regression was a primary endpoint in one of the phase II studies with RVX-208, an endpoint that was not met, thus raising the question of how successful RVX-208 is going to be in the ongoing phase III trial.
However, when weighing this fact in the overall assessment of RVX-208, it is important to note that atherosclerotic plaque rupture - the final stage of atherosclerosis - is what causes heart attacks. Thus, plaque stability - rather than plaque volume - might had been a better choice as endpoint for the phase II trials, but for practical reasons - and due to the incomplete understanding of the mode of action of RVX-208 at the time of designing the phase II trials - such an endpoint was not possible.
It is also relevant to mention that plaque regression actually was greater in the RVX-208 treated group than in the placebo group, the difference was just not large enough to be statistically significant. Moreover, the patient population in the phase II study included both diabetic and non-diabetic patients, and subsequent analysis of the data suggests that diabetes patient benefit much more from RVX-208 than non-diabetics. In the ongoing phase III trial, only diabetes patients (type 2) are enrolled.
RVX-208, inflammation and clinical trial results
The above science based evidence supports the hypothesis that RVX-208 is an anti-inflammatory drug that ameliorates atherosclerosis. However, as promising as RVX-208 may be, the only thing that really matters is clinical trial data. The three phase II clinical trials with RVX-208 were aimed at showing that RVX-208 increases HDL, increases apoA1 (a prominent protein in HDL), or reduces arterial plaque, respectively.
With only one in three trials meeting its respective primary endpoint (the SUSTAIN trial showed a statistically significant elevation of HDL - i.e. "good" cholesterol), the primary endpoint from the other two phase II trials were not met, although both studies showed trends towards efficacy.
However, the post hoc analysis of the combined data from the two 26-weeks long phase II studies revealed a remarkable (and statistically significant) 55% relative risk reduction of major adverse cardiac events - and when looking at the diabetes patients in the studies, the relative risk reduction was as high as 77% (p=0.01). It is well established that inflammation and diabetes are coupled, and given that RVX-208 has clear anti-inflammatory effects, it is not surprising that diabetics benefit the most from RVX-208.
That inflammation is front and center of the mode of action was underscored at a New York Academy of Science event in April last year, where Resverlogix mentioned that the observed reduction in MACE was "almost exclusively accounted for by favorable effects in those with DM [diabetes mellitus] co-morbidity and/or those with heightened inflammation (elevated C-reactive protein)" (Kulikowski's abstract at NYAS event, April 2016). I take that to mean that patients with diabetes benefited from RVX-208 while patients that are not diabetic and do not have heightened inflammation do not benefit from RVX-208.
This does not really take much away from RVX-208 in terms of sales potential, as diabetes associated heart disease is a huge indication. The sentence in Kulikowski's abstract is extremely interesting as it so beautifully connects the preclinical data showing a benefit from BET inhibitors in inflammatory diseases with the benefit of RVX-208 in clinical trials.
Thus, pre-clinical data show that RVX-208 has an anti-inflammatory effect and the clinical trial data indicate that patients with heightened inflammation (which include diabetics) benefit from the anti-inflammatory effects of RVX-208 - that makes sense. In that light, it is also unsurprising that patients who do not have heightened inflammation do not benefit from a drug that reduces inflammation.
Additional support of a therapeutically relevant anti-inflammatory action of RVX-208 is found in the post-hoc analysis of the patient with impaired kidney function. This subgroup - comprising 35 patients treated with RVX-208 and 13 patients on placebo in the two 26 weeks long phase II studies - showed a statistically significant improvement of estimated glomerular filtration rate (eGFR, a measure of the function of the kidneys) of 3.4%.
The eGFR of the placebo patients decreased 5.9% relative to baseline (Resverlogix news release, 1 June 2015). Again, RVX-208 appears to work in a population characterized by chronic low grade inflammation. Improvement in eGFR in low-eGFR patients is a secondary endpoint in the ongoing phase III trial.
Big Pharma and BET inhibitors
For obvious reasons, big pharmaceutical companies rarely reveal the direction of their early stage research. However, a look at the published patent applications give a reasonably good indication of what is going on. In the past 12 months, a quite substantial number of patent applications covering BET inhibitors have been published (US patent and trademark office).
There are a number of small companies, such as Resverlogix, Constellation, Forma Therapeutics and Zenith Epigenetics (a Resverlogix spin off) that are active in the BET bromodomain inhibition field, but big pharmaceutical companies are certainly also active. In the past 12 months, AbbVie (NYSE:ABBV) published at least 5 patent applications with the title "Bromodomain Inhibitors", Gilead (NASDAQ:GILD), Pfizer (NYSE:PFE), Novartis (NYSE:NVS), Bayer (OTCPK:BAYZF), Celgene (NASDAQ:CELG) and GlaxoSmithKline (NYSE:GSK) also had several BET protein inhibition patent applications published.
Most of the patent applications were filed more than a year ago (a patent application is usually published no later than 18 months after it is filed), but some of the patent applications were filed in 2016, suggesting that several big pharmaceutical companies are active in the BET inhibitor field. While BET inhibitors have mainly received interest in cancer indications, it is interesting to note that the patent applications routinely mention that BET bromodomain inhibitors have anti-inflammatory effects. The patent applications from Novartis even mentions RVX-208 as an example of a BET bromodomain inhibitor.
BETonMACE and the question of clinical equipoise
In November 2015, the first patient was enrolled in a phase III clinical trial, named BETonMACE, with RVX-208. The patients in the study have coronary artery disease and type 2 diabetes mellitus, the group that appeared to benefit the most in the phase II clinical trials. The primary endpoint is a reduction in 3-point MACE, i.e. cardiovascular death, non-fatal myocardial infarction (heart attack), and stroke.
There are several secondary endpoints, but one of the most interesting secondary endpoints is improvement in kidney function in the subgroup of patients with reduced kidney function (eGFR < 60 mL/min/1.7 m2). Target enrollment is 2,400 patients and as of October 2016, Resverlogix said that the study was approximately one third enrolled - 800 patients. The trial is event driven, i.e. the study stops after 250 patients have had a major adverse cardiac event. After 125 such events, there is going to be a futility analysis. The timing of the 125 events and 250 events is difficult to estimate, but a rough estimate (this estimate is based on my calculations and they are not official estimates from Resverlogix) is that 125 events are reached in Q4 2017, and 250 events are reached late 2018 or early 2019.
While the futility analysis after 125 events is solely intended to provide a stop/go for the remaining part of the study, there is always an ethical question - a question of so-called "clinical equipoise" that the data monitoring committee (DMC) must consider. Clinical equipoise is the balancing of the interest of the patients and the interest in a solid scientific evaluation of a drug. Thus, it is not ethical to continue a trial where the drug is highly unlikely to show a benefit - it is the purpose of the futility analysis to stop the trial if there is no or very little effect of the drug.
However, it is also unethical to continue to give patients placebo if the drug clearly works. I wrote Resverlogix to ask if BETonMACE could be stopped early for efficacy, receiving the answer that for Resverlogix to be able to have the drug approved, they needed data from the completed study - not just interim data - and that there was therefore not a (very small) p-value that could trigger early termination for efficacy.
That, however, does not overrule the ethical considerations of the DMC, which may decide to recommend early termination irrespective of the instructions from the company, or - as the FDA guidance for Data Monitoring Committees states: "even when there is a stated intention to stop early only for futility reasons [...] interim review of outcome data always raises the possibility that the DMC may find early results so persuasive that it would recommend early termination of the trial" (quote from FDA guidance, Data Monitoring Committees).
The literature and phase II data would suggest that the effect of RVX-208 could be quite substantial and it is not completely out of the question that when analyzing the unblinded data for futility, the DMC might recommend stopping the trial early for efficacy. Consequently, while the BETonMACE study is likely to take another 2 years to complete according to study design - there is at least a small chance that extremely positive results could come out of the study late 2017.
This would obviously have a very, very positive effect on the share price, but ironically, early termination of BETonMACE would probably delay final approval of the drug, as the patient population is likely to be deemed too small for proper assessment of the safety of the drug, thus requiring a second phase III study.
Insiders and financing
The largest shareholders in Resverlogix are Eastern Capital Ltd. (19.5%), a company owned by billionaire Kenneth Dart; Shenzhen Hepalink (12.6%), a Chinese pharmaceutical company; NGN Biomed Opportunity II (7.6%), a venture capital fund; Donald J. McCaffrey (4.3%), Resverlogix CEO; and Norman C.W. Wong (3.0%). Thus, a total of approximately 47% of the outstanding common shares are owned by these insiders (to be precise, NGN ceased to be an insider on April 2, 2016 when they stepped down from the board of directors).
With the exception of the SVP of Clinical Development, Michael Sweeney, who sold half of his - with his spouse jointly owned - common shares in March last year, none of these insiders have sold any shares over the past 5 years. Actually, in 2014, Resverlogix directors and officers subscribed for a total of 1 million shares (approximately 1% of outstanding shares) in a private placement.
Last time Resverlogix raised money was in 2015, where Shenzhen Hepalink and Eastern Capital Ltd. purchased a total of 18,870,000 shares at CAD 2.67 (Resverlogix News Release, April 2015). Shenzhen Hepalink also signed a royalty based licensing agreement with Resverlogix granting them the rights to RVX-208 in China and Taiwan.
With the current cash burn rate, Resverlogix has at the very most enough funds for two more quarters - likely less. Thus, a new financing deal must soon be struck. Moreover, a CAD 68.8 million loan matures on August 28, 2017. The loan is secured by an irrevocable standby letter of credit arranged by Eastern Capital Ltd.
How Resverlogix is going to raise money is still to be announced, and the following is pure guesswork on my part, but I tend to think that there will be a loan extension and that Eastern Capital will receive some warrants to secure the loan. As for funds for continuing the ongoing phase III trial, a private placement involving Shenzhen Hepalink, NGN and/or Eastern Capital is probably the most likely scenario. Ideally, a non-diluting licensing deal involving Japan or Latin America would be used to raise money, but I tend to think that such a deal is less likely at present.
The scientific literature has many examples of BET inhibitors showing promise in atherosclerosis and chronic kidney disease. With respect to chronic kidney disease, some of the most telling examples in the literature (the list is nowhere near exhaustive) are e.g. Xiong et al., 2016 who recently found that "...pharmacological inhibition of BET proteins could be a potential treatment for renal fibrosis".
Another recent example is Suarez-Alvarez et al., 2017 who conclude that "...inhibitors of BET proteins could have important therapeutic applications in inflammatory renal diseases." Yet another example is Liu et al., 2014 who found that "... BET bromodomain inhibitors [...] could be developed as a novel therapeutic approach for treatment of DN [diabetic nephropathy]." Diabetic nephropathy is one of the stages leading to chronic kidney disease and ultimately to end stage renal disease.
As for atherosclerosis, the key paper remains Brown et al., 2014 who found that "...BET bromodomain inhibition abrogates [...] atherosclerosis in vivo.". In a more recent paper by Huang et al., 2017, the authors reach what appears to be a somewhat similar conclusion, i.e. that "BET bromodomain is important for regulating endothelial inflammation. Strategies targeting endothelial BET bromodomain may provide a new therapeutic approach for controlling inflammatory-related diseases."
While not relevant for the ongoing phase III clinical trial, it is highly relevant for the therapeutic potential of BET bromodomain inhibition that there appears to be effects on other inflammatory diseases as well. Examples of this are Zhang et al, 2015 who reported that BET-bromodomain inhibition benefits rheumatoid arthritis, and Ding et al., 2015 who identified BRD4 as a target for liver fibrosis - a condition that contributes to chronic liver disease.
When looking at the recent science behind BET bromodomain inhibitors, it is important to keep the timeline in mind: It is almost five years ago that Resverlogix announced that RVX-208 is a BET bromodomain inhibitor. It is three years ago researchers from Harvard Medical School published pre-clinical evidence that BET-inhibition reduces atherosclerosis. A little over 1 year ago, Resverlogix announced that the first patient had been randomized and commenced dosing in a phase III clinical trial with RVX-208.
While top journal publish papers showing extremely promising pre-clinical data on BET bromodomain inhibition, Resverlogix has already advanced a BET bromodomain inhibitor to clinical phase III and enrolled hundreds of patients. That is quite an accomplishment and speaks to Resverlogix' head start in the field of BET bromodomain inhibitors in inflammatory diseases.
If it is because Resverlogix is not listed on the NASDAQ or if it is because Resverlogix has a somewhat mixed history when it comes to meeting the primary endpoints in their clinical trials, Resverlogix appears to be flying under the radar in most contexts.
However, given the recent scientific results showing benefit of BET bromodomain inhibition in various inflammatory diseases, it would be surprising if Resverlogix is not able to raise funds on reasonable terms from either existing investors or through a licensing deal with big pharma, but it is nonetheless an unwelcome uncertainty that Resverlogix has not yet secured funding for the continuation of the phase III clinical trial with RVX-208.
Disclosure: I am/we are long RVXCF.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: 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. I own shares in RVX.TO (traded on the Toronto Stock Exchange). In the quotes from the original sources, I occasionally included comments of my own or omitted parts of the sentence that did not relate to the point I wanted to make – such comments and omissions are indicated by [ ].
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