Resverlogix To Release Phase 3 Clinical Trial Data On A First-In-Class BET Bromodomain Inhibitor – Seeking Alpha

Resverlogix is a few days away from releasing topline results from their phase 3 clinical trial, BETonMACE, a trial that aims at showing that Apabetalone (RVX208), a BET bromodomain inhibitor, reduces the risk of heart attacks, stroke and cardiac death in a high-risk population of diabetes patients with low HDL and established cardiovascular disease. The last patient has received the last dose of Apabetalone (or placebo), the last patient has had the last follow-up and the database lock took place on September 19. Management has put out on or about September 30 as the date where topline results will be released. With Apabetalone being the only compound in clinical trials, the results from BETonMACE very much represents a binary event: If successful, the future of Resverlogix and its shareholders looks bright and prosperous. If not successful, existing shareholders will see the value of their investment evaporate in a matter of seconds after the topline data are announced. That is the backdrop of the upcoming announcement of topline results please note that it can go either way, we will know within a week or so.

Let it be said already at this point: I own shares in Resverlogix; my view on the science may be biased or even incorrect; I may have misunderstood some or all of the numerous articles I have read on the subject; I have no medical degree whatsoever. THIS ARTICLE IS NOT INVESTMENT ADVICE.

With that out of the way, this article provides an update on the science behind Apabetalone, a field that has progressed tremendously over the past couple of years, but first a bit of history.

When Resverlogix in April 2012 announced that the mode of action of Apabetalone at that time only known as RVX208 - was through BET bromodomain inhibition (Resverlogix, news release), there was not much of a reaction on the stock market or in the scientific community. The minimal reaction was presumably due the fact that at that time, not much was known about the pharmaceutical potential of BET bromodomain inhibition. Today, seven years later, that picture has changed dramatically. Thus, preclinical experiments have indicated BET bromodomain inhibition as a promising target in liver fibrosis, non-alcoholic steatohepatitis ("NASH"), kidney fibrosis, heart failure, rheumatic disease and most importantly atherosclerosis. There are many more articles than the examples given above, but suffice to say that the concept of BET bromodomain inhibition as a pharmaceutical concept appears to be supported by numerous articles often in high-ranking journals. However, the focus of this article is on cardiovascular diseases, where there is a growing understanding of the importance of BET bromodomain inhibition. A short but quite telling comment in a 2014 issue of the Harvard Gazette testifies to the importance that researchers at top rated universities already at that time (5 years ago) ascribed to BRD4 inhibition as a target in the treatment of atherosclerosis. I will return to the seminal scientific article that was referred to in The Harvard Gazette comment.

Apabetalone is a small molecule drug candidate that researchers at Resverlogix found in a screen for compounds that upregulated ApoA1, a protein found in HDL, i.e. found in so-called good cholesterol. The primary hypothesis at that time (in 2012) was that by boosting ApoA1, HDL-levels would also increase, which in turn would lead to a reduction of atherosclerotic plaque plaque that causes heart attacks (myocardial infarctions) if rupturing. In line with this hypothesis, an ongoing (still back in 2012) phase 2 double blinded clinical trial the ASSURE trial had reduction of atherosclerotic plaque as the primary endpoint. This kind of endpoint is what is known as a surrogate endpoint, a type of endpoint that is often chosen when the clinically relevant endpoint such as myocardial infarctions and stroke are so rare that it would require a prohibitively large number of enrolled patients to have enough events to show a statistically significant effect. Consequently, surrogate endpoints with believed correlation to a clinically relevant endpoint are sometimes used in lieu of the clinically relevant endpoint. Particularly for the case of atherosclerotic plaque, which is typically close to asymptomatic, the extent to which atherosclerotic plaque is reduced is much less interesting than the extent to which the patients are protected from incidents of heart problems such as myocardial infarctions and unstable angina.

The following year, i.e. 2013, topline results for the ASSURE trial were announced. The primary endpoint of plaque reduction was not statistically significant. To put it mildly, the stock price plummeted. However, subsequent post-hoc analysis of actual cardiovascular events, such as cardiovascular deaths and revascularizations, revealed a statistically significant effect favoring RVX208 over placebo. Thus, while the company had hoped that a surrogate endpoint would support a hypothesis of reduced cardiovascular events, they actually saw a statistically significant effect on cardiovascular events but the surrogate endpoint failed to show statistical significance. A clinically relevant endpoint was met, but the surrogate endpoint failed to show statistical significance. As much as this sounds promising, the analysis must be treated with utmost caution, as this was a post-hoc analysis i.e. not a predefined endpoint, and certainly not the primary endpoint. While it cannot be stressed enough that a great deal of caution is warranted when interpreting such results, against a backdrop of scientific journals starting to write about BRD4 inhibition as a target in atherosclerosis, the post-hoc analysis was intriguing. Could it be that the drug actually worked, but the surrogate endpoint for reasons we do not yet understand, failed to show that the drug worked? This is the question that Resverlogix set out to answer in the BETonMACE clinical trial, a randomized, placebo controlled, double blind phase 3 trial that has ended up enrolling 2,425 patients with diabetes, low HDL and a recent event of coronary artery disease (BETonMACE clinical trial). The primary endpoint is a composite of narrowly defined major adverse cardiovascular events, consisting of cardiovascular death, non-fatal myocardial infarction, and stroke.

Before embarking on the discussion of the potential or Apabetalone, a short overview of the function of the targets of Apabetalone, i.e. the BET proteins or Bromodomain and ExtraTerminal domain proteins is needed. There are four different BET proteins, BRD2, BRD3, BRD4 and the testis-specific BRDT. Each of these four proteins have two so-called bromodomains, BD1 and BD2. The BD1-bromodomains from the four proteins have more similarity to each other than they have to the BD2-brodomomains (and vice versa). Bromodomains bind acetylated lysine, which may be found in acetylation modified histones or acetylation modified transcription factors. The function of BRD4 is the best described of the four BET proteins, and it is also the one that appears to be the protein through which Apabetalone exerts its function. BRD4 is a so-called epigenetic reader, which in the case of BET brodomomain proteins implies that it reads and executes on epigenetic acetylation marks on the histones, the proteins around which DNA is wound. When doing so, BRD4 helps bring key components of the replication machinery to specific sites on DNA, which in turn facilitates transcription of the genes where it binds. However, there are also acetylated lysine residues in many transcription factors, which means that BRD4 through the two bromodomains can bind to both acetylated histones and acetylated transcription factors, and since there are two bromodomains, simultaneous binding of both a histone and a transcription factor is possible. This is a bit simplified, but the key message is that BRD4 is important for transcription of genes and BRD4 has two bromodomain, BD1 and BD2. Most bromodomain inhibitors, e.g. JQ1, bind both BD1 and BD2 with approximately the same affinity, these inhibitors are so-called pan-BET inhibitors. Some are more specific and may preferentially bind to BD1 domains, whereas Apabetalone binds preferentially to BD2. The BD2 selectivity of Apabetalone is important to keep in mind, as it means that the effects of pan-BET inhibitors are not necessarily applicable for Apabetalone.

To set the stage for the understanding of the mode of action of Apabetalone, a couple of words on the impact of inflammation is important. Inflammation is a part of the immune system and inflammation is as such essential for fighting infections and aberrant cells that could otherwise cause cancer. However, if inflammation is not properly resolved, or if the inflammatory processes are constantly being activated, the condition is described as chronic low-grade inflammation a condition that is involved in atherosclerosis (link). A large clinical trial called STABILITY involving more the 15,000 patients looked at the association between inflammatory biomarkers and clinical outcomes, finding that an inflammatory marker, interleukin 6 (IL6) was (quote) independently associated with the risk of major coronary events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease, which indicates a potential pathophysiological association (Held et al., 2017). That is quite an impressive list of unwanted clinical outcomes all of them associated with the upstream inflammatory cytokine, IL6. These results leave little doubt that IL6 related inflammatory responses play a key role for the major adverse cardiovascular events that constitute the primary endpoint of the BETonMACE trial. Upstream in the regulation of IL6, we find the NFkB (strictly speaking, the k is actually the Greek letter kappa) transcription factor, whose activation causes production of IL6 and many other inflammation components (Brasier, 2010). Blocking the activity of NFkB using a bromodomain inhibitor (JQ1) was the effect that Brown et al. (2014) described back in 2014, prompting the commentary in the Harvard Gazette with the quote from J. Bradner (one of the authors) that bromodomain inhibition could halt the progression of coronary disease. It is worth pointing out that the paper by Brown et al. (2014) came out two years later than the Resverlogix news release stating that Apabetalone (at that time called RVX208) was a BET bromodomain inhibitor.

The key to understanding how inflammation affects the cardiovascular system is to look at the endothelial cells, i.e. the cells lining all blood vessels. The endothelial cells are the gatekeepers to the rest of the body, allowing transport of nutrients across the endothelial cell layer. The endothelial cells are also involved in requesting immune cells from the blood stream in case anomalies (infections, irritants are cells that have gone awry) are detected in the surrounding tissue or in the endothelial cells themselves. When immune cells keep being requested to the same area of a blood vessel, there is a risk that immune cells start building up and get converted to so-called foam cells, causing plaque to build up. A well described cause of persistent immune cell attachment to the endothelial cells is low density lipoprotein ("LDL"), which particularly when oxidized is known to be an irritant to the endothelial cells. Reduction of (LDL) is what is achieved by the statin and PCSK9 drugs, such as Atorvastatin, Rosuvastatin, Repatha and Praluent. Particularly when inflammation is not resolved properly, the presence of plaque with its dead and dying immune cells may itself be an irritant, starting a vicious cycle with more and more immune cells arriving and wreak havoc in the vessel wall. The irritants may also be inflammatory cytokines from distant tissue e.g. from visceral adipose tissue (which is a reason that obesity is a cardiovascular risk factor) or the irritation may simply be the shear stress resulting from the blood flow being wrong (which is a reason that a sedentary life style is a cardiovascular risk factor). In all cases, the endothelial cells will respond, either by recruiting immune cells, or as will be discussed later by undergoing a process towards a senescent state or a transition to less endothelial cell like cells called mesenchymal cells.

In the following, the clinical and preclinical data pertinent to the clinical effect and mode of action of Apabetalone will be discussed.

When looking at the effect of Apabetalone, it may be argued that the most relevant and compelling evidence is to be found in the results from the phase 2 trials. The Phase 2 trials with Apabetalone were named ASSURE, SUSTAIN and ASSERT. ASSERT was a dose finding study aimed at showing an increase in apoA1 (primary endpoint was not met); SUSTAIN aimed at showing an increase in HDL (primary endpoint was met); and ASSURE aiming at showing a decrease in atherosclerotic plaque (primary endpoint was not met). None of these trials had cardiovascular events as a primary endpoint, but when the studies were pooled and analyzed together for cardiovascular events by Nicholls et al. (2018) the authors found that Patients treated with apabetalone experienced fewer major adverse cardiovascular events than those treated with placebo. It should be noted that the definition of cardiovascular events also included coronary revascularization and hospitalization for cardiovascular causes, endpoints that are not considered major adverse cardiac events in the BETonMACE trial. In statistical terms, the main conclusions from the pooled analysis were that when combining all the data, there was a statistically significant reduction in cardiovascular events of 44% (p=0.0232) when all patients (798 patients) were included in the analysis. Importantly for the following, the effect was found to be even greater 57% relative risk reduction (p=0.0181) when a subpopulation of diabetes patients was considered, and the effect was even greater relative risk reduction of 62% (p=0.0166) when a subpopulation of patients with elevated hsCRP an inflammation marker was considered. Inflammation is the keyword.

The results from the phase 2 trials are clearly important for the assessment of the chances of the BETonMACE trial being successful, but as mentioned previously, the analysis was done post-hoc, with all the caution this calls for. However, the clinical data are surprisingly well supported by pre-clinical data that have been established by independent research groups after the completion of the phase 2 trials.

In previous articles, I have focused on research done by independent research groups to avoid dealing with any potential bias in data interpretations provided by researchers from Resverlogix. I will make a couple of exceptions in this article, as e.g. the recent paper by Tsujikawa et al. (2019) (the authors are from Resverlogix and University of Calgary) is too important to be left out. In this paper, the authors analyzed the plasma protein profile of patients on the ASSURE study. The profiles of 1,300 different proteins were then subjected to a so-called SOMASCAN Ingenuity Pathway Analysis, resulting in the finding that the protein profile differences indicated reduction of proteins in the IL6-signaling pathway. The authors also described in vitro results indicating that while Apabetalone did not prevent NFkB (or more precisely, RelA/p65, which is a subunit of NFkB) from binding to promoters on the DNA, Apabetalone reduced BRD4 co-location with NFkB which in effect reduces the transcription of genes from NFkB dependent promoters. It was also shown in the paper by Tsujikawa et al. (2019) that transcription of VCAM and IL8, proteins involved in attachment of immune cells (monocytes) to endothelial cells (the cell type lining the inside of blood vessels) were reduced. The results are particularly interesting as they not only indicate that key proteins, such as IL6, IL8, MCP1 and VCAM, are affected by Apabetalone the results also show that the dose used in the clinical trial is sufficiently high to result in a detectable effect in the plasma protein profile. A similar type of Ingenuity Pathway Analysis was done in small phase 1 clinical trial with chronic kidney disease patients, and also in this case, NFkB- and IL6-signaling were found to be downregulated by Apabetalone (Wasiak et al., 2018). Thus, given the results from the STABILITY trial mentioned above, where IL6 was found to be involved in cardiovascular events, Apabetalone appears to be hitting the right target by reducing IL6 pathway-signaling.

It is well known that atherosclerotic plaque contains senescent cells, i.e. cells that have entered a state where they are irreversibly blocked from future cell division. Senescence is a means of preventing cancer cells from dividing, and as such not a trait that one would want to deprive cells of. However, as was the case for the immune cell mediated inflammation discussed above, any system however essential in certain aspects may become a liability if dysregulated. The same holds true for the Senescence Associated Secretory Phenotype (SASP). An interesting paper in Science (Childs et al., 2016) describes how senescent cells drive plaque growth through secretion of SASP components such as VCAM and MCP1. When looking up what is typically included as SASP component, two so-called canonical SASP components are reported to be interleukin 6 and interleukin 8 (IL6 and IL8) (Soto-Gamez and Demaria, 2017). Given that these four SASP proteins, VCAM, MCP1, IL6 and IL8 were also reported to be repressed by Apabetalone (Tsujikawa et al., 2019), the notion that Apabetalone inhibits SASP gains in credibility. If Apabetalone does indeed inhibits SASP, it would not be the first report of BET bromodomain inhibition was shown to inhibit SASP, as results described in an article by Tasdemir et al. (2016) showed that pan-BET bromodomain inhibition reduced SASP.

Critical reading of this article inevitably prompts questions about potential undesired effect of, e.g., dampening SASP. While it definitely cannot be ruled out that there could be such undesired effects, there is some degree of re-assurance found in the fact that metformin a tried and tested drug used for decades to treat diabetes inhibits SASP (Moiseeva et al., 2013). The way metformin does so is actually through inhibition of NFkB, which at this point should sound quite familiar. Moreover, in the article by Tasdemir et al. (2016), they showed that bromodomain inhibition appeared to leave the cell cycle arrest function of senescence unaffected, thus limiting the risk that cancer could result from bromodomain inhibition.

For reference, a review of SASP in relation to cardiovascular disease and diabetes which is obviously extremely relevant considering that BETonMACE exclusively enrolled diabetes patients is found in Shakeri et al. (2018), highly recommended. The implications of SASP on aging and age-related disease are also interesting I touched upon it in a previous article but that discussion is beyond the scope of this article.

It is an established fact that physical exercising is good for the cardiovascular system. Part of the reason for this has to do with the way the blood flows. Thus, sensing of the flow in terms of shear stress transmits signals to the endothelial cells that integrate the nature of the flow, where high shear stress is atheroprotective (stress in the case has to do with the shear, even if this sounds counter-intuitive that high shear stress should be a good thing), whereas oscillating or low shear stress promotes atherosclerosis (is atherogenic). As a consequence of this, plaque has a tendency to develop around branches of the vessels and at bends, where in the latter case, the plaque has a tendency to develop at the inner curvature of the bend, which is where the flow and thereby also the shear stress is lowest.

Low shear stress has been reported to result in so-called endothelial-to-mesenchymal transition (EndMT), in a process that depends on a protein called TWIST1 (Mahmoud et al., 2016).

EndMT is essential in embryonic development, but in adults, the effects of EndMT can be quite dire. A paper in Nature Communications by Evrard et al. (2016) with the title Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability sort of nails it already in the title EndMT causes plaque instability, which is what leads to myocardial infarctions (heart attacks). A recent review by Kovacic et al. (2019) elaborates a bit further on the topic, stating that mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Quite fortunately, the function of TWIST1 has been studied in detail, and it turns out that it is dependent of BD2 (and not BD1) in BRD4. Blocking or removing BD2 abolishes the interaction between BRD4 and TWIST (Shi et al., 2014). Consequently, TWIST1 is likely to be a target of Apabetalone, as Apabetalone blocks BD2 in BRD4, thereby preventing endothelial cells from undergoing EndMT.

While not an endpoint in the BETonMACE trial, it is worth mentioning that Resverlogix earlier this year received a grant for studying Apabetalone as a potential therapy for pulmonary arterial hypertension, PAH, which is also an indication reported by Kovacic et al. (2019) to be caused by EndMT. Resverlogix subsequently announced the publication of an article on apabetalone in relation to PAH (Resverlogix, News Release). Even more interesting is the fact that only BD2 of BRD4 (and not BD1) was found to be required for EndMT and Apabetalone (RVX208) has actually been specifically found to block EndMT (Zhang et al., 2019). It does not get any more direct than that, Apabetalone has been reported to block EndMT.

Zhang et al. (2019) also described the importance of BD2 in neointima formation. Neointima formation is a process by which the blood vessels seek to repair an injury e.g. caused by a stent being placed in a coronary artery and it is as such part of the restenosis process. Stenosis is the clogging of the arteries the reason for stents being placed and restenosis is certainly a thing to avoid as it leads to arteries clogging again (in the location where the stent was placed). I have tried to look for evidence in the phase 2 clinical trial data that Apabetalone prevents restenosis. While never mentioned by Resverlogix, there is actually also some suggestions from the clinical trial data that could suggest that Apabetalone prevents restenosis. Thus, there exists a publicly available summary report for the ASSURE trial posted on the EU clinical trials register (click on the summary report), where a lot of details about the ASSURE study are given including pharmacokinetics (only source of that piece of information, I believe) and adverse events. When searching for restenosis, a table with the relevant information is found. In this table (Table 12.3 on page 92), it can be seen that 2 out of 243 RVX208 (i.e. Apabetalone) treated patients had in-stent restenosis, whereas 3 out of 80 patients on placebo had in-stent restenosis. Percentagewise, there was a 3.8% frequency of restenosis in the placebo arm and 0.8% in-stent restenosis in the RVX208-arm. Applying a chi-squared test, the p-value comes out to be p=0.066. This is typically not considered statistically significant (p < 0.05), but it is none-the-less close and it definitely represents some sort of trend. Actually, when looking at the reports of major adverse events, as many as 4 placebo-patients (and surprisingly only 1 RVX208-patient?) are listed as having in-stent restenosis [for those who would like to check the data, I found in-stent restenosis to be reported for the following placebo treated patients: 502-036, 911-004, 911-009 and 207-017. According to the reports on serious adverse events, starting on page 122, only one RVX208 treated patient, 505-020, had in-stent restenosis]. If the calculation of statistical significance is done on a basis of 4 placebo patients and 2 RVX208 patients, the p-value becomes p=0.016; if the calculation is done on 4 placebo patients and 1 RVX208 patient, the p-value becomes p=0.0039. It should be mentioned that a prerequisite for having in-stent restenosis is that the patient actually has a stent it has not been possible to find publicly available information on how many placebo- and RVX208-treated patients had such stents, which means that the above calculations are subject to a great deal of uncertainty.

Even if the above attempts at statistical analysis of restenosis event are flawed (and they are flawed), it is worth noting that BET bromodomain inhibition has also been reported by other research groups to have in vivo effects towards prevention of restenosis in rat carotid arteries (Wang et al., 2015, Commentary to Wang et al. 2015, Bromodomain blockade for intimal hyperplacia A Good BET?). An added benefit of a drug that inhibits TWIST1 is the inhibition of Wnt5a signaling (Shi et al., 2014). Blocking Wnt5a has been reported to decrease foam cell (plaque) formation and a signaling pathway responsible for lipid accumulation in macrophages (immune cells present in plaque), Ackers et al., 2018. Data from articles by authors from Resverlogix confirms that Apabetalone inhibits Wnt5a (Gilham et al., 2019).

As for safety issues related to a compound that blocks endothelial-to-mesenchymal transition, it is once again possible to find a marketed diabetes drug, this time Liraglutide (marketed as Victoza and Saxenda by Novo Nordisk), where the mode-of-action involves EndMT. Thus, as recently as a couple of months ago, it was reported that Liraglutide inhibits endothelial-to-mesenchymal transition, and it attenuates neointima formation after injury (Tsai et al., 2019). That sounds very similar to the effect that Zhang et al. (2019) found to be the case for Apabetalone. Interestingly, liraglutide has been reported to reduce death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke the same composite endpoint as is used in BETonMACE (Marso et al., 2016).

As described in my previous articles, a protein with the somewhat (misleadingly) anonymous name of p53 is also likely to play an important role in cardiovascular disease. There has been very interesting papers recently on the subject (e.g. Yokoyama et al., 2019), but in the interest of keeping the update relatively short, I will just reiterate that I still think p53 plays an important role in cardiovascular disease in relation to the mode of action of Apabetalone, and while the p53-BRD4 interaction is not bromodomain dependent, binding of p53 to phosphorylated BRD4 leads to unblocking of the BD2 domain (Wu et al., 2013), which plays into the notion that Apabetalone has a role to play in relation to p53.

Given that BET bromodomain inhibition has so many different effects, it is remarkable that only a very limited number of articles describe unwanted side effects. One of the side effects of BET bromodomain inhibition was reported by Bolden et al., 2014, who found that sustained BET bromodomain protein inhibition caused stem cell depletion in the small intestine. The authors used BRD4 silencing, i.e. all effects of BRD4 were muted not only those associated with bromodomains, but every function associated with BRD4 (which also has non-bromodomain protein interactions). The authors pointed out that their results stood in contrast to the fact that a pan-BET inhibitor, JQ1, did not cause the same issues as BRD4 silencing. Moreover, when I contacted Resverlogix a couple of years ago to clarify the question, they said that they had not observed issues with stem cells in the small intestine but they had also not looked specifically for this effect. While it cannot be ruled out that Apabetalone could negatively impact intestinal stem cells, the fact that JQ1 did not appear to have this effect, suggests that this is probably not a major issue.

Another concern was reported in Nature Neuroscience by Korb et al., 2015, who reported that BET inhibitor JQ1 blocks memory in mice, but decreases seizure susceptibility. Without knowing how researchers and management at Resverlogix reacted when they read this paper (which I am sure they have), I take the liberty of guessing that it must have been an even mix of disbelief and cringing frustration. The authors injected JQ1 into mice and performed various tests on them, finding that JQ1 negatively impacted memory formation, but appeared to decrease the risk of seizures. However, the authors omitted information on the kind of compound they were using. JQ1 is definitely a BET bromodomain inhibitor, but it is also a compound that belongs to a class of pharmaceuticals that have exactly the side effects observed by Korb et al. (2015). A quick search on Wikipedia shows that JQ1 belongs to a class of compounds called thienotriazolodiazepines, which is a class of compounds that react and have similar effects as 1,4 benzodiazepines e.g. Valium (diazepam). Diazepines are known to have side effects called anterograde amnesia (inability to create new memories), and diazepines can also be used to treat seizures. The nature of the chemical class of JQ1 was unfortunately not considered at all in the paper. I take the liberty of suggesting that with a very high likelihood, the effects observed by Korb et al. (2015) had to do with JQ1 having diazepine like properties and nothing to do with JQ1 being a BET inhibitor.

Ironically, JQ1 was later suggested as a therapy for dementia and the authors suggested that JQ1 should be tested in the context of learning and memory (Benito et al., 2017). I have not looked into the question of JQ1 having any such positive effects on memory and learning, but the memory formation issues observed by Korb et al. (2015) were clearly not indicated by the results by Benito et al. (2017).

A better established side effect is the observation that Apabetalone in phase 2 trials gave rise to liver enzyme elevations. These elevations were transient and reversible and have not caused the data monitoring board to ask for modifications during the BETonMACE trial. However, liver enzyme elevations should not be ignored and they cannot be totally dismissed, particularly not because they could indicate toxicity issues in the liver.

With topline results from a BETonMACE set to be announced on or about September 30, 2019, the next 5-10 days will be the culmination of years of research by Resverlogix. It is not only the topline data that are coming up soon, however, three days before topline results are expected, i.e. on September 27, a loan of USD 11.5M matures. Resverlogix currently does not have the funds to pay back the loan, but Resverlogix wrote in the news release (link above) that they expect to pay back the loan on or before maturity.

The topline results may not only include data on the primary endpoint the major adverse cardiovascular events they may also include results from two secondary endpoints. These endpoints relate to chronic kidney disease, where the renal function is measured using eGFR, and vascular cognitive dementia, where the Montreal Cognitive Assessment (MOCA) is used. Both of these indications are very big in terms of patient populations, and particularly the vascular cognitive dementia part could turn out to be an even greater story than the primary endpoint, as this could suggest that Apabetalone could be used to treat Alzheimers disease. With all the recent articles on benefits of BET bromodomain inhibition in various indications, BETonMACE could turn out to be either a huge disappointment or it could represent a deluge of positive effects. Whatever the future has in store for Resverlogix, if topline results turn out to be positive, announcing the topline results from BETonMACE will be remembered as Their finest hour.

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. I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: I am long RVX.TO, Resverlogix stock traded on the Toronto Stock Exchange.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). I have no intention of buying or selling any shares in Resverlogix before October 1, 2019.

Editor's Note: This article discusses one or more securities that do not trade on a major U.S. exchange. Please be aware of the risks associated with these stocks.

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Resverlogix To Release Phase 3 Clinical Trial Data On A First-In-Class BET Bromodomain Inhibitor - Seeking Alpha