Resverlogix Corporate Update Tuesday September 29, 2015

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SLIDE 1

(Title Slide: Resverlogix Corporate Update September 25, 2015)

My name is Don McCaffrey. I’m the President and CEO of Resverlogix. I know a lot of you in the room. It’s a pleasure to have you here today. Especially with all the traffic out there and all the other personalities in town, it’s nice that you were able to make it.

SLIDE 2

(Today’s Agenda)

So let’s go through the slides. I’m actually really looking forward to today, because unlike most presentations, I only have to talk for about three or four slides and we have all our experts taking care of the rest of the time. So we’ll go through the introduction; the unmet medical needs in metabolic diseases; we’ll talk about some of our past clinical trial presentation; phase III clinical study planning; the unmet need in chronic kidney disease, which I think you’ll find very fascinating, the epigenetic mechanism, this section is going to detail a lot of what we’ve been doing in the last two years as far as the research behind our exciting multi-modal approach; we’ll talk a little bit about market opportunities, because I think that helps you understand the potential for this market; and the primary market research that’s already been done. And I’ll finish up with some discussion at the end.

SLIDE 3

(Today’s Presenters)

So I’ve already introduced myself. Our first speaker will be Professor Kausik Ray, and as you can tell from all the initials behind his name, he’s one of our key opinion leaders. Then we’ll have follow-up from Michael Sweeney. He is our Vice President of Clinical Development at Resverlogix. And in past history, he was about eleven years, I believe, at Pfizer across the street, and working on many of their clinical programs. Then we’ll have Kam Kalantar-Zadeh, and again as you can tell he’s the other key opinion leader from all of the initials there. We’ll have a discussion about the mechanism of action from Evelina Kulikowski. And then Ken Lebioda will talk a little bit about the business development plan. So they will introduce themselves as they go as well.

SLIDE 4

(Major Opportunities)

Basically, today we really want to cover the major opportunities that we have here. We have a patent life that extends to 2033, so that is very much in our favor. We’re the first and only in-class BET bromodomain inhibitor, and we’re at least eight years ahead of anybody else, so we love that. We’re not one of the “me too” type of categories out there, and we have a very unique market that we can share with you today. We’ve got a very strong safety profile; we’re approaching a thousand patients that have been dosed with this drug. So we know about the safety and we’re excited about what we’ve learned on that, especially in the last six months. The epigenetic mechanism we’ll talk a lot about. And the orphan indications. We announced our first pilot project yesterday, that well be going after PNH – proximal nocturnal hemoglobinurea. There are probably people out there that didn’t know I could say that. My own staff.

SLIDE 5

(Upcoming Milestones)

Alright. As far as the timelines go, we can touch on that as well. We’ve got some really good progress going. And with the main program being the BETonMACE program - it’s a long program, two to three years, so that’s why we wanted to really make sure that there are a lot of inflection points coming up during that time. And you’ll see that today when we’re talking about our program, the orphan disease issues and some of the other business potential that I’ll talk about at the end. So we’ve put some cards on the table for you to write down questions if you want. We will do a Q&A at the end, the panel will come up and we will do a Q&A, there will be a couple of mics around the room to ask questions. So we’re really looking forward to today.

SLIDE 6

(Agenda Slide – Unmet Need in Metabolic Diseases highlighted)

And on that note, I think we will start with Kausik coming up to tell us a little bit about the issues. And there’s an ongoing joke about - there is a square button on here that if you push it shuts everything down. And we’ve got a bet going as to which one of us is going to hit it first.

Kausik: What, you mean that one? Oh, OK, right.

SLIDE 7

(Subtitle Slide: Tackling CV risk in T2D)

So good afternoon ladies and gentlemen, I’m Kausik Ray, I’m from London, UK, as you can tell by my accent. To give you a little bit of background, I’m a preventive cardiologist, and I’ve been involved in clinical trials for about ten years, and population research as well. So we do a lot of the large-scale epidemiological studies. So I’ve spent really a good part of my professional life looking at diabetes, lipids and cardiovascular disease risk; and I’m going to share some of those thoughts with you.

SLIDE 8

(Slide says Diabetes is a global public health challenge)

So really, the first and obvious thing is that there’s no point in developing something, if there isn’t really a big public health need.

SLIDE 9

(Prevalence of diabetes in 2030)

And we have a big problem when you start looking at diabetes. This is a global health challenge. So if you look at the projections for diabetes from where we were in 2010, with about 285 million people affected - Diabetes pretty much affects every region of the world. It’s not just a disease of developed countries, it’s also importantly a disease of developing countries as well; and so if you look at a small change in the prevalence, going from 6.6 going to 7.8 percent, in absolute terms it’s a huge difference in the number of people affected, to well over 400 million. And just so that you know, in some parts of the world, like in the Middle East, the Gulf countries for example, the prevalence of diabetes is about one in three. So there’s a huge problem there that we’ve got to face. Now why is it a problem?

SLIDE 10

(Estimated life years lost among those with Diabetes)

Well, this is some of the work that we did. So it’s the largest study ever done, half a million people. And I’ll walk you through this. Men on the left, women on the right. If you develop diabetes at aged forty, it takes about six to seven years of life away. This is not counting the heart attacks, the blindness, the kidney failures and all those other things that go with diabetes. It actually robs you of almost a decade if you like, or half a decade of life. Most of those deaths are vascular deaths. There’s an increase in the risk of cancer deaths and things like infections as well. The other key thing is we’re actually seeing diabetes at an earlier and earlier age. You know, so in many places, diabetes is now occurring - this is the adult onset type two diabetes, if you like - is occurring as early as the thirties. And the other, sort of on a lighter note, you’ll see basically if you develop diabetes aged about ninety, it probably doesn’t matter because you’re pretty close to dying anyway, so it’s really not going to have a big impact. But on a serious note, we are seeing people younger and younger, and there’s a huge burden. If you think about the economy for example. If you lose your viable work force disappearing.

SLIDE 11

(Diabetes doubles the risk of vascular events [Emerging Risk Factors Collaboration])

Ok, if you’re not familiar with this type of presentation, I’ll just walk you through this again. This is our work. Over half a million people, so 26,000 heart disease events. Diabetes exactly doubles the rate of coronary artery disease. And your first event is often a fatal one. It also increases the risk of strokes and both hemorrhagic and those that are caused by blood clots, ischemic strokes, and also things like aneurysms, etc. So it’s associated with bad vascular events.

SLIDE 12

(Diabetes and prior MI carry similar CV risk)

This is really just showing you, and I’ll walk you again through this, the risk of future heart attacks by age. So the risk of heart disease increases as we age. And that’s this graph, men and women. Now if you’ve had a heart attack, your risk of a second event, at any age, goes up. And that’s what it looks like, so you’re always going to be at slightly higher risk. That’s in the middle, that’s in the white. But if you basically have diabetes and no previous history of an MI, your risk is the same as somebody that’s had a previous heart attack. And this is why diabetes is often referred to as a heart disease equivalent. And here it’s really important, because that’s the population that we’re going to study in our outcome study. If you’ve had a heart attack and you’ve got diabetes, your risk just gets amplified that much further at any age, so you’ve got double-trouble basically. So here again, we are into the realms of an unmet need.

SLIDE 13

(Diabetes-related CV complications have declined with improved care, but substantial burden remains)

Treatments have improved. This is an event rate, or complications if you like. Vascular events over time. They have declined, because we’ve got some useful and good treatments. And they’ve declined but they remain much higher in diabetes populations compared to people without diabetes. So we recognize that there is still much much more to do.

SLIDE 14

(Slide says Diabetes and MI patients carry the greatest cardiovascular risk) Now

SLIDE 15

(Graph: Kaplan-Meier Cumulative Incidence Curves for the Composite End Point of Cardiovascular Death, Myocardial Infarction or Stroke in the Entire Population With a 4-Year Follow-up and Key Subgroups)

I’ll show you why this is really going to be even more of a problem in somebody that’s just had a heart attack in a second. So let me walk you through this. So this is time at the bottom, and this is the risk of having a heart attack, a stroke or dying. So these are common vascular outcomes. This is the average. And what you can see with an average event rate over time in people at risk is yeah, it goes up. But there’s a wide range of risk. So at the top, this is a group who’ve just had a heart attack in the last year or so. And here, are people for example, who smoke, whose blood pressure is uncontrolled. So they’re not at the same level of risk as somebody who has just had a vascular event, an acute event. So you’ve got to be a lot more aggressive and treat those people. But importantly if you now treat them, actually you save many more events, so treatment’s actually much much more cost-effective when you look at people up here, compared to people down here.

SLIDE 16

(Graph: Risk of Ischemic Events in the Subsequent 4 Years of Follow-up in Patients According to Baseline Risk Category)

So I just want you to focus on the right. This is a big study that was done. So if I take all heart attack patients for example here, that’s the average event rate. But I can actually break that down much further. See if I’ve got diabetes and I’ve just had a heart attack, my event rate is much much higher than if I’m a non-diabetic and had a heart attack. So you can see how important risk factors are additive, and they can amplify your risk of future events. And if you go down the bottom here, for example, these are people who have not got any vascular disease, and the event rates are a lot lower, but the diabetics always do much much worse.

SLIDE 17

(Graph: Four Year Event Rate % in Patients with Prior ischemic events, stable atherosclerosis without prior ischemic events and risk factors only)

Here is an important caveat that we want to throw in. Why are we going to study a patient population with diabetes who’ve just had a vascular event in the last year? Well, just look at this group here. These two groups are people who have at some stage had a heart attack. The top bar is the group that just had an event in the last year. And the other group is a population who’ve had this event at some stage in the past. And then you’ve got some people who might present with angina and have a bypass. So their events are lower. So if you pick a high enough group, you’ve got a group with high unmet need. So as you’ll see later on, Ken Lebioda is going to show some data about what other physicians feel about where we think we should have been targeting these populations. And from your point of view as investors, you might want to consider this. I mean I come from a very poor country called England, you may have heard of it, and we have this socialized health care system. So payers are very keen on absolute risk and absolute deterrent rate. So when you develop drug trials, and you develop these areas, they say we’re not going to pay for everybody across the board. We want those who are going to be at really high risk. And that’s why designing studies to pick up unmet needs like those who’ve just had a cardiovascular disease event and have other risk factors as well, just pushes that bar much much further. And then actually you have a smaller number you need to treat to avoid an event, and it becomes much more cost-effective.

SLIDE 18

(Heading: CV death is increased in patients with diabetes and multiple risk factors. Graph: X axis risk factors, y axis age adjusted CVD death risk per 10,000)

This is just showing you, we know that our lifestyles are getting less healthy. That’s probably not something I want to tell you over a meal. But we know that the more uncontrolled factors you have, if your blood pressure’s high, if your cholesterol levels are high, these are all additive. Now, if you put another layer on top of that and you add diabetes, it really starts to go up much much further. So diabetes tends to accelerate conventional factors.

SLIDE 19

(Urgent need for novel therapies targeting additional pathways)

So if you look at this whole area, there is clearly a need for novel therapies targeting additional pathways.

SLIDE 20

(Reducing CV risk in T2D may need a multifactorial approach)

What do we have currently? If we’re trying to reduce cardiovascular disease risk, we have things that control cholesterol, blood pressure, weight loss is largely lifestyle, there are drugs being developed also for that, glucose control, and drugs that reduce the stickiness of platelets, so aspirin and other agents. And they’ve had an impact. However, in terms of incremental benefit, perhaps we might struggle a little bit, because you’re talking about drugs that are well established. They’ve got a good effect, and trying to target those same pathways might not give you as big a return as targeting novel pathways of things that we know are important. Things like inflammation, the complement system, potentially there’s also added benefit on other lipids not targeted here, and incremental control of glucose. So those are potential new targets. And if your drug helps all of these, you’ve got a much bigger bang for your buck. So there in summary is where we are, and I think here is where we will probably go in the future. And that really leads me to summarize.

SLIDE 21

(Summary)

Diabetes. Your top take home message. This is going to be a major area globally. So we’ve got a lot of people at risk. When you’ve got diabetes, you’re going to be at much higher risk of having a heart disease, but when you’ve had a heart attack and you’ve got diabetes, your risk is going to be even higher. We know that our current treatments actually improve the outcomes, but these people are at life-long risk because diabetes doesn’t just go away, and it’s a progressive process as well. So there really is an urgent need for novel therapies that target all aspects of the pathophysiology of cardiovascular disease in people with diabetes. So I’m going to stop there...

SLIDE 22

(Agenda slide with items 3 and 4 highlighted: Clinical Data Presentation: Dr. Michael Sweeney and Phase 3 Clinical Trial Planning: Dr. Michael Sweeney)

…and hand over to Mike.

Mike: Thank you Kausik. I’m going to take you first for some of our existing data, and then the plans for our Phase III study.

SLIDE 23 (Overview of Apabetalone (RVX-208)

So in summary, Apabetalone or RVX-208 is the first selective BET inhibitor to be in the clinic, and as Don mentioned it is about eight years ahead at least of anything else. As Kausik mentioned, the residual risk in the population we are targeting is very high with diabetes and CAD (coronary artery disease). And we work on an epigenetic mechanism, which Evelina will talk about in more detail later, modifying multiple risk factors and multiple approaches. Those multiple pathways give us a single target, but synchronized multiple biological actions. And we have very encouraging Phase II results, which I’ll show you in a moment.

SLIDE 24

(Apabetalone (RVX-208) has a multimodal approach to accomplishing its goal of MACE reduction)

It is the multiple actions that are important. All of these, reverse cholesterol transport, metabolic, inflammation, thrombosis – all of these contribute to cardiovascular events in the diabetic patient. We have effects on a number of the vascular mediators, reverse cholesterol transportation, reduced ALP, which we’ll talk about a lot later, and reduction of platelet activity.

SLIDE 25

(Apabetalone (RVX-208) Development to Date)

We have a large database at this stage of development. We have almost one thousand patients that we have treated, of which 706 have received active, and the remainder placebo. Of our patients, around about 600 (576) have stable coronary artery disease, and they were studied in three studies. One of which was a 12-week dose-finding study, and then there were two 24-week studies which I’m going to talk about a lot more, called ASSURE and SUSTAIN. They were patients with stable coronary artery disease.

SLIDE 26

(Phase 2b (RVX222-CS-007/008) Study Characteristics

The populations of both are broadly similar, and broadly similar to the population of coronary artery disease patients as a whole. We have HDL cholesterol of less than 45, so low HDL cholesterol, they’re all randomized versus placebo, and six months of treatment duration, which is typical for a Phase II study in this area, and all on a background of standard of care, with high-potency statins, either atorvastatin or rosuvastatin. Slight differences are that the ASSURE study looked at patients who were scheduled for coronary artery angiogram due to deteriorating symptoms. The SUSTAIN study was stable patients.

SLIDE 27

(ASSURE and SUSTAIN Patient Screening)

Our total population in this study was 500 patients randomized in the combination. Almost all patients are included in the analysis. Our modified intention to treat includes 166 in the placebo, and 331. So of the 499, only two patients are not included, because they actually never received any therapy.

SLIDE 28

(Phase 2b Lipid and Inflammation Data)

Looking at the risk factors that everyone’s familiar with, we see a consistent modest effect on lipids, via HDL cholesterol, ApoA-1. The lipid particles for HDL are those that are anti-atherogenic are the ones that we have the biggest effect upon. And inflammation, there is a decline of hs-CRP and a decline in ALP. So the risk factors are all moving in the right direction.

SLIDE 29

(ASSURE and SUSTAIN, Apabetalone (RVX-208) lowers MACE by 55%)

What’s most important though is when we looked at MACE in these studies, and this was a retrospective meta-analysis, we see a reduction in MACE events of about 50%, which starts almost immediately. So we think there’s a large inflammatory component, a large anti-platelet and complement component. And it continues out until the end of the studies in 2010.

SLIDE 30

(Effect Accentuated in Patients with Enhanced Inflammatory State – Diabetes Mellitus)

How do we know it’s inflammatory? If we look at two subpopulations, first of all the diabetes population, and then the high CRP population indicative of a high inflammatory state and activated vasculature, we see a greater reduction in the diabetics…

SLIDE 31

(Effect Accentuated in Patients with Enhanced Inflammatory State – Baseline hsCRP >2 mg/dL)

…and a greater reduction in the patients with raised CRP. So, we feel that it’s the anti-inflammatory, anti-platelet, anti-complement which Evelina’s going to talk about later, that contributes the majority of the efficacy to the drug, and the lipid effects are minor contributors.

SLIDE 32

(Hepatic Adverse Events Summary)

Obviously, we have some adverse events. Every product has adverse events. The overall adverse events are approximately similar between active and placebo. The main adverse event that we see that is different is an increase in hepatic enzymes. Seven to eight percent of patients have a rise of ALT greater than three times the upper limit of normal. Of these patients, if you stop the drug, they revert back in a matter of days. Usually for five times the upper limit of normal, it’s about 15 days for them to revert back. There’s no inflammatory component. For the lesser elevations, if you re-start, or if you continue, the drug is well tolerated, and these ALTs reverse with continued therapy. We did not see a Hy’s law. That’s something that the FDA worries about. If you see an increase in bilirubin at the same time as increasing enzymes, that’s indicative of serious liver damage. We have not seen a case of Hy’s law. We actually do not see a raise in bilirubin in these studies. They tend to occur early. They tend to occur within four to six weeks. We’ve only ever seen one case after twelve weeks, and that was a patient who had coincidental acute cholecystitis. And a lot of the patients with ALT elevations were seropositive for Hepatitis A or were taking drugs known to increase the ALT.

SLIDE 33

(What could underlie the transient ALT elevations?)

We think we’re getting to the bottom of this adverse event. We’ve done a lot of work in the laboratory to investigate this. And we seem to see that there is a change in bile acid metabolism in selected patients, because BET inhibition does change the expression of bile transporters and bile enzymes in selected individuals. So there’s an increase in influx of cholesterol, and a change in bile pathway, and a down regulation, transient. But this down-regulation does not persist for long; there is an adaption within the liver cell, which accounts for why the enzyme levels go away with continued therapy. The net effect is an increase in bile acids in a very small number of patients. And we’re working in the lab to confirm this hypothesis. One of the reasons behind our BETonMACE study, apart from outcomes, is to get a very large safety database, to truly document the incidence and the consequences of these hepatic enzyme increases.

SLIDE 34

(BETonMACE – Effects of RVX-208 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease)

Which brings me nicely to our phase III study, which we call the BETonMACE study. It is a large Phase III multi-center study, looking at the time to MACE events in patients with low HDL cholesterol, diabetes, currently treated with standard-of-care statins. It’s that exact population that Professor Ray was referring to earlier, that have very few current therapeutic options, and a very high rate of events.

SLIDE 35

(BETonMACE: Study Population and Basic Design)

It’s a large study. It’s more than 150 global sites with two-and-a-half thousand patients (2,400 on slide). Event-based. Where we’ll continue the study until we reach 250 primary events. The primary events are the narrow MACE events. That’s MI (myocardial infarction), cardiovascular death, or strokes. We’re looking at male or female, type II diabetes, with a recent acute coronary syndrome between 7 and 90 days. It’s very similar to the population for the EXAMINE study, which looked at alogliptin. It’s 100 mg b.i.d. (bis in die, twice per day, i.e. 200 mg. per day.) vs. placebo, on the background of standard-of-care. And to ensure standard-of-care, we are actually providing the statins for this study. We’re providing the statins for the patients to ensure every patient is receiving standard-of-care. Study duration will be two-and-a-half to three years, depending upon the event rate. And in the background here we’ll also be working on the orphan drug and we’ll have regular DSMV. So there will be plenty of news coming within the two and a half years to keep the interest around the area. Our first patient is going to be recruited in the second half of this year.

SLIDE 36

(BETonMACE: Sample Size)

Where did we come to our sample size? Two-and-a-half thousand patients gives 80% power for a 30% relative risk reduction, which is much less than we saw in our Phase II studies. However, you always anticipate that your Phase III will be less than your Phase II. And the EXAMINE study tells us that we’ll have about a ten-and-a-half percent (10.5%) event rate in the placebo arm at 18 months. And our projections are for about a seven-and-a-half percent (7.47%) rate in the active arm. So we’re well powered for a 30% reduction.

SLIDE 37

(BETonMACE: Endpoints)

The primary endpoint is the classic time from randomization to the first occurrence of stroke, MI or cardiovascular death. Secondary endpoint at the insistence of the regulators is all-cause mortality, because we had some good strong feedback from the regulators in both UK, Germany and Sweden. And we’re also looking at some changes in lipoprotein concentrations (slide also says diabetes mellitus variables, alkaline phosphatase and kidney function). Our safety endpoints are focused around hepatic adverse events (AEs), and very close monitoring in hepatic adverse events together with the standard AE’s. But in addition, because of the current controversy around low lipid levels and cognition in elderly patients, we are also assessing all of our patients over 70 with the Montreal Cognitive Assessment scale, or the MOCA just to confirm that we do not deleteriously affect this.

SLIDE 38

(BETonMACE Subgroups)

We have a number of subgroups. Again, the regulators have asked for a number of subgroup analyses. For the Rosuvastatin group and the Atorvastatin group. The immediate post ACS (acute coronary syndrome) vs. the ACS greater than a month ago (≤30 days vs. >30 days). (Above and below) The medians of the various lipid parameters. The median HbA1c. And also those patients who have a low as opposed to a normal eGFR (≥60 vs. <60). In addition, we will have a subgroup within the study where the patients have an eGFR <60 and we will be looking at their GFR change, as we’ve had some encouraging data on the Phase 2.

SLIDE 39

(Agenda slide with item 5 highlighted: Unmet Need in Chronic Kidney Disease: Dr. Kamyar Kalantar-Zedah)

And with that, that brings me very nicely, having talked to kidney, to hand the podium over to Dr. Kalantar-Zadeh.

Kam Kalantar-Zadeh: Thank you Mike. OK.

SLIDE 40

(Chronic Kidney Disease Progression)

My name is Kam Kalantar-Zadeh. I’m a nephrologist, kidney specialist, Professor of Medicine at the University of California, and Chief of Nephrology at University of California Irvine. So it is a great pleasure to come all the way from California to New York, as always. So I would like to emphasize the concept of chronic kidney disease, CKD chronic kidney disease, and its importance, its burden of disease in this nation and globally. Chronic Kidney Disease is a disease that is progressive. Once you have chronic kidney disease, it just gets worse and worse. And goes towards these stages 1, 2, 3, 4, 5. Stage 5, as you know these are patients that require dialysis or kidney transplantation. The cardiovascular burden is quite high. So let’s go over this again.

SLIDE 41

(Prevalence and Economic Burden of Chronic Kidney Disease)

You see a number of statements here about the burden of this disease. Chronic Kidney Disease. Twenty to thirty million people in America have chronic kidney disease. Estimates from other nations are similar. China for example has 120 million Chinese with chronic kidney disease. It’s one of the top ten causes of death in this nation. Chronic kidney disease not only has a high burden of disease, but also is quite expensive. Because patients eventually need kidney replacement therapy. Many of them start dialysis, without which they could not survive. Patients on dialysis have mortality that is worse than cancer. It’s embarrassing for a nephrologist like me to say that a patient on dialysis has survival that is worse than cancer. As you can see, the five-year death rate is 64%. Nowadays most cancers have better survival. And very expensive.

SLIDE 42

(Unmet Need in Chronic Kidney Disease Patients)

So up to this point, we have nothing to stop progression of chronic kidney disease. There have been a number of interventions, medications, agents to slow down the progression. And some of them work, some of them are questionable, some of them not quite effective. So these are different statements as you can see here that we’re still looking for something that could be the ultimate cure, which does not exist. And something that could also intervene, and something that could deal with what you see here, the high burden of cardiovascular disease. Why? Because having chronic kidney disease and having end stage renal disease, we have renal replacement therapy for that, dialysis and kidney transplantation. But that doesn’t solve the problem of cardiovascular events and cardiovascular deaths. Many of them die because cardiovascular disease and cardiovascular events.

SLIDE 43

(ALP as a Prognostic Biomarker: ALP linked to Mortality, Cardiovascular Disease and Diabetes)

Now with this slide I’d like to introduce to you something that all clinicians know about. It’s called alkaline phosphatase. Alkaline phosphatase is an enzyme that is measured in your blood. It comes from the liver, from bone and from the intestinal tract. It’s usually measured routinely with any comprehensive blood panel. Studies in the past and recently have shown a remarkable and consistent association of alkaline phosphatase with cardiovascular disease. And you may say, “how come I didn’t hear about that?” So let’s go over this. Alkaline phosphatase here, in statement number 1: Higher levels of serum alkaline phosphatase (ALP) are associated with increased mortality in the general population and in patients post MI, and in patients with chronic kidney disease. (Statement 2) The highest quartile of serum alkaline phosphatase was associated with higher prevalence of myocardial infarction, stroke, congestive heart failure and diabetes. (Paraphrase of statement 3) And in different studies, different sources of serum alkaline phosphatase has a critical role in (vascular) calcification, so I’ll show you this is the proof of concept, how an enzyme which was not important until yesterday is going to be important.

SLIDE 44

(Serum alkaline phosphatase (ALP) at baseline and prospective mortality in 58,058 hemodialysis patients: 2001-2003)

This is one of the data from a dialysis patient cohort, here. You’re looking at 58,000 dialysis patients from New York to California. The bar shows the distribution of serum alkaline phosphatase across these 58,000 patients. What is remarkable is that this shows the higher the serum alkaline phosphatase, the higher the mortality in these 58,000 patients. And this incremental linear association appears to be too good to be true. That means the higher is the worst, the lower is better. So alkaline phosphatase high is bad, low is good. So this was one of the discoveries in 2006, highly cited.

SLIDE 45

(Higher tertiles of serum alkaline phosphatase are associated with risk of death in general population (without CKD)

Now what about the general population? A few years later, my colleague, Tonelli from Canada also published this in Circulation (2009). He looked at serum alkaline phosphatase across one of the general population cohort. And what he found was that the higher serum alkaline phosphatase, in people who don’t even have chronic kidney disease, the higher is cardiovascular events and mortality, as you can see across. So remarkable, you may say, “Why didn’t people pay attention to that?” The reason was because until now there was nothing to intervene. So there’s a biomarker, and you discover an association. Well nice, but so what? What can we do?

SLIDE 46

(What is the link between serum alkaline phosphatase (ALP) and cardiovascular outcomes?)

Alright now. Why is alkaline phosphatase associated with mortality? There are several hypotheses. We are not quite sure. One is the vascular calcification hypothesis. It is known that the higher is the vascular calcification score, that is the more calcification you have on your coronary arteries, the worse is your predicted survival. So that’s relatively known. There are ongoing discussions, but it’s considered quite consistent, and without much question.

SLIDE 47

(Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification)

Now here are a number of statements toward proof of concept. Similar studies by my colleagues. Dr. O’Neil in Atlanta, in experimental models, animals and in vitro, showing the role of a molecule called pyrophosphate. Because we want to link alkaline phosphatase to vascular calcification. So there is another molecule called pyrophosphate. Pyrophosphate protects vessels against vascular calcification. And alkaline phosphatase inhibits pyrophosphate, therefore leads to vascular calcification. Right? Inhibitor of inhibitor is bad. And here, several other things, to do with pyrophosphate. Essentially, he’s running all these experiments showing that this so-called tissue non-specific alkaline phosphatase is the culprit by going after pyrophosphate, which protects your vessels, and leading to worsening vascular calcification. So therefore, the last statement, if this hypothesis, this proof of concept is proven in future studies, we are hoping, that was just 2008, this mechanism may eventually identify alkaline phosphatase as a target to lower and to improve cardiovascular disease events and survival. So it was left alone, because there was nothing to do this.

SLIDE 48

(ALP is related to vascular calcification)

Now here also, two more sides just proof of concept. This is one of them just showing that in a study of over a hundred patients with CKD, those with higher coronary arterial calcification in any of their coronary arteries, these are the four different areas of coronary arteries, their alkaline phosphatase was higher. So remarkable association between coronary calcification and level of alkaline phosphatase.

SLIDE 49

(ALP and outcomes in CKD: Support in literature)

And so many papers have been published, mostly in nephrology, my field, where alkaline phosphatase is measured more routinely.

SLIDE 50

(Can serum alkaline phosphatase (ALP) be lowered?)

Now let’s connect this to what was discovered. Can serum alkaline phosphatase or ALP be lowered? Is there an intervention? There was not. I was essentially myself sitting there thinking why I spent so much of my time writing papers, discovering this alkaline phosphatase, so what? So until these great people contacted me and we had this collaboration. Is there an intervention to lower serum alkaline phosphatase in both CKD and non-CKD patients? Is there a proactive way to lower alkaline phosphatase and by doing so, to show that cardiovascular outcomes are improved?

SLIDE 51

(Phase 2 Studies: ALP Quartiles and MACE)

So going back now to what Mike presented in Phase II studies and Phase III studies. At baseline and towards the end what they have found, the higher is alkaline phosphatase, the worse was the adverse cardiac events. The more likely, the more frequent. So there is a proof of concept even in this cohort in this clinical trial.

SLIDE 52

(RVX-208 Downregulates Alkaline Phosphatase Expression: Primary Human Hepatocytes (multiple donors)

Then going back to experiments. When you want to build something, you want to show something is credible, it has to show across both experiments in vitro, animal models and then in real clinical trials. And you’re looking at two sets of primary human hepatocytes. Resverlogix scientists, they bought these human hepatocytes. They placed their molecule RVX-208, this is the one that you are sitting here for, they placed this in these experimental in vitro dishes and what they found was that there is 80% decline in alkaline phosphatase upon exposure to the molecule 208. Quite remarkable. And as you can see within 48 hours it was the measurement, and even within 20 hours, and sustained decline in alkaline phosphatase gene expression. So gene expression should now translate into level.

SLIDE 53

(RVX-208 lowering of ALP is time and dose dependent)

That’s what they also found. These are now Phase II studies coming here, looking at. The next step toward biological plausibility is dose-response. If something is really lowering something, the higher is the dose, the more effective it is, and that is what you see there very nicely. No 208, no change in alkaline phosphatase. More and more and more, that means higher dose, more effective. It starts actually quite fast. That means the molecule actually lowers alkaline phosphatase quite fast, within the shortest period of time. And then the effect is sustained. Sustainability. So very nice proof of concept.

SLIDE 54

(RVX-208 induced lowering of serum ALP is maintained for at least 6 months)

And then also looking at the clinical trials that were explained to you by Mike, SUSTAIN and ASSURE. This is the standard of care, which includes patients who received statins. Typically, over 30% of them (?) received statins we know by the start of the study, because everybody should receive standard of care. So some declining alkaline phosphatase, but much more marked declining alkaline phosphatase when the patients received the molecule 208 is used. So the treatment arm vs. placebo arm in both studies. With again, consistent, fast, and sustainable.

SLIDE 55

(RVX-208 lowers serum ALP in patients with Diabetes Mellitus)

And here also, this is toward the end of my presentation, you see looking at different subgroups. Patients whose alkaline phosphatase at the beginning was higher. The drop in alkaline phosphatase was two times more than the drop with standard of care. So -12 vs. -6. And these are patients that are considered high-risk for coronary artery disease. Diabetic patients. Low HDL. And also looking at the other iterations, patients with low HDL vs. high HDL, the alkaline phosphatase drop was even more remarkable in those with higher risk.

SLIDE 56

(Conclusions)

So in summary, what I’ve presented to you in the past 10 to 12 minutes. In both the general population and in CKD patients, higher alkaline phosphatase is known and is shown to be associated with worse cardiovascular disease events and outcomes and worse survival. Higher alkaline phosphatase is associated with vascular calcification. It is probably one of the most important culprits in vascular calcification in all of us. Clinical studies show that molecule RVX-208 can lower alkaline phosphatase. So for the first time we have something that can proactively and consistently can lower alkaline phosphatase. And lowering alkaline phosphatase is time and dose dependent. So it’s beyond proof of concept, actually quite effective. And the alkaline phosphatase lowering effect of 208 is maintained for up to six months. This is the length of the studies that they have been done so far. And 208 can lower alkaline phosphatase in patients with diabetes, including high risk for coronary artery disease.

SLIDE 57

(Agenda slide with item 6 highlighted: Epigenetic Mechanism of Action and Novel Biology: Dr. Ewelina Kulikowski)

So I’m going to stop here, and thank you for this privilege. Thank you.

Good afternoon, my name is Ewelina Kurikowski and I head the scientific development at Resverlogix.

SLIDE 58

(Epigenetics)

And what my section here will focus on really is a little more about 208. So I’m not sure how familiar everyone is with epigenetics, or if everyone here understands kind of how it works. But in essence, epigenetics is really what dictates why every single cell in your body has the same DNA sequence, but every single cell has a different function depending on the tissue it’s in, or the organ. And that occurs due to post-translational modifications of the chromatin. And the mechanisms of that are done by enzymes that are known as writers or erasers. So these are enzymes that will add modifications or remove them, such as acetylation or methylation. And these are recognized by proteins called the readers, which in our case are the BET proteins. And in so doing, they recruit transcriptional machinery, transcription factors to the DNA and either enhance or repress transcription. So RVX-208 works on these readers, on these BET proteins.

SLIDE 59

(Apabetalone (RVX-208) is a BET inhibitor)

So what’s shown here at the bottom on the very far left is a BET protein in contact with an acetylated lysine. So lysines are acetylated in the chromatin, usually in highly transcribed regions. This would be a normal state the cell might be in where BET proteins are at the enhancers. You can see that with the addition of RVX-208, you can see a dissociation of that. So this reader is no longer reading this acetylated lysine, and this is going to have an impact on the transcription that’s happening in that enhancer site where this is found. So in our case, we actually found RVX- 208 in a cell screen looking for compounds that increase apolipoprotein A-1 (ApoA-1). So in our cell assays at the time, about ten years ago, we did not know how 208 worked initially. This was a protein readout from the cell. It wasn’t until very recently that we learned the mechanism by which RVX-208 regulates Apo-A1, and the additional factors I’ll talk about today, is through this BET inhibition mechanism.

SLIDE 60

(Apabetalone (RVX-208) is a Selective BET Inhibitor)

Just a little bit more about BET proteins. So BET proteins have binding pockets as I showed you, with the ability to bind acetylated lysine. And those pockets are called bromodomains. And there are usually two, BD-1 or BD-2. That’s what you can see on this part of the panel here. You can see in the tree, these are all the proteins that contain bromodomains. But only these ones are the ones that are the readers on the DNA, and these ones are referred to as the BET proteins. And in all the work that we’ve done, we’ve been very interested to understand how 208 binds these bromodomain pockets, and how that translates into activity. And without getting into all of the details, what we’ve found was that RVX-208 selectively binds to bromodomain 2 within these BET proteins, most specifically protein BRD-4. That is our target. The other BET protein inhibitors that you might hear about in clinical development in the oncology space, they often bind both BD-1 and BD-2. We call that a pan effect. And we believe that has utility for cancer indications where you’re looking to potentially kill the cells. So they’re a lot more toxic, pan-inhibitors are more toxic. I think that the key to why we see such beautiful toxicity profiles which are very low on the toxicity scale both in vitro and in vivo and in humans, is that they have this selectivity to BD-2.

SLIDE 61

(Apabetalone (RVX-208 Selectivity: BD2 specific gene expression signature in microarrays)

So I’ll go into a lot of the data in one second. So I’ll introduce microarrays at this point, because that kind of brings home the point on the BD2 selectivity. So what microarrays in essence are, are a way to survey global gene expression. So in vitro, the only way to examine whether a cell or a construct is responding to RVX-208 is to look at the gene expression profile. So what’s being upregulated, what’s being downregulated, what is the cell doing in response to our drug. But the way to do that, knowing that we have a BET inhibitor, and we’re going to affect transcription globally, is to do a microarray analysis, which in essence lets you look at 20,000 genes almost at the same time. Because you’re going to break those genes down into pathways and you can have a look at what’s being affected in response to your drug. I show this here, because this is an example of a microarray we did in whole blood from three healthy volunteers. Normally what I would have here is there would be gene names within each of the boxes that you see, yellow or blue. I’m not giving you those gene names today, but those genes have been segregated based on how highly they are downregulated. So in the far panel on the left, you can see that for the RVX-208 dose with BD2, these are all the genes that have been downregulated, again they’re not listed, from the most downregulated to the least. And on the other side of the panel here, the ones that are the most upregulated to the least. And I just want to bring your attention to the difference of RVX-208 at that BD2 selective dose to JQ1. And JQ1 is a pan BET inhibitor that is often heard about in this particular area. It is not a clinical candidate, but it is a compound that has been built upon so companies such as Bradners, Tensha Therapeutics, they have inhibitors within that class. So those are pan inhibitors, they inhibit both of those bromodomains, and they clearly have a completely different profile than RVX-208 does. And we really feel that that is one of the reasons that we see the toxicity profile that we do. And also we believe that that is really part of the effect that I’ll tell you about in terms of the biology.

SLIDE 62

(BET Inhibition Beyond Lipids)

So the rest of my talk will be focusing on the biology that we’ve recently uncovered in doing all of this microarray work. So as Mike already showed you, the data we saw on MACE was really striking to us, and somewhat surprising at the time. We were so focused on Apo-A1 and HDL, and we wondered how 7 to 10% increases in Apo-A1 or HDL could translate into these massive MACE effects that we were observing. So we knew we had to go back and find out what else does this drug do. And so the way to do that initially was to do this microarray analysis, but now instead of whole blood, we also looked at liver cells. And the reason the liver is important is because, first it’s where traditionally all of our cell screens have been done in the liver, as this is the site of action for Apo-A1 induction. But also because our drug preferentially concentrates in the liver, at least in mouse models. So we knew that this was really going to be the site of activity. And what we found, and what I’ll show you in the next few slides, was that we definitely touch on reverse cholesterol transport, we knew that already from all of our clinical data. But what was new to us was that we had really these amazing effects, on complement, on coagulation, on vascular inflammation, and calcification as Kam just mentioned. And we also knew that we had effects on diabetes based on the data that we saw in the clinical trials.

SLIDE 63

(Downregulation of Pathways with Roles in CVD/MACE)

So this is a slide just again describing the microarray in primary human hepatocytes. And I should mention that these are cells that are not immortalized, they are literally cells taken from patients that have donated their livers after death of course. And you can buy these cells, and have them shipped to you. They have a very short life span. They are supposed to be very representative of what a normal liver cell would be like. They are not immortalized in any way. And all of the work I will show you is in these primary cells. And by the way, we’ve done this work in multiple donors, up to seven different donors, so this isn’t specific to one particular patient. And what you see here is that first off what we see with the micro-arrays is that the upregulated pathways, I haven’t put them here, but all the up-regulated pathways were consistent with a BET inhibitor, in that we affected genes and pathways important for transcription. So you would expect that. We saw transcription machinery changes; we saw changes in transcription factors, telomere maintenance, and centromere maintenance. So everything that you would expect. And that would be something that would be common to JQ1 and other BET inhibitors. What we saw in terms of the down-regulated pathways were really quite striking and specific to our drug. And we were very excited about that. You can see the complement, cholesterol biosynthesis, fatty acyl-CoA biosynthesis, fibrin clotting, diabetes and acute phase response here. And what you’re looking at is a heat map. So the genes within each of these pathways are listed next to the heat maps. And you can appreciate that whatever’s in blue is down regulated whatever’s in yellow is upregulated. And we looked at even these pathways, we were very struck by the amount of genes that we downregulated. We literally cool these pathways down.

SLIDE 64

(Downregulation of Pathways with Roles in CVD/MACE)

So that was our kind of first look at it. When we actually went in now, and went past just looking at the genes but actually looking at the whole pathway top to bottom. You can see at the top here these are the microarray pathway analyses. Again, they’re in blue. We down regulate all of these pathways. These are actually our top pathway downregulated in liver cells is in the complement. That is our number one effect, with the largest magnitude and reproducible between different donors and different conditions. What’s at the bottom now is actually, it’s an IPA, so it’s an ingenuity pathway analysis to show you what each of these genes is doing in the entire pathway. So normally, if you started with this, every single circle on either side would be clear. If you upregulate a particular gene it would be orange or yellow. If you down-regulate it, it’s blue. And I think I don’t have to convince you that when we saw this we were very excited. We could not believe that we had this attenuatory effect on the complement pathway, acute phase response, coagulation. I’m not showing you and I’m not going to talk about, but we saw the same for NF-Kappa-B signaling, we saw inflammatory signaling all cooled. So we really were having these anti-inflammatory effects. We knew we had indication that this was happening probably about eight or nine years ago when we were focusing on vascular inflammation, but we were really delighted to see that this was happening in liver cells; and this is the site of action for our drug.

SLIDE 65

(Apabetalone (RVX-208) Downregulates the Complement Cascade

So this is the complement cascade, and if you can believe this is the most simplest slide that I could find of the cascade. Because it’s very complicated, convoluted, there are a lot of players. In essence, there are three different ways that you can activate complement. Complement is an innate immune system response normally to microbial pathogens, at least that’s what historically it’s been known to do, but of course, we now know that it plays great roles in all types of diseases. The red arrows represent the targets. Some of those genes that we’ve seen in the microarrays that are downregulated. So where drugs for example in orphan and I’ll mention that at the end, may target one of these, at the level of C5 is one example, Eculizumab (Soliris, used for PNH), we modulate the entire cascade by modulating the level of each of these. And I’d like to point out, we don’t shut anything down completely. It is a cool down; it is attenuation. And I should point out also that in any of our clinical trials to date, we have never seen an increase in infections, or infestations, which would be something that you might worry about if you are shutting these down completely. So we feel that what we’re doing, and what we’ve observed so far, is that we’re cooling or we’re modulating this cascades. And this probably for cardiovascular disease, especially at sites of local inflammation such as the plaque, is really beneficial. So these mediators are made in the liver, and the mode of action is in the blood and in different tissues, and we think that by affecting it in this fashion, we’re having a benefit on MACE.

SLIDE 66

(Apabetalone (RVX-208) Downregulates the Complement Cascade)

So this slide summarizes really a lot of work that we’ve done. I’ve only shown you a little bit of that work, but as I mentioned most components of this cascade are produced in the liver. Microarrays from primary human hepatocytes in multiple donors have all consistently shown effects on this pathway. We, of course, the first thing we did after that, so you look at the microarray data and you say this is great, but does this really hold true at each of the genes, when you actually go in and do the work on each of these genes? And initially we went into hepatoma cells, so these are cell lines very commonly used in any type of research, Q7 HepG2 cells. And we found we downregulated these components in those cell types. Of course we went in to the primary human hepatocytes from which the microarray came from, and in multiple donors, we saw the same thing. And then we wondered well, if we’re decreasing basal levels of these complement factors, what happens in an inflammatory state? So in a normal human or in these in vitro systems, you’d want to stimulate with an inflammatory mediator, the levels go up, and then you add 208 and see if you can bring them back down. So we did that by co-administering our drug with the mediator, we did that by pre-administering the mediator with our drug. And either way we saw levels downregulated to basal or slightly below. So we were very happy that this happened in an inflammatory state, which would be the case in a human with cardiovascular disease. Finally, and so that data you can kind of see it over here, I don’t give you each of the components here, but these are MRNA expression changes in five of the complement components. You can see that anywhere from, so this one was not statistically significant, but you can see that from these we’re seeing 50 40, up to 80% down regulation of these at the gene expression level in primary human hepatocytes, which are what this is. Over here. So from our old days of looking at mouse studies with Apo-A1, we had a mouse that had a humanized liver. So one of the challenges of studying lipoproteins in mice is that their systems are very different from humans. So we worked with a group at the time on a chimeric mouse. So in essence, this mouse had hepatic cells of human origin. So you could use human probes and you could look at all of these proteins with human antibodies and such. And when we went back now and just had look at what happened in these humanized chimeric mice, again the factors we actually saw in vivo, and we didn’t, you know, we recently did this work, we realized that we were having these effects in vivo too. So in treating these animals, we were really seeing changes in their gene expression of these complement factors.

SLIDE 67

(Apabetalone (RVX-208) Downregulates the Coagulation Cascade)

So similarly to the Complement cascade, we looked at the same thing for coagulation. This was again, one of our top five or six pathways that we downregulated. The red arrows again demonstrate on the microarray where we saw gene expression changes, and of course to confirm that, you need to do each of these genes individually in the cells.

SLIDE 68

(Apabetalone (RVX-208) Downregulates the Coagulation Cascade)

And that’s what’s summarized here. Again so, this was done in multiple donors of primary human hepatocytes across multiple parts of the cascade. Here is the data. This is again from primary human hepatocytes. These are clotting factors. I haven’t told you which ones they are, but you can appreciate statistically significant that we really see cooling of a lot of these in the liver. In the mouse model I previously mentioned, same thing. We see decreases up to 20-50% in some of these factors. So we were very excited about that, because that helped bridge the gap we had identified with what we were seeing with MACE, with what we thought our drug was doing.

SLIDE 69

(Apabetalone (RVX-208) is Anti-Inflammatory and Anti-Atherogenic

So on to atherogenic and inflammatory mediators. So I just told you about complement coagulation, but of course, we were always interested in atherosclerosis and vascular inflammation.

So this data here is not now from liver cells but now from whole blood. So we took blood from three healthy patients. We took it out, we treated it ex vivo with our drug, and we looked at what happens to global gene expression changes in these cells. And what you see over here is these are all the pathways that we affect in whole blood. So these are monocytes, leukocytes, these are all types of cells that might be involved in plaque build-up as well as plaque inflammation. And you can appreciate that a lot of these pathways are involved in inflammatory signaling, endothelial activation, plaque stability, platelet biology, macrophage biology, so this was very consistent with what we had seen previously, probably about six or seven years ago, with our vascular inflammation work.

And then when we looked at our top, 64 in this case, genes which we downregulated, or upregulated in fact, in response to RVX 208, and we looked at what are these genes doing, what are their functions, we found that a vast majority of them were pro-atherogenic genes. And in blue, you can see that we really downregulate these, some of them as early as three hours, some up to 24 hours. The anti-atherogenic genes which you might want to enhance, we saw about a 50% increase in some of those, at least in the ones we looked at. Fifty percent (50%) of the genes that we looked at had an increase in those anti-atherogenic genes.

Now what was truly exciting to us also was that based on that, we identified novel biomarkers that were really new to us.

CCL2 (MCP1), that’s actually one that we had looked at before. That’s involved in attracting leukocytes to plaque, and we knew we downregulated it. So we were really potentially decreasing inflammation.

CCR2 is the receptor of that.

A new one for us was Parc. CCL 18. So Parc is produced in plaque. And I’ll show you in another slide here that Parc has been linked to, it’s actually known as a signature gene that goes up during acute myocardial infarction. So the fact that we were downregulating it in whole blood was really exciting. And we saw similar effects with other tissues that we’ve looked at.

Osteopontin (OPN) is another one I’ll mention in a little bit more detail. Osteopontin is also a predictor of MACE so it’s a biomarker known to predict MACE. Its levels are linked to MACE. It is also a marker of liver injury, which for us was very important, because we were still trying to figure out what’s happening with our ALT elevation. So the fact that we really downregulate osteopontin was a wonderful indicator that we were not inducting any kind of liver injury or tissue damage.

Fibronectin and some others are listed as well.

SLIDE 70

(Apabetalone (RVX-208) is Anti Inflammatory and Anti-Atherogenic)

So back to some of the ones I just mentioned. A recent study, well a few years ago now, by Muller et al. (EuroIntervention 2011) looked at sites of occlusion during an acute myocardial infarction. And they actually took the blood from these sites, and then compared it to peripheral blood, which was blood further away from the acute myocardial infarction occlusion. And they identified seven genes that were completely upregulated in those patients that were assayed for this. And when we looked at those seven genes, we inhibited four of those seven, and they were in our top ten genes affected. So that’s what you see here. Fibronectin was one of our top genes, that was actually the highest inhibition, was on Fibronectin, at three hours in whole blood. You can see MCP-1, PARC, and Osteopontin. So these are really biomarkers of occluded plaque, and the fact that we were downregulating them to this level in whole blood was very exciting for us. This confirmed the anti-atherogenic anti-inflammatory effect that we were starting to think is part of the big picture of what we’re affecting here.

SLIDE 71

(Apabetalone (RVX-208) Reduces Osteopontin Expression)

One slide on Osteopontin. So we went in of course and looked specifically, this is in human hepatocytes. This is actually in cells that are U937 cells that we’ve differentiated into macrophages, which are a big player in plaque. And you can see that we really downregulate osteopontin by 80-90%. And then here’s the data from the microarrays, and we inhibit it here 70-85%. As I’ve mentioned it’s a phospho protein, but it predicts MACE in patients with CAD. It has a role in biomineralization, potentially a role there with the ALP that Kam mentioned. And it’s a marker of liver injury. So when we did our work, which, I don’t think we’ve really talked about the safety too much, but when we did some work with safety expert Dr. Paul Watkins, he said to us, “what does your osteopontin look like in your patients that have ALT elevations”? And he was very concerned that if it’s high, then you’re seeing some kind of inflammatory response. And we did this work and we actually also looked at clinical samples in those patients. And we didn’t see the increases that you would expect if you were really inducing any kind of liver injury. So we were excited about that as well

SLIDE 72

(Follow Up Clinical Analysis)

So really, what’s the next step? What’s going to convince us that this is truly happening in cardiovascular disease? Well you need to look in the clinical samples. And we are so fortunate to have clinical samples archived from all of our clinical trials up to date, treated with RVX-208 from three to six months from these patients. So what we initially did is we went in and we took our best, our favorite patients, and we did a small subgroup analysis. And we looked at complement, we looked at coagulation, we looked at inflammatory mediators across the board. And we were happy to see that we saw the changes we saw in vitro in these clinical samples as well. But that said, these were small subgroup analyses. And so to really confirm is this really truly happening in our patients, we’ve actually embarked upon a large investigational study with a group out of Colorado. And they have a beautiful elegant assay to look at 1,300 plasma proteins. So not just the 40 or 50 we’re interested in, but across the board 1,300 proteins in our entire cohort from the ASSERT study and some ASSURE patients. And what we’re hoping to see is that we not only see these markers correlate to the in vitro work, but to see a dose-response in these markers as well. And hopefully to identify novel biomarkers that we haven’t yet thought to look at.

SLIDE 73

(Summary)

So in summary, mirco-array and gene expression analysis individually and in our cell work has demonstrated these anti-inflammatory effects and effects on complement coagulation. We’ve been able to do this in liver cells; we’ve been able to do this in whole blood as well. Our preliminary data from the clinical sample analysis is in line with the data we’ve observed in vitro, which has been really wonderful. As soon as you see that, then you know that this could be part of the biology that’s really driving the MACE reductions. It’s not just the reverse cholesterol transport but it’s these anti-inflammatory effects that are known to have a role in cardiovascular disease. And of course, the biomarker studies are really the way for us to move forward on that.

SLIDE 74

(Orphan Diseases)

And one or two final slides for me. Based on what I’ve shown you on complement, we got pretty excited because targeting complement in orphan disease, complement-mediated diseases in orphan disease – you know, that’s the holy grail of treating some of these very rare diseases. I mentioned to you Eculizumab. It is a drug that right now, it’s one of the most expensive drugs in the world at half a million dollars a year per patient. And it targets C5, which is one of those complement components I mentioned. So we believe that, if possible - if what we’re seeing in cardiovascular disease patients is any indication of what we could be seeing in patients that actually have an over-active complement cascade, such as in paroxysmal nocturnal hemoglobinuria, then we think we’re going to have an impact on orphan diseases that are mediated by an over-active complement. So our plan moving forward is to take 208 into a proof-of-concept trial in PNH patients, to first see if we’re seeing this translation into the clinic. And in patients that have too much complement activity, which results in hemolysis and all of the terrible complications of this very rare disorder. There’s reason to keep moving forward into particularly other indications, and some kidney ones, you know with the effects that we already see on the kidney. Hemolytic uremic syndrome is a mean one, and glomerulonephritis, which are both driven by complement.

At the bottom is just a graph just summarizing. You know, 208 is just the first one we’ll move forward but there are others. We do have a whole host of compounds that we haven’t yet moved forward into the clinic, because we had of course, 222 and we were so happy with it. Sorry, 208. But there are others, and we have set up screens for them now, more from an orphan perspective and of course cardiovascular disease as well.

SLIDE 75

(Orphan Disease Overview)

My final slide is just an overview of what an orphan disease is. You can see the low prevalence rates. PNH are the ones that we’re going after now. But if you can believe, 75% of these patients are not treated adequately because of the cost of Eculizumab and all of the tough adverse events and complications of taking it. There really is a space for us to try a drug like 208 that would potentially keep complement in check and prevent the kind of life-threatening thrombotic events from occurring that would put somebody onto the Eculizumab. So there are seventy-five percent of the patients out there with this disease that are not treated. They’re just treated with blood transfusions and platelet therapy and iron for anemia and all of that. So we really think that there’s an opportunity here. And hopefully if 208 does what we think it does, we would move that forward, but there are other molecules that are just waiting in the queue. So…

SLIDE 76

(Agenda Slide with items 7 and 8 highlighted: 7. Market Opportunity: Ken Lebioda; 8. Primary Market Research: Ken Lebioda)

…with that, I will pass off to Mr. Lebioda.

Ken Lebioda: Thanks Eva. Fantastic science. My name is Ken Lebioda. I’m the Senior Vice President of business and market development.

SLIDE 77

(Residual Risk in Vascular Disease: Pipeline Value)

So we’ve talked a lot today about the residual risk in high-risk vascular disease. It’s a huge commercial opportunity. Deutsche Bank put out a very good report a few years ago, focusing on just the residual market in cardiovascular disease. They stated that it was worth up to 90 billion dollars. A lot of good drugs are out there right now, but there still is this huge unmet medical need that has been outlined by the key opinion leaders earlier today.

So we are entering into Phase III within the next month or two months. And when you do comparators, it’s quite remarkable when you look at what are these assets worth. In the hands of big pharma, they’re worth a lot. These are just some examples where the, CETP class; Pfizer had one, Torcetrapib; the Dalcetrapib (Hoffmann-La Roche); Darapladib, which was GSK’s. Unfortunately, all of these drugs have failed, but at the time, they ascribed huge market value opportunities for these pharmas if they worked. So here were the pipeline values of those. So this is the reason why we’re so focused and so excited about what our opportunity is for reduction in these types of high-risk patients.

SLIDE 78

(Apabetalone (RVX-208) Value Proposition: Efficient Residual Reduction of MACE in Diabetes)

We think we have a very unique value proposition for physicians, for patients, and more specifically for payers. In diabetics, there have been a lot of studies out there. And there’s been a new one in SGLD2 inhibition from Lilly that appears to have had pretty good results for MACE reduction over a four-year period. But if you drill down into some of the data subgroups, it probably provides more questions than answers. But when you look at glucose reduction as it relates to efficient MACE reduction. A lot of these studies highlighted that there was really no effect. And that’s what we want to come in and change the paradigm. Our paradigm is to create a new MACE paradigm that in high-risk residual patients, we want to have an efficient MACE reduction, and our early data thus far illustrates that we have a very strong potential to do just that.

SLIDE 79

(Potential Target Indications: High Risk Vascular Markets)

So we are very target focused. When you look at the three big groups that we’d be focusing on, diabetes with low HDL, underlying coronary artery disease. That’s what BETonMACE is going to be focusing on. As a subset with the BETonMACE, we estimate based on our historical data, that we will have somewhere in the neighborhood of about fifty percent-ish CKD patients. That’s the bottom left. So in BETonMACE we could have up to three, four or five hundred CKD patients. We’re going to look at that very carefully as well. That’s why we brought Dr. Zadeh on. And then there are other opportunities in high-risk residual vascular disease, such as peripheral arterial disease and so forth. So in essence, this very enriched, very targeted group still represents close to eighteen to twenty million patients. So it’s a huge huge opportunity for us.

SLIDE 80

(KOL Market Research)

So what we’ve done, is we’ve done active outreach to KOLs (key opinion leaders), more specifically in the United States. We are going to do active outreach to now physicians in Europe and Australia. But we hired this one strategic consultant on numerous occasions. And we asked the question with twenty physicians, most were in the United States. Five were in the European Union. Cardiologists, endocrinologists and nephrologists. These are the focus groups that we’re focusing on right now. We also interviewed five payers in the United States who cover a lot of managed care lives, up to 170 million lives, so about two thirds of the population in the United States. And it was pretty clear what was coming back from them. There is definitely a significant unmet need. And they like the fact that we are really targeting on the patients that we will make a big difference. As Kausik had lain out earlier, we don’t want to treat everybody, we just want to treat patients who we think we can have a real impact on. So we just wanted to kind of highlight some of the findings from this.

SLIDE 81

(KOL/Health System Affiliations)

So here are the physicians that we spoke to from this first group of patients, sorry, of physicians that we spoke to. All key opinion leaders, cardiologists, nephrologists, and endocrinologists. Some with, you know, the past president of the French Cardiology Society, some from New York, North Carolina, etc. etc. And it was interesting. A lot of them really, before we started this process, they really didn’t have a good idea about BET inhibition and the potential to reduce MACE in these high-risk patients. So after this exercise was completed, 100% of all the physicians stated that whenever this clinical trial appears, they would love to be an investigator for the Apabetalone. So we were very pleased to see that.

SLIDE 82

(Endocrinologists and Cardiologists Unmet Need)

So when we asked some of the questions, and those are highlighted in the blue bars. The level of importance of MACE reduction in these target groups, type 2 diabetics, low HDL levels. It’s very consistent for both endocrinologists, cardiologists – this is just some examples - and nephrologists. And these are just some examples. They state that there’s definitely a very high level of unmet need, and they really want to see something there.

SLIDE 83

(Novel Approach to MACE Reduction)

And so another question was asked, where, the importance of a new approach to reduce MACE. So not LDL lowering, not sugar or glucose lowering, but a new approach. Which we firmly believe and the data suggests that BET inhibition is that new approach. And there was still a very high level of importance and a high level of voting that yeah, they really want to see that. That we want to have a new approach.

SLIDE 84

(Select BET Inhibition)

This just goes back to when we started this process. The current knowledge of epigenetics and BET inhibition was fairly low. So we’re a small company. We’re doing active outreach now. We’re talking to more and more people, such as yourselves and in the medical community to make sure that our story’s being known. And so it was nice to see that the level of interest after this exercise was very high. They said, OK, we think that the mechanism of BET inhibition was a viable mechanism to reduce MACE.

SLIDE 85

(Potential Prescribing Behavior)

So when we asked the question of also potential prescribing behavior, and this is based on the fact that they had reported data in here that there’s major gaps in current drugs that really aren’t doing an efficient job of reducing MACE. They said that I we can fill that gap, if we see what we hope to see in BETonMACE, a reduction of 20, 25, 30 percent in major cardiovascular events, these are the consistent results in nephrologists, endocrinologists and cardiologists as to how they would prescribe the drug. So by year two, you can see a pretty high level of prescribing, which indicates that these individuals are looking for a solution for these high-residual patients.

SLIDE 86

(Importance of MACE Reduction)

Now these are questions more specific to payers. And Kausik had lined out earlier that it’s important, that there’s the four Ps in the spectrum of pharmaceutical drug development. You have your patients, you have your physicians, your pharmacists, but you have your payers. So it’s great to have clinical data, but you’d better be efficient in lowering events. And that was the concept of the number needed to treat. I always like to say that the number needed to treat is like golf. You have to shoot below a 70. If you can shoot below a 70, and your drug is priced appropriately, the payers really like you and they start to pay attention. And reimbursement is much much easier. So that was very important because our, and you’ll see in subsequent slides here, that our current data on number needed to treat is very low.

We also basically asked the question, which is, “if you have good glucose levels that are managed, do you think those patients are still vulnerable to cardiovascular disease?” And these key opinion leaders said absolutely, yeah. Which kind of ties in the fact that you can modulate and control sugar levels, but however, we’re still seeing these large diseases, heart attack, stroke and death. That’s why we’re here. We want to lower that.

SLIDE 87

(Preliminary NNT Analysis: Modeling)

So this is our early preliminary number needed to treat analysis. And the way you have to look at this analysis, is you have to look at it as annualized over per year. And currently from our pooled ASSURE and SUSTAIN, we see about a 21 for NNT. So this is exceedingly great for us. We do have to try to replicate it, but in BETonMACE, this is almost too good to be true. But it’s a very good signal that if we see anything below 50-60 we’d be delighted. And that is represented by about a 25 to 30 percent relative risk reduction. This is just to highlight what we’ve seen so far.

SLIDE 88

(Potential Pricing)

So when we talked to the payers, and we said,” If you see 25 to 30% I mean, what are you thinking, or 20%”? How could we start to price model this? Which helps us understand much better, what is the value of this asset, RVX-208 at its current and in future stages of development? So here are the numbers that the U.S. payers said that they’d be very comfortable with. The four to five thousand dollar price point; if you can keep it below that, you get a preferred co-pay. And so our modeling right now is somewhere in the neighborhood of between three and forty-two hundred dollars per year. And if you see that with number needed to treat below thirty, below forty. $100,000 of drug to prevent an event is actually very very efficient. When you look at some of the data that is out there on other LDL lowering drugs, some of their numbers are coming in at about eight hundred or nine hundred thousand dollars. So that is a very important value proposition that we want to bring to the payer community.

SLIDE 89

(Prescribing Behavior – SERMO Survey Findings)

So this is a second outreach that we did, which covered almost two thousand physicians. We had 625 primary care physicians, 550 cardiologists, 420 endocrinologists, and 325 nephrologists. And we asked a series of questions, but this was a very important question. Where we said, “If select BET inhibition in a large Phase III prospective study illustrates this efficient reduction of MACE, would you prescribe? What’s your level of interest? “

And most of the physicians here stated that if you see 25 or 30 percent, with pretty much a high level of interest, eighty-five percent of these individuals said that they would start to prescribe. So this starts to tell us that these new approaches such as BET inhibition, if they truly make a difference in prospective studies such as BETonMACE, the value of this asset is very significant.

SLIDE 90

(Summary)

So in summary, high risk vascular disease retains a very high level of commercial interest and a high level of value for everybody within the pharmaceutical and life sciences industry.

Our understanding right now is that there is potential up to 18 million patients in the top seven markets. This doesn’t even include China or BRIC countries. We just closed one of the largest single molecule deals with a very good partner, Hepalink, in China. So we’re delighted by that.

Efficient MACE reduction is a very important thing that everybody is going to be looking for. And so our early market research illustrates that, if we see what we hope to see in BETonMACE, there will be a very strong pull into the market from these key opinion leaders. We are going to continue that effort with more outreach in physicians in Australia and Europe this year.

And we’ve also worked with leading individuals such as IMS and others on really starting to build very very accurate early pharmaco-economic models, more detailed than what you saw in our Numbers Needed to Treat. But they’ve done some early, and HEOR means Health Economics Outcomes Research, Number Needed to Treat and other different variables that look at the value proposition and the early reports that we’re getting from them right now has illustrated that Apabetalone looks very promising. And so on that point…

SLIDE 91

(Agenda Slide with item highlighted: )

… I will move it over to Don

Don McCaffrey: Thank you Ken. I’m just going to summarize a little bit here and then we can get right to the Q&A. As you can see, it’s pretty exciting data that we’ve compiled over the last two years and what we’re going forward with. So we have a lot to work with, and it’s getting pretty exciting.

SLIDE 92

(Financial Profile)

So just a quick financial profile. We are still Canadian stock listed only. We are looking at moving to the NASDAQ, and we hope to do that soon. We have talked to NASDAQ and everything seems to be in place. We have Board approval. So we’re excited. We’re also sitting on the most cash we’ve ever had, so that is a real plus as well.

SLIDE 93

(RVX-208 Additional Clinical Plan Potentials)

I’m glad that Ewelina had to pronounce all those words in the potential indications that we can go into in complement, but there are a lot of directions here for us. And this has been very well planned, because we knew that we were going to have about a three-year gap in data while the BETonMACE trial is in full function. So we’ve designed it so that there will be a lot of value and inflection points during that three-year period.

Chronic Kidney Disease is a huge potential for us. I think you can understand from Kam’s excitement that we really have something there, and we will build towards that.

Peripheral arterial disease. That’s very much a natural, especially with all the anti-inflammatory components going on.

Alzheimer’s. We’ve talked about Alzheimer’s for a while. We were waiting for some NIH funding, which is always in the process. But at the most recent international Alzheimer’s conference, the big study subject, the big breakthrough was the relationship to complement in Alzheimer’s. So we’re very excited about moving forward with that potential as well.

And then of course the orphan indications. Which orphan drugs seem to be very popular with pharma these days? Eight ten years ago everybody switched into oncology, now it’s orphan indications. So to be able to enter those indications with RVX-208 already as a Phase II B drug is fantastic. And to back-up molecules for that program for other indications is even better.

SLIDE 94

(Early revenue opportunities include regional licensing deals and orphan indications)

And we will continue with some of the plans that we’ve talked about over the past. The orphan indications, as we started rolling that out yesterday.

We will continue with regional deals potential as well. We are in discussion. We like regional components. We try to stay away from the main countries that would get you your highest value in global deals. But there are a lot of places where we can utilize regional pricing for bringing in revenues at a lot earlier point.

SLIDE 95

(2015- Milestone Check List)

And of course the final milestone checklist. We’ve had a good year. Proven MACE reduction. We’ve brought in $82 million in the last year, so that was pretty good. And clinical launch of the Phase III trial, the design is already done, the launch is imminent here. And presentations in just about every major event there was last year. We had, I think it was 12 accepted. I just list a few of them here. But it’ll be the same next year. You’re going to hear a lot more about us. Especially now that we’re rolling this data out. It’s really quite exciting. And the business development is ongoing in regional and other areas.

So on that, we’re going to break and…

SLIDE 96

(Q&A)

…go to Q&A. There will be two microphones floating around the room. Sarah’s going to hand them out. And love to hear your questions, looking forward to it. Thank you.

Test these mics, make sure they’re on. Yup. Alright do we have some questions from there? Look forward to any of them. OK. Sarah will bring you the mic.

Q: Hi Good afternoon. I’m going to ask a question about the clinical trial period. It’s a period estimated to be two years, one hundred and four weeks. Is that something by design, something particular to you, something you’ve been advised by the FDA? I’m curious about the background.

A: It’s an event-driven trial. So looking at the background rate in previous studies of the number of MACE events, we realized that we required 250 of them, and the average exposure to gain this based on previous studies is eighteen months So if you then have a year, year and a half to recruit the patients it comes to two or two-and-a-half or three years. So it’s actually designed as to include the period that we feel that we need to have the 250 events.

Don: Next question, please. Don’t be shy.

Q: Much of your data shows what happens when a person has diabetes. However, in the civilized world mostly, diabetes is under control for the patient with glucose control with high blood pressure etcetera, more or less. To what extent does your information therefore have to be modified in comparison?

A: So the problem with diabetes is that it is progressive and even when you have good glucose control that you actually still get progression of disease. So if you take somebody who’s had diabetes for about ten years or so, even, it doesn’t really matter what the range of HbA1C, the glucose control is, they will still have a high level of progression. Because the population that we are targeting particularly has the highest level of risk, they’ve had a heart attack you know, recently, and they’ve got a factor which is not going to go away. So even when you basically control blood pressure, glucose, lipids, etc. just having diabetes just accelerates this whole process. And then if you look at for example the complications, like if you develop renal disease or microvascular disease, it starts to go up like this. And so, if you like, the best way to actually not get those complications is not to have diabetes in the first place, but once you have it, you’re on this trajectory. And all you are potentially doing with glucose control is just slowing down the trajectory, but it’s still progressive.

DM: Yeah. I’d like to add to that. In the recent ACCORD trial, which was run by Henry Ginsberg here from New York, who also sits on a committee, our steering committee with this gentleman, he showed in that trial that no matter how well your glucose is maintained, that patient is still going to die from cardiovascular disease at a rate of about sixty-eight percent.

Q: Yes, your phase II data seems to be very encouraging, and you are about to start a Phase III study. I just wanted to get some sense of, besides the data you presented for the Phase II study, is there any other - what’s the differences really in terms of patient cohort between the Phase II and Phase III, as well as, was there any other data in the Phase II suggesting that the MACE outcome of the Phase III can be achieved or potentially be achieved?

A: You know in Phase III we have targeted that group of patients which did best in the Phase II, the ones that had the greatest MACE reduction. So whereas our Phase II was cardiovascular patients, usually with stable cardiovascular disease, our Phase III is going to focus on the highest-risk patients where we saw the highest benefit in Phase II. And that’s where our confidence is that we will meet the primary endpoint in Phase III. They are all patients with diabetes, low HDL, extremely high risk.

Q: I recall that you presented that the baseline for the Phase III MACE events was about 10 percent or 11 percent, is that for that particular cohort, or is there more to it.

A1: Initial answer from me is that it’s that particular cohort based on the examined study, but obviously, Professor Ray has got a lot more experience on this than I have.

A2: Yes, so if you look at the modeling that’s been done, there was a trial called, and it’s the only one recently that’s been done where you’ve had patients straight after a heart attack, and it was called EXAMINE and it was done with just a pure glucose lowering agent. And it just showed that the compound was safe. There was no benefit on MACE; there was no harm on MACE. It improved glucose a little bit and this is the FDA requirement. And so, because everybody in that study had to be diabetic as well, the event rate at one year is what you can predict from that. Now, what we will have is probably a slightly higher event rate, because we’re also going to be recruiting on the basis of a low HDL. So the event rate that we’ve actually picked is a more conservative one. And when you actually add to that the fact that you’ve got a low HDL, we would expect a slightly higher event rate. So when you apply the relative risk reductions, we actually have more chance of success, you know, along the lines that you’ve just asked, because you’re enriching for people who are more likely to develop cardiovascular disease in the eighteen months, two years of follow-up.

Q: Yes Don, I think you mentioned in your opening remarks, that to achieve 250 events, it will take about three years. I believe that’s what you said. But you also said that there would be many opportunities for interim analysis along the way; can you expand a little bit on that?

A1: Not interim analysis of that particular trial. The opportunities that I was talking about were new orphan indications that take much much less time. So being able to keep news flow going. We won’t be doing any interim sneak peaks at the BETonMACE, I think that’s highly frowned upon.

A2: There will be obviously safety data. As part of the charter for running this study, there will be safety data and the data safety monitoring committee will look at that. So I think that will obviously be important. And with any drug class that you have, any new one particularly, you need not just the efficacy but the safety. So the fact that as we go along, getting a positive sort of sign, that no, there’s actually nothing to worry about and it’s safe to continue, is actually going to be very encouraging for the study as well. All studies have an analysis plan like that, so we won’t be any different. But in general, we won’t be doing multiple looks, there will probably be one analysis that we will do based on a certain number of events.

Q: For a patient in the eighties who has no history of diabetes himself or in the family, and who has good blood pressure, lipid control, glucose properly, weight control, the question is how much of a danger is it to inflammatory, that is in the vascular can be have inflamed, as being a cause of a blockage? How much of a danger, I think there’s a test, what is it, C something can be tested, and what can be done based on present drugs?

A: So in terms of, all of us have some level of inflammation, and the more risk factors you have, the higher the level of CRP, which was the marker you’re referring to. It’s a non-specific marker. It’s not a target for treatment. So specifically in your patient population that you’ve just described, if everything is otherwise OK, but CRP is high, that is a marker of somebody who is going to die more readily or develop a cardiovascular event. We don’t have specific treatments that really lower that. There are treatments that are being developed, that will target inflammation. So our drug is one drug that would we know, we showed you some data in people with a high CRP the clinical event reduction was lower in that population (I think maybe he meant to say higher, as in clinical events were lower, and reduction was higher), so we know that that drug worked. There are two other drugs being tested currently. One is a monoclonal antibody, so it will be very expensive. The other one is a drug that’s used for arthritis, methotrexate. That’s an NIH trial that’s being done. But if you look at what happens in the monitoring, in terms of reducing the white cell counts, I’m not really sure that’s a drug that I want to be taking for the rest of my life, so you know, irrespective of what it shows on that benefit. So we do have an unmet need for inflammation. And that’s one of the things that really excites us about this compound, is that it actually reduces the genes that govern inflammation. It does it very very quickly. But it doesn’t completely knock it out so that you then are more at risk of infections, at least, you know, in the Phase II data we’ve seen.

Q: Based on these studies, is it more danger of blockage in the artery from inflammation than from higher lipids?

A: They are both complementary. So if you think about lipid levels, if you have a high cholesterol level and you have a high CRP, that’s a marker of the worst group. And if you have both low, that’s a marker of the best group. If you have one or the other, that’s the middle group.

A2: If I could also expand on this. There are studies that may suggest that other risk factors that our colleague astutely alluded to are even more important. Now, I’m not here as a kidney specialist to say that cardiologists were wrong for the past forty or fifty years targeting cholesterol. But we have already targeted cholesterol for the past forty or fifty years. And we are already doing this. And we are already lowering this in most patients. So yet, we still have cardiovascular disease burden and events. So therefore, that’s why there are studies that are showing that those non-cholesterol related risk factors are as important if not more important than.

A3: I think without doubt it’s that today they’ve become more important now. Because if you think about the biggest bang for your buck and you start here and you’ve already reduced a lot of the blood pressure and risks, well the law of diminishing returns states that if you keep targeting that particular pathway you’re going to get less and less return. And all of these treatments are going to be add-ons. So then, from a payer perspective people ask, hmmm do we really want for that NNT (numbers needed to treat)? Now on the other hand, if you target residual risk and what else is driving, as you very nicely said, those recurrent events, well actually they become much much more important now. And if you actually target those, now you actually modify something that you were never able to modify before. So, you know, in the present environment of best clinical care, these novel treatments, niche areas that they might seem, but they’re actually probably going to give you a bigger return.

Q: This question is probably for Don or Ken. It’s in two parts. You’re well-funded at the moment. Might you expect if all goes well that you will not, or might you need further funding to get over the line with your first product to the market? And secondly when might you expect if all goes well to get that first product to the market? Will it be two years?

A: The first product to the market could be two years with an orphan indication. And as far as the funding questions go, I always answer that the same way. We’re a biotech company; we’re always in funding mode. We’ve done very well. We’ve seen the price go up quite a bit. So it’s allowed us a little more free room, elbow room on the open markets. We will never say we’re not looking for money. We would like to at much higher rates do something. We’re also still in discussions with other regional licensing potentials. And/or we would even look at things like first right of refusals, which would put a lot of money into the coffers and allow us to really expand on some of these programs

Q: A follow up question here. In terms of the Phase III study, the primary endpoint is more narrow MACE instead broad MACE. What’s the rationale behind that and what kind of discussion did you have with FDA to get that. And another one for Don is what’s the cost for the phase III study?

A1: Well, the rationale behind it is that that was requested by the regulators. The regulators wanted the hard endpoints as the primary endpoints, with the broad as the secondary. And it’s really precedent in the regulators that we consulted, that that’s what they required in the past.

A2: And you asked about the cost of the trial. We’re not fully aware of it yet because it is event based, 250 events. I’m really hoping they get there way faster than they think they will. But we will keep the market updated on that cost as we go through the next three years.

Q: (About as close as I could get. May need some revision. Time 1:41:43)

Just wanted to comment on the conversation several questions ago. Statins as a class reduce C-reactive protein approximately 15%. And it’s thought that one of the ways that LDL-reducing medications work is that they reduce inflammation. The mere fact of lowering LDL has a potent anti-inflammatory effect. Also alluding to Paul Ridker’s c-reactive protein work in the JUPITER trial, there’s a group of patients that have a low LDL but they still have a high C-reactive protein. These people still have cardiac events. So perhaps it’s LDL and C-reactive protein. But statins as a class do modify C - reactive protein by approximately 15%.

A: I absolutely agree with that, that statins do reduce CRP. I mean you’ll have heard about the latest class of lipid-lowering agents, the PCSK9 inhibitors, they have as big an effect on cholesterol, but they don’t lower C-reactive protein. So that would probably suggest that the statins have an effect that is separate from the LDL lowering effect. And that might be, that the presumed mechanism is intrahepatic production of CRP. But we know that inflammation is definitely associated with adverse outcomes. So targeting both makes a lot of sense. This is why obviously there’s an interest. There is the Novartis compound in testing. There’s the NIH trial that I was talking about. And we’ll effectively be the third, but with a very different mode of action.

Don: Any other questions? Well, I really appreciate everybody coming today. It was very nice start to share some of this exciting data. As you can see, we’ve got a lot on our plate. We’re financed up for it, we’re very excited, we’ve got a lot of support from key opinion leaders around the world, and we’re looking forward to moving forward. Thank you.

Resverlogix Corporate Update Tuesday September 29, 2015

http://services.choruscall.ca/links/resverlogix150929.html

SLIDE 1

(Title Slide: Resverlogix Corporate Update September 25, 2015)

My name is Don McCaffrey. I’m the President and CEO of Resverlogix. I know a lot of you in the room. It’s a pleasure to have you here today. Especially with all the traffic out there and all the other personalities in town, it’s nice that you were able to make it.

SLIDE 2

(Today’s Agenda)

So let’s go through the slides. I’m actually really looking forward to today, because unlike most presentations, I only have to talk for about three or four slides and we have all our experts taking care of the rest of the time. So we’ll go through the introduction; the unmet medical needs in metabolic diseases; we’ll talk about some of our past clinical trial presentation; phase III clinical study planning; the unmet need in chronic kidney disease, which I think you’ll find very fascinating, the epigenetic mechanism, this section is going to detail a lot of what we’ve been doing in the last two years as far as the research behind our exciting multi-modal approach; we’ll talk a little bit about market opportunities, because I think that helps you understand the potential for this market; and the primary market research that’s already been done. And I’ll finish up with some discussion at the end.

SLIDE 3

(Today’s Presenters)

So I’ve already introduced myself. Our first speaker will be Professor Kausik Ray, and as you can tell from all the initials behind his name, he’s one of our key opinion leaders. Then we’ll have follow-up from Michael Sweeney. He is our Vice President of Clinical Development at Resverlogix. And in past history, he was about eleven years, I believe, at Pfizer across the street, and working on many of their clinical programs. Then we’ll have Kam Kalantar-Zadeh, and again as you can tell he’s the other key opinion leader from all of the initials there. We’ll have a discussion about the mechanism of action from Evelina Kulikowski. And then Ken Lebioda will talk a little bit about the business development plan. So they will introduce themselves as they go as well.

SLIDE 4

(Major Opportunities)

Basically, today we really want to cover the major opportunities that we have here. We have a patent life that extends to 2033, so that is very much in our favor. We’re the first and only in-class BET bromodomain inhibitor, and we’re at least eight years ahead of anybody else, so we love that. We’re not one of the “me too” type of categories out there, and we have a very unique market that we can share with you today. We’ve got a very strong safety profile; we’re approaching a thousand patients that have been dosed with this drug. So we know about the safety and we’re excited about what we’ve learned on that, especially in the last six months. The epigenetic mechanism we’ll talk a lot about. And the orphan indications. We announced our first pilot project yesterday, that well be going after PNH – proximal nocturnal hemoglobinurea. There are probably people out there that didn’t know I could say that. My own staff.

SLIDE 5

(Upcoming Milestones)

Alright. As far as the timelines go, we can touch on that as well. We’ve got some really good progress going. And with the main program being the BETonMACE program - it’s a long program, two to three years, so that’s why we wanted to really make sure that there are a lot of inflection points coming up during that time. And you’ll see that today when we’re talking about our program, the orphan disease issues and some of the other business potential that I’ll talk about at the end. So we’ve put some cards on the table for you to write down questions if you want. We will do a Q&A at the end, the panel will come up and we will do a Q&A, there will be a couple of mics around the room to ask questions. So we’re really looking forward to today.

SLIDE 6

(Agenda Slide – Unmet Need in Metabolic Diseases highlighted)

And on that note, I think we will start with Kausik coming up to tell us a little bit about the issues. And there’s an ongoing joke about - there is a square button on here that if you push it shuts everything down. And we’ve got a bet going as to which one of us is going to hit it first.

Kausik: What, you mean that one? Oh, OK, right.

SLIDE 7

(Subtitle Slide: Tackling CV risk in T2D)

So good afternoon ladies and gentlemen, I’m Kausik Ray, I’m from London, UK, as you can tell by my accent. To give you a little bit of background, I’m a preventive cardiologist, and I’ve been involved in clinical trials for about ten years, and population research as well. So we do a lot of the large-scale epidemiological studies. So I’ve spent really a good part of my professional life looking at diabetes, lipids and cardiovascular disease risk; and I’m going to share some of those thoughts with you.

SLIDE 8

(Slide says Diabetes is a global public health challenge)

So really, the first and obvious thing is that there’s no point in developing something, if there isn’t really a big public health need.

SLIDE 9

(Prevalence of diabetes in 2030)

And we have a big problem when you start looking at diabetes. This is a global health challenge. So if you look at the projections for diabetes from where we were in 2010, with about 285 million people affected - Diabetes pretty much affects every region of the world. It’s not just a disease of developed countries, it’s also importantly a disease of developing countries as well; and so if you look at a small change in the prevalence, going from 6.6 going to 7.8 percent, in absolute terms it’s a huge difference in the number of people affected, to well over 400 million. And just so that you know, in some parts of the world, like in the Middle East, the Gulf countries for example, the prevalence of diabetes is about one in three. So there’s a huge problem there that we’ve got to face. Now why is it a problem?

SLIDE 10

(Estimated life years lost among those with Diabetes)

Well, this is some of the work that we did. So it’s the largest study ever done, half a million people. And I’ll walk you through this. Men on the left, women on the right. If you develop diabetes at aged forty, it takes about six to seven years of life away. This is not counting the heart attacks, the blindness, the kidney failures and all those other things that go with diabetes. It actually robs you of almost a decade if you like, or half a decade of life. Most of those deaths are vascular deaths. There’s an increase in the risk of cancer deaths and things like infections as well. The other key thing is we’re actually seeing diabetes at an earlier and earlier age. You know, so in many places, diabetes is now occurring - this is the adult onset type two diabetes, if you like - is occurring as early as the thirties. And the other, sort of on a lighter note, you’ll see basically if you develop diabetes aged about ninety, it probably doesn’t matter because you’re pretty close to dying anyway, so it’s really not going to have a big impact. But on a serious note, we are seeing people younger and younger, and there’s a huge burden. If you think about the economy for example. If you lose your viable work force disappearing.

SLIDE 11

(Diabetes doubles the risk of vascular events [Emerging Risk Factors Collaboration])

Ok, if you’re not familiar with this type of presentation, I’ll just walk you through this again. This is our work. Over half a million people, so 26,000 heart disease events. Diabetes exactly doubles the rate of coronary artery disease. And your first event is often a fatal one. It also increases the risk of strokes and both hemorrhagic and those that are caused by blood clots, ischemic strokes, and also things like aneurysms, etc. So it’s associated with bad vascular events.

SLIDE 12

(Diabetes and prior MI carry similar CV risk)

This is really just showing you, and I’ll walk you again through this, the risk of future heart attacks by age. So the risk of heart disease increases as we age. And that’s this graph, men and women. Now if you’ve had a heart attack, your risk of a second event, at any age, goes up. And that’s what it looks like, so you’re always going to be at slightly higher risk. That’s in the middle, that’s in the white. But if you basically have diabetes and no previous history of an MI, your risk is the same as somebody that’s had a previous heart attack. And this is why diabetes is often referred to as a heart disease equivalent. And here it’s really important, because that’s the population that we’re going to study in our outcome study. If you’ve had a heart attack and you’ve got diabetes, your risk just gets amplified that much further at any age, so you’ve got double-trouble basically. So here again, we are into the realms of an unmet need.

SLIDE 13

(Diabetes-related CV complications have declined with improved care, but substantial burden remains)

Treatments have improved. This is an event rate, or complications if you like. Vascular events over time. They have declined, because we’ve got some useful and good treatments. And they’ve declined but they remain much higher in diabetes populations compared to people without diabetes. So we recognize that there is still much much more to do.

SLIDE 14

(Slide says Diabetes and MI patients carry the greatest cardiovascular risk) Now

SLIDE 15

(Graph: Kaplan-Meier Cumulative Incidence Curves for the Composite End Point of Cardiovascular Death, Myocardial Infarction or Stroke in the Entire Population With a 4-Year Follow-up and Key Subgroups)

I’ll show you why this is really going to be even more of a problem in somebody that’s just had a heart attack in a second. So let me walk you through this. So this is time at the bottom, and this is the risk of having a heart attack, a stroke or dying. So these are common vascular outcomes. This is the average. And what you can see with an average event rate over time in people at risk is yeah, it goes up. But there’s a wide range of risk. So at the top, this is a group who’ve just had a heart attack in the last year or so. And here, are people for example, who smoke, whose blood pressure is uncontrolled. So they’re not at the same level of risk as somebody who has just had a vascular event, an acute event. So you’ve got to be a lot more aggressive and treat those people. But importantly if you now treat them, actually you save many more events, so treatment’s actually much much more cost-effective when you look at people up here, compared to people down here.

SLIDE 16

(Graph: Risk of Ischemic Events in the Subsequent 4 Years of Follow-up in Patients According to Baseline Risk Category)

So I just want you to focus on the right. This is a big study that was done. So if I take all heart attack patients for example here, that’s the average event rate. But I can actually break that down much further. See if I’ve got diabetes and I’ve just had a heart attack, my event rate is much much higher than if I’m a non-diabetic and had a heart attack. So you can see how important risk factors are additive, and they can amplify your risk of future events. And if you go down the bottom here, for example, these are people who have not got any vascular disease, and the event rates are a lot lower, but the diabetics always do much much worse.

SLIDE 17

(Graph: Four Year Event Rate % in Patients with Prior ischemic events, stable atherosclerosis without prior ischemic events and risk factors only)

Here is an important caveat that we want to throw in. Why are we going to study a patient population with diabetes who’ve just had a vascular event in the last year? Well, just look at this group here. These two groups are people who have at some stage had a heart attack. The top bar is the group that just had an event in the last year. And the other group is a population who’ve had this event at some stage in the past. And then you’ve got some people who might present with angina and have a bypass. So their events are lower. So if you pick a high enough group, you’ve got a group with high unmet need. So as you’ll see later on, Ken Lebioda is going to show some data about what other physicians feel about where we think we should have been targeting these populations. And from your point of view as investors, you might want to consider this. I mean I come from a very poor country called England, you may have heard of it, and we have this socialized health care system. So payers are very keen on absolute risk and absolute deterrent rate. So when you develop drug trials, and you develop these areas, they say we’re not going to pay for everybody across the board. We want those who are going to be at really high risk. And that’s why designing studies to pick up unmet needs like those who’ve just had a cardiovascular disease event and have other risk factors as well, just pushes that bar much much further. And then actually you have a smaller number you need to treat to avoid an event, and it becomes much more cost-effective.

SLIDE 18

(Heading: CV death is increased in patients with diabetes and multiple risk factors. Graph: X axis risk factors, y axis age adjusted CVD death risk per 10,000)

This is just showing you, we know that our lifestyles are getting less healthy. That’s probably not something I want to tell you over a meal. But we know that the more uncontrolled factors you have, if your blood pressure’s high, if your cholesterol levels are high, these are all additive. Now, if you put another layer on top of that and you add diabetes, it really starts to go up much much further. So diabetes tends to accelerate conventional factors.

SLIDE 19

(Urgent need for novel therapies targeting additional pathways)

So if you look at this whole area, there is clearly a need for novel therapies targeting additional pathways.

SLIDE 20

(Reducing CV risk in T2D may need a multifactorial approach)

What do we have currently? If we’re trying to reduce cardiovascular disease risk, we have things that control cholesterol, blood pressure, weight loss is largely lifestyle, there are drugs being developed also for that, glucose control, and drugs that reduce the stickiness of platelets, so aspirin and other agents. And they’ve had an impact. However, in terms of incremental benefit, perhaps we might struggle a little bit, because you’re talking about drugs that are well established. They’ve got a good effect, and trying to target those same pathways might not give you as big a return as targeting novel pathways of things that we know are important. Things like inflammation, the complement system, potentially there’s also added benefit on other lipids not targeted here, and incremental control of glucose. So those are potential new targets. And if your drug helps all of these, you’ve got a much bigger bang for your buck. So there in summary is where we are, and I think here is where we will probably go in the future. And that really leads me to summarize.

SLIDE 21

(Summary)

Diabetes. Your top take home message. This is going to be a major area globally. So we’ve got a lot of people at risk. When you’ve got diabetes, you’re going to be at much higher risk of having a heart disease, but when you’ve had a heart attack and you’ve got diabetes, your risk is going to be even higher. We know that our current treatments actually improve the outcomes, but these people are at life-long risk because diabetes doesn’t just go away, and it’s a progressive process as well. So there really is an urgent need for novel therapies that target all aspects of the pathophysiology of cardiovascular disease in people with diabetes. So I’m going to stop there...

SLIDE 22

(Agenda slide with items 3 and 4 highlighted: Clinical Data Presentation: Dr. Michael Sweeney and Phase 3 Clinical Trial Planning: Dr. Michael Sweeney)

…and hand over to Mike.

Mike: Thank you Kausik. I’m going to take you first for some of our existing data, and then the plans for our Phase III study.

SLIDE 23 (Overview of Apabetalone (RVX-208)

So in summary, Apabetalone or RVX-208 is the first selective BET inhibitor to be in the clinic, and as Don mentioned it is about eight years ahead at least of anything else. As Kausik mentioned, the residual risk in the population we are targeting is very high with diabetes and CAD (coronary artery disease). And we work on an epigenetic mechanism, which Evelina will talk about in more detail later, modifying multiple risk factors and multiple approaches. Those multiple pathways give us a single target, but synchronized multiple biological actions. And we have very encouraging Phase II results, which I’ll show you in a moment.

SLIDE 24

(Apabetalone (RVX-208) has a multimodal approach to accomplishing its goal of MACE reduction)

It is the multiple actions that are important. All of these, reverse cholesterol transport, metabolic, inflammation, thrombosis – all of these contribute to cardiovascular events in the diabetic patient. We have effects on a number of the vascular mediators, reverse cholesterol transportation, reduced ALP, which we’ll talk about a lot later, and reduction of platelet activity.

SLIDE 25

(Apabetalone (RVX-208) Development to Date)

We have a large database at this stage of development. We have almost one thousand patients that we have treated, of which 706 have received active, and the remainder placebo. Of our patients, around about 600 (576) have stable coronary artery disease, and they were studied in three studies. One of which was a 12-week dose-finding study, and then there were two 24-week studies which I’m going to talk about a lot more, called ASSURE and SUSTAIN. They were patients with stable coronary artery disease.

SLIDE 26

(Phase 2b (RVX222-CS-007/008) Study Characteristics

The populations of both are broadly similar, and broadly similar to the population of coronary artery disease patients as a whole. We have HDL cholesterol of less than 45, so low HDL cholesterol, they’re all randomized versus placebo, and six months of treatment duration, which is typical for a Phase II study in this area, and all on a background of standard of care, with high-potency statins, either atorvastatin or rosuvastatin. Slight differences are that the ASSURE study looked at patients who were scheduled for coronary artery angiogram due to deteriorating symptoms. The SUSTAIN study was stable patients.

SLIDE 27

(ASSURE and SUSTAIN Patient Screening)

Our total population in this study was 500 patients randomized in the combination. Almost all patients are included in the analysis. Our modified intention to treat includes 166 in the placebo, and 331. So of the 499, only two patients are not included, because they actually never received any therapy.

SLIDE 28

(Phase 2b Lipid and Inflammation Data)

Looking at the risk factors that everyone’s familiar with, we see a consistent modest effect on lipids, via HDL cholesterol, ApoA-1. The lipid particles for HDL are those that are anti-atherogenic are the ones that we have the biggest effect upon. And inflammation, there is a decline of hs-CRP and a decline in ALP. So the risk factors are all moving in the right direction.

SLIDE 29

(ASSURE and SUSTAIN, Apabetalone (RVX-208) lowers MACE by 55%)

What’s most important though is when we looked at MACE in these studies, and this was a retrospective meta-analysis, we see a reduction in MACE events of about 50%, which starts almost immediately. So we think there’s a large inflammatory component, a large anti-platelet and complement component. And it continues out until the end of the studies in 2010.

SLIDE 30

(Effect Accentuated in Patients with Enhanced Inflammatory State – Diabetes Mellitus)

How do we know it’s inflammatory? If we look at two subpopulations, first of all the diabetes population, and then the high CRP population indicative of a high inflammatory state and activated vasculature, we see a greater reduction in the diabetics…

SLIDE 31

(Effect Accentuated in Patients with Enhanced Inflammatory State – Baseline hsCRP >2 mg/dL)

…and a greater reduction in the patients with raised CRP. So, we feel that it’s the anti-inflammatory, anti-platelet, anti-complement which Evelina’s going to talk about later, that contributes the majority of the efficacy to the drug, and the lipid effects are minor contributors.

SLIDE 32

(Hepatic Adverse Events Summary)

Obviously, we have some adverse events. Every product has adverse events. The overall adverse events are approximately similar between active and placebo. The main adverse event that we see that is different is an increase in hepatic enzymes. Seven to eight percent of patients have a rise of ALT greater than three times the upper limit of normal. Of these patients, if you stop the drug, they revert back in a matter of days. Usually for five times the upper limit of normal, it’s about 15 days for them to revert back. There’s no inflammatory component. For the lesser elevations, if you re-start, or if you continue, the drug is well tolerated, and these ALTs reverse with continued therapy. We did not see a Hy’s law. That’s something that the FDA worries about. If you see an increase in bilirubin at the same time as increasing enzymes, that’s indicative of serious liver damage. We have not seen a case of Hy’s law. We actually do not see a raise in bilirubin in these studies. They tend to occur early. They tend to occur within four to six weeks. We’ve only ever seen one case after twelve weeks, and that was a patient who had coincidental acute cholecystitis. And a lot of the patients with ALT elevations were seropositive for Hepatitis A or were taking drugs known to increase the ALT.

SLIDE 33

(What could underlie the transient ALT elevations?)

We think we’re getting to the bottom of this adverse event. We’ve done a lot of work in the laboratory to investigate this. And we seem to see that there is a change in bile acid metabolism in selected patients, because BET inhibition does change the expression of bile transporters and bile enzymes in selected individuals. So there’s an increase in influx of cholesterol, and a change in bile pathway, and a down regulation, transient. But this down-regulation does not persist for long; there is an adaption within the liver cell, which accounts for why the enzyme levels go away with continued therapy. The net effect is an increase in bile acids in a very small number of patients. And we’re working in the lab to confirm this hypothesis. One of the reasons behind our BETonMACE study, apart from outcomes, is to get a very large safety database, to truly document the incidence and the consequences of these hepatic enzyme increases.

SLIDE 34

(BETonMACE – Effects of RVX-208 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease)

Which brings me nicely to our phase III study, which we call the BETonMACE study. It is a large Phase III multi-center study, looking at the time to MACE events in patients with low HDL cholesterol, diabetes, currently treated with standard-of-care statins. It’s that exact population that Professor Ray was referring to earlier, that have very few current therapeutic options, and a very high rate of events.

SLIDE 35

(BETonMACE: Study Population and Basic Design)

It’s a large study. It’s more than 150 global sites with two-and-a-half thousand patients (2,400 on slide). Event-based. Where we’ll continue the study until we reach 250 primary events. The primary events are the narrow MACE events. That’s MI (myocardial infarction), cardiovascular death, or strokes. We’re looking at male or female, type II diabetes, with a recent acute coronary syndrome between 7 and 90 days. It’s very similar to the population for the EXAMINE study, which looked at alogliptin. It’s 100 mg b.i.d. (bis in die, twice per day, i.e. 200 mg. per day.) vs. placebo, on the background of standard-of-care. And to ensure standard-of-care, we are actually providing the statins for this study. We’re providing the statins for the patients to ensure every patient is receiving standard-of-care. Study duration will be two-and-a-half to three years, depending upon the event rate. And in the background here we’ll also be working on the orphan drug and we’ll have regular DSMV. So there will be plenty of news coming within the two and a half years to keep the interest around the area. Our first patient is going to be recruited in the second half of this year.

SLIDE 36

(BETonMACE: Sample Size)

Where did we come to our sample size? Two-and-a-half thousand patients gives 80% power for a 30% relative risk reduction, which is much less than we saw in our Phase II studies. However, you always anticipate that your Phase III will be less than your Phase II. And the EXAMINE study tells us that we’ll have about a ten-and-a-half percent (10.5%) event rate in the placebo arm at 18 months. And our projections are for about a seven-and-a-half percent (7.47%) rate in the active arm. So we’re well powered for a 30% reduction.

SLIDE 37

(BETonMACE: Endpoints)

The primary endpoint is the classic time from randomization to the first occurrence of stroke, MI or cardiovascular death. Secondary endpoint at the insistence of the regulators is all-cause mortality, because we had some good strong feedback from the regulators in both UK, Germany and Sweden. And we’re also looking at some changes in lipoprotein concentrations (slide also says diabetes mellitus variables, alkaline phosphatase and kidney function). Our safety endpoints are focused around hepatic adverse events (AEs), and very close monitoring in hepatic adverse events together with the standard AE’s. But in addition, because of the current controversy around low lipid levels and cognition in elderly patients, we are also assessing all of our patients over 70 with the Montreal Cognitive Assessment scale, or the MOCA just to confirm that we do not deleteriously affect this.

SLIDE 38

(BETonMACE Subgroups)

We have a number of subgroups. Again, the regulators have asked for a number of subgroup analyses. For the Rosuvastatin group and the Atorvastatin group. The immediate post ACS (acute coronary syndrome) vs. the ACS greater than a month ago (≤30 days vs. >30 days). (Above and below) The medians of the various lipid parameters. The median HbA1c. And also those patients who have a low as opposed to a normal eGFR (≥60 vs. <60). In addition, we will have a subgroup within the study where the patients have an eGFR <60 and we will be looking at their GFR change, as we’ve had some encouraging data on the Phase 2.

SLIDE 39

(Agenda slide with item 5 highlighted: Unmet Need in Chronic Kidney Disease: Dr. Kamyar Kalantar-Zedah)

And with that, that brings me very nicely, having talked to kidney, to hand the podium over to Dr. Kalantar-Zadeh.

Kam Kalantar-Zadeh: Thank you Mike. OK.

SLIDE 40

(Chronic Kidney Disease Progression)

My name is Kam Kalantar-Zadeh. I’m a nephrologist, kidney specialist, Professor of Medicine at the University of California, and Chief of Nephrology at University of California Irvine. So it is a great pleasure to come all the way from California to New York, as always. So I would like to emphasize the concept of chronic kidney disease, CKD chronic kidney disease, and its importance, its burden of disease in this nation and globally. Chronic Kidney Disease is a disease that is progressive. Once you have chronic kidney disease, it just gets worse and worse. And goes towards these stages 1, 2, 3, 4, 5. Stage 5, as you know these are patients that require dialysis or kidney transplantation. The cardiovascular burden is quite high. So let’s go over this again.

SLIDE 41

(Prevalence and Economic Burden of Chronic Kidney Disease)

You see a number of statements here about the burden of this disease. Chronic Kidney Disease. Twenty to thirty million people in America have chronic kidney disease. Estimates from other nations are similar. China for example has 120 million Chinese with chronic kidney disease. It’s one of the top ten causes of death in this nation. Chronic kidney disease not only has a high burden of disease, but also is quite expensive. Because patients eventually need kidney replacement therapy. Many of them start dialysis, without which they could not survive. Patients on dialysis have mortality that is worse than cancer. It’s embarrassing for a nephrologist like me to say that a patient on dialysis has survival that is worse than cancer. As you can see, the five-year death rate is 64%. Nowadays most cancers have better survival. And very expensive.

SLIDE 42

(Unmet Need in Chronic Kidney Disease Patients)

So up to this point, we have nothing to stop progression of chronic kidney disease. There have been a number of interventions, medications, agents to slow down the progression. And some of them work, some of them are questionable, some of them not quite effective. So these are different statements as you can see here that we’re still looking for something that could be the ultimate cure, which does not exist. And something that could also intervene, and something that could deal with what you see here, the high burden of cardiovascular disease. Why? Because having chronic kidney disease and having end stage renal disease, we have renal replacement therapy for that, dialysis and kidney transplantation. But that doesn’t solve the problem of cardiovascular events and cardiovascular deaths. Many of them die because cardiovascular disease and cardiovascular events.

SLIDE 43

(ALP as a Prognostic Biomarker: ALP linked to Mortality, Cardiovascular Disease and Diabetes)

Now with this slide I’d like to introduce to you something that all clinicians know about. It’s called alkaline phosphatase. Alkaline phosphatase is an enzyme that is measured in your blood. It comes from the liver, from bone and from the intestinal tract. It’s usually measured routinely with any comprehensive blood panel. Studies in the past and recently have shown a remarkable and consistent association of alkaline phosphatase with cardiovascular disease. And you may say, “how come I didn’t hear about that?” So let’s go over this. Alkaline phosphatase here, in statement number 1: Higher levels of serum alkaline phosphatase (ALP) are associated with increased mortality in the general population and in patients post MI, and in patients with chronic kidney disease. (Statement 2) The highest quartile of serum alkaline phosphatase was associated with higher prevalence of myocardial infarction, stroke, congestive heart failure and diabetes. (Paraphrase of statement 3) And in different studies, different sources of serum alkaline phosphatase has a critical role in (vascular) calcification, so I’ll show you this is the proof of concept, how an enzyme which was not important until yesterday is going to be important.

SLIDE 44

(Serum alkaline phosphatase (ALP) at baseline and prospective mortality in 58,058 hemodialysis patients: 2001-2003)

This is one of the data from a dialysis patient cohort, here. You’re looking at 58,000 dialysis patients from New York to California. The bar shows the distribution of serum alkaline phosphatase across these 58,000 patients. What is remarkable is that this shows the higher the serum alkaline phosphatase, the higher the mortality in these 58,000 patients. And this incremental linear association appears to be too good to be true. That means the higher is the worst, the lower is better. So alkaline phosphatase high is bad, low is good. So this was one of the discoveries in 2006, highly cited.

SLIDE 45

(Higher tertiles of serum alkaline phosphatase are associated with risk of death in general population (without CKD)

Now what about the general population? A few years later, my colleague, Tonelli from Canada also published this in Circulation (2009). He looked at serum alkaline phosphatase across one of the general population cohort. And what he found was that the higher serum alkaline phosphatase, in people who don’t even have chronic kidney disease, the higher is cardiovascular events and mortality, as you can see across. So remarkable, you may say, “Why didn’t people pay attention to that?” The reason was because until now there was nothing to intervene. So there’s a biomarker, and you discover an association. Well nice, but so what? What can we do?

SLIDE 46

(What is the link between serum alkaline phosphatase (ALP) and cardiovascular outcomes?)

Alright now. Why is alkaline phosphatase associated with mortality? There are several hypotheses. We are not quite sure. One is the vascular calcification hypothesis. It is known that the higher is the vascular calcification score, that is the more calcification you have on your coronary arteries, the worse is your predicted survival. So that’s relatively known. There are ongoing discussions, but it’s considered quite consistent, and without much question.

SLIDE 47

(Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification)

Now here are a number of statements toward proof of concept. Similar studies by my colleagues. Dr. O’Neil in Atlanta, in experimental models, animals and in vitro, showing the role of a molecule called pyrophosphate. Because we want to link alkaline phosphatase to vascular calcification. So there is another molecule called pyrophosphate. Pyrophosphate protects vessels against vascular calcification. And alkaline phosphatase inhibits pyrophosphate, therefore leads to vascular calcification. Right? Inhibitor of inhibitor is bad. And here, several other things, to do with pyrophosphate. Essentially, he’s running all these experiments showing that this so-called tissue non-specific alkaline phosphatase is the culprit by going after pyrophosphate, which protects your vessels, and leading to worsening vascular calcification. So therefore, the last statement, if this hypothesis, this proof of concept is proven in future studies, we are hoping, that was just 2008, this mechanism may eventually identify alkaline phosphatase as a target to lower and to improve cardiovascular disease events and survival. So it was left alone, because there was nothing to do this.

SLIDE 48

(ALP is related to vascular calcification)

Now here also, two more sides just proof of concept. This is one of them just showing that in a study of over a hundred patients with CKD, those with higher coronary arterial calcification in any of their coronary arteries, these are the four different areas of coronary arteries, their alkaline phosphatase was higher. So remarkable association between coronary calcification and level of alkaline phosphatase.

SLIDE 49

(ALP and outcomes in CKD: Support in literature)

And so many papers have been published, mostly in nephrology, my field, where alkaline phosphatase is measured more routinely.

SLIDE 50

(Can serum alkaline phosphatase (ALP) be lowered?)

Now let’s connect this to what was discovered. Can serum alkaline phosphatase or ALP be lowered? Is there an intervention? There was not. I was essentially myself sitting there thinking why I spent so much of my time writing papers, discovering this alkaline phosphatase, so what? So until these great people contacted me and we had this collaboration. Is there an intervention to lower serum alkaline phosphatase in both CKD and non-CKD patients? Is there a proactive way to lower alkaline phosphatase and by doing so, to show that cardiovascular outcomes are improved?

SLIDE 51

(Phase 2 Studies: ALP Quartiles and MACE)

So going back now to what Mike presented in Phase II studies and Phase III studies. At baseline and towards the end what they have found, the higher is alkaline phosphatase, the worse was the adverse cardiac events. The more likely, the more frequent. So there is a proof of concept even in this cohort in this clinical trial.

SLIDE 52

(RVX-208 Downregulates Alkaline Phosphatase Expression: Primary Human Hepatocytes (multiple donors)

Then going back to experiments. When you want to build something, you want to show something is credible, it has to show across both experiments in vitro, animal models and then in real clinical trials. And you’re looking at two sets of primary human hepatocytes. Resverlogix scientists, they bought these human hepatocytes. They placed their molecule RVX-208, this is the one that you are sitting here for, they placed this in these experimental in vitro dishes and what they found was that there is 80% decline in alkaline phosphatase upon exposure to the molecule 208. Quite remarkable. And as you can see within 48 hours it was the measurement, and even within 20 hours, and sustained decline in alkaline phosphatase gene expression. So gene expression should now translate into level.

SLIDE 53

(RVX-208 lowering of ALP is time and dose dependent)

That’s what they also found. These are now Phase II studies coming here, looking at. The next step toward biological plausibility is dose-response. If something is really lowering something, the higher is the dose, the more effective it is, and that is what you see there very nicely. No 208, no change in alkaline phosphatase. More and more and more, that means higher dose, more effective. It starts actually quite fast. That means the molecule actually lowers alkaline phosphatase quite fast, within the shortest period of time. And then the effect is sustained. Sustainability. So very nice proof of concept.

SLIDE 54

(RVX-208 induced lowering of serum ALP is maintained for at least 6 months)

And then also looking at the clinical trials that were explained to you by Mike, SUSTAIN and ASSURE. This is the standard of care, which includes patients who received statins. Typically, over 30% of them (?) received statins we know by the start of the study, because everybody should receive standard of care. So some declining alkaline phosphatase, but much more marked declining alkaline phosphatase when the patients received the molecule 208 is used. So the treatment arm vs. placebo arm in both studies. With again, consistent, fast, and sustainable.

SLIDE 55

(RVX-208 lowers serum ALP in patients with Diabetes Mellitus)

And here also, this is toward the end of my presentation, you see looking at different subgroups. Patients whose alkaline phosphatase at the beginning was higher. The drop in alkaline phosphatase was two times more than the drop with standard of care. So -12 vs. -6. And these are patients that are considered high-risk for coronary artery disease. Diabetic patients. Low HDL. And also looking at the other iterations, patients with low HDL vs. high HDL, the alkaline phosphatase drop was even more remarkable in those with higher risk.

SLIDE 56

(Conclusions)

So in summary, what I’ve presented to you in the past 10 to 12 minutes. In both the general population and in CKD patients, higher alkaline phosphatase is known and is shown to be associated with worse cardiovascular disease events and outcomes and worse survival. Higher alkaline phosphatase is associated with vascular calcification. It is probably one of the most important culprits in vascular calcification in all of us. Clinical studies show that molecule RVX-208 can lower alkaline phosphatase. So for the first time we have something that can proactively and consistently can lower alkaline phosphatase. And lowering alkaline phosphatase is time and dose dependent. So it’s beyond proof of concept, actually quite effective. And the alkaline phosphatase lowering effect of 208 is maintained for up to six months. This is the length of the studies that they have been done so far. And 208 can lower alkaline phosphatase in patients with diabetes, including high risk for coronary artery disease.

SLIDE 57

(Agenda slide with item 6 highlighted: Epigenetic Mechanism of Action and Novel Biology: Dr. Ewelina Kulikowski)

So I’m going to stop here, and thank you for this privilege. Thank you.

Good afternoon, my name is Ewelina Kurikowski and I head the scientific development at Resverlogix.

SLIDE 58

(Epigenetics)

And what my section here will focus on really is a little more about 208. So I’m not sure how familiar everyone is with epigenetics, or if everyone here understands kind of how it works. But in essence, epigenetics is really what dictates why every single cell in your body has the same DNA sequence, but every single cell has a different function depending on the tissue it’s in, or the organ. And that occurs due to post-translational modifications of the chromatin. And the mechanisms of that are done by enzymes that are known as writers or erasers. So these are enzymes that will add modifications or remove them, such as acetylation or methylation. And these are recognized by proteins called the readers, which in our case are the BET proteins. And in so doing, they recruit transcriptional machinery, transcription factors to the DNA and either enhance or repress transcription. So RVX-208 works on these readers, on these BET proteins.

SLIDE 59

(Apabetalone (RVX-208) is a BET inhibitor)

So what’s shown here at the bottom on the very far left is a BET protein in contact with an acetylated lysine. So lysines are acetylated in the chromatin, usually in highly transcribed regions. This would be a normal state the cell might be in where BET proteins are at the enhancers. You can see that with the addition of RVX-208, you can see a dissociation of that. So this reader is no longer reading this acetylated lysine, and this is going to have an impact on the transcription that’s happening in that enhancer site where this is found. So in our case, we actually found RVX- 208 in a cell screen looking for compounds that increase apolipoprotein A-1 (ApoA-1). So in our cell assays at the time, about ten years ago, we did not know how 208 worked initially. This was a protein readout from the cell. It wasn’t until very recently that we learned the mechanism by which RVX-208 regulates Apo-A1, and the additional factors I’ll talk about today, is through this BET inhibition mechanism.

SLIDE 60

(Apabetalone (RVX-208) is a Selective BET Inhibitor)

Just a little bit more about BET proteins. So BET proteins have binding pockets as I showed you, with the ability to bind acetylated lysine. And those pockets are called bromodomains. And there are usually two, BD-1 or BD-2. That’s what you can see on this part of the panel here. You can see in the tree, these are all the proteins that contain bromodomains. But only these ones are the ones that are the readers on the DNA, and these ones are referred to as the BET proteins. And in all the work that we’ve done, we’ve been very interested to understand how 208 binds these bromodomain pockets, and how that translates into activity. And without getting into all of the details, what we’ve found was that RVX-208 selectively binds to bromodomain 2 within these BET proteins, most specifically protein BRD-4. That is our target. The other BET protein inhibitors that you might hear about in clinical development in the oncology space, they often bind both BD-1 and BD-2. We call that a pan effect. And we believe that has utility for cancer indications where you’re looking to potentially kill the cells. So they’re a lot more toxic, pan-inhibitors are more toxic. I think that the key to why we see such beautiful toxicity profiles which are very low on the toxicity scale both in vitro and in vivo and in humans, is that they have this selectivity to BD-2.

SLIDE 61

(Apabetalone (RVX-208 Selectivity: BD2 specific gene expression signature in microarrays)

So I’ll go into a lot of the data in one second. So I’ll introduce microarrays at this point, because that kind of brings home the point on the BD2 selectivity. So what microarrays in essence are, are a way to survey global gene expression. So in vitro, the only way to examine whether a cell or a construct is responding to RVX-208 is to look at the gene expression profile. So what’s being upregulated, what’s being downregulated, what is the cell doing in response to our drug. But the way to do that, knowing that we have a BET inhibitor, and we’re going to affect transcription globally, is to do a microarray analysis, which in essence lets you look at 20,000 genes almost at the same time. Because you’re going to break those genes down into pathways and you can have a look at what’s being affected in response to your drug. I show this here, because this is an example of a microarray we did in whole blood from three healthy volunteers. Normally what I would have here is there would be gene names within each of the boxes that you see, yellow or blue. I’m not giving you those gene names today, but those genes have been segregated based on how highly they are downregulated. So in the far panel on the left, you can see that for the RVX-208 dose with BD2, these are all the genes that have been downregulated, again they’re not listed, from the most downregulated to the least. And on the other side of the panel here, the ones that are the most upregulated to the least. And I just want to bring your attention to the difference of RVX-208 at that BD2 selective dose to JQ1. And JQ1 is a pan BET inhibitor that is often heard about in this particular area. It is not a clinical candidate, but it is a compound that has been built upon so companies such as Bradners, Tensha Therapeutics, they have inhibitors within that class. So those are pan inhibitors, they inhibit both of those bromodomains, and they clearly have a completely different profile than RVX-208 does. And we really feel that that is one of the reasons that we see the toxicity profile that we do. And also we believe that that is really part of the effect that I’ll tell you about in terms of the biology.

SLIDE 62

(BET Inhibition Beyond Lipids)

So the rest of my talk will be focusing on the biology that we’ve recently uncovered in doing all of this microarray work. So as Mike already showed you, the data we saw on MACE was really striking to us, and somewhat surprising at the time. We were so focused on Apo-A1 and HDL, and we wondered how 7 to 10% increases in Apo-A1 or HDL could translate into these massive MACE effects that we were observing. So we knew we had to go back and find out what else does this drug do. And so the way to do that initially was to do this microarray analysis, but now instead of whole blood, we also looked at liver cells. And the reason the liver is important is because, first it’s where traditionally all of our cell screens have been done in the liver, as this is the site of action for Apo-A1 induction. But also because our drug preferentially concentrates in the liver, at least in mouse models. So we knew that this was really going to be the site of activity. And what we found, and what I’ll show you in the next few slides, was that we definitely touch on reverse cholesterol transport, we knew that already from all of our clinical data. But what was new to us was that we had really these amazing effects, on complement, on coagulation, on vascular inflammation, and calcification as Kam just mentioned. And we also knew that we had effects on diabetes based on the data that we saw in the clinical trials.

SLIDE 63

(Downregulation of Pathways with Roles in CVD/MACE)

So this is a slide just again describing the microarray in primary human hepatocytes. And I should mention that these are cells that are not immortalized, they are literally cells taken from patients that have donated their livers after death of course. And you can buy these cells, and have them shipped to you. They have a very short life span. They are supposed to be very representative of what a normal liver cell would be like. They are not immortalized in any way. And all of the work I will show you is in these primary cells. And by the way, we’ve done this work in multiple donors, up to seven different donors, so this isn’t specific to one particular patient. And what you see here is that first off what we see with the micro-arrays is that the upregulated pathways, I haven’t put them here, but all the up-regulated pathways were consistent with a BET inhibitor, in that we affected genes and pathways important for transcription. So you would expect that. We saw transcription machinery changes; we saw changes in transcription factors, telomere maintenance, and centromere maintenance. So everything that you would expect. And that would be something that would be common to JQ1 and other BET inhibitors. What we saw in terms of the down-regulated pathways were really quite striking and specific to our drug. And we were very excited about that. You can see the complement, cholesterol biosynthesis, fatty acyl-CoA biosynthesis, fibrin clotting, diabetes and acute phase response here. And what you’re looking at is a heat map. So the genes within each of these pathways are listed next to the heat maps. And you can appreciate that whatever’s in blue is down regulated whatever’s in yellow is upregulated. And we looked at even these pathways, we were very struck by the amount of genes that we downregulated. We literally cool these pathways down.

SLIDE 64

(Downregulation of Pathways with Roles in CVD/MACE)

So that was our kind of first look at it. When we actually went in now, and went past just looking at the genes but actually looking at the whole pathway top to bottom. You can see at the top here these are the microarray pathway analyses. Again, they’re in blue. We down regulate all of these pathways. These are actually our top pathway downregulated in liver cells is in the complement. That is our number one effect, with the largest magnitude and reproducible between different donors and different conditions. What’s at the bottom now is actually, it’s an IPA, so it’s an ingenuity pathway analysis to show you what each of these genes is doing in the entire pathway. So normally, if you started with this, every single circle on either side would be clear. If you upregulate a particular gene it would be orange or yellow. If you down-regulate it, it’s blue. And I think I don’t have to convince you that when we saw this we were very excited. We could not believe that we had this attenuatory effect on the complement pathway, acute phase response, coagulation. I’m not showing you and I’m not going to talk about, but we saw the same for NF-Kappa-B signaling, we saw inflammatory signaling all cooled. So we really were having these anti-inflammatory effects. We knew we had indication that this was happening probably about eight or nine years ago when we were focusing on vascular inflammation, but we were really delighted to see that this was happening in liver cells; and this is the site of action for our drug.

SLIDE 65

(Apabetalone (RVX-208) Downregulates the Complement Cascade

So this is the complement cascade, and if you can believe this is the most simplest slide that I could find of the cascade. Because it’s very complicated, convoluted, there are a lot of players. In essence, there are three different ways that you can activate complement. Complement is an innate immune system response normally to microbial pathogens, at least that’s what historically it’s been known to do, but of course, we now know that it plays great roles in all types of diseases. The red arrows represent the targets. Some of those genes that we’ve seen in the microarrays that are downregulated. So where drugs for example in orphan and I’ll mention that at the end, may target one of these, at the level of C5 is one example, Eculizumab (Soliris, used for PNH), we modulate the entire cascade by modulating the level of each of these. And I’d like to point out, we don’t shut anything down completely. It is a cool down; it is attenuation. And I should point out also that in any of our clinical trials to date, we have never seen an increase in infections, or infestations, which would be something that you might worry about if you are shutting these down completely. So we feel that what we’re doing, and what we’ve observed so far, is that we’re cooling or we’re modulating this cascades. And this probably for cardiovascular disease, especially at sites of local inflammation such as the plaque, is really beneficial. So these mediators are made in the liver, and the mode of action is in the blood and in different tissues, and we think that by affecting it in this fashion, we’re having a benefit on MACE.

SLIDE 66

(Apabetalone (RVX-208) Downregulates the Complement Cascade)

So this slide summarizes really a lot of work that we’ve done. I’ve only shown you a little bit of that work, but as I mentioned most components of this cascade are produced in the liver. Microarrays from primary human hepatocytes in multiple donors have all consistently shown effects on this pathway. We, of course, the first thing we did after that, so you look at the microarray data and you say this is great, but does this really hold true at each of the genes, when you actually go in and do the work on each of these genes? And initially we went into hepatoma cells, so these are cell lines very commonly used in any type of research, Q7 HepG2 cells. And we found we downregulated these components in those cell types. Of course we went in to the primary human hepatocytes from which the microarray came from, and in multiple donors, we saw the same thing. And then we wondered well, if we’re decreasing basal levels of these complement factors, what happens in an inflammatory state? So in a normal human or in these in vitro systems, you’d want to stimulate with an inflammatory mediator, the levels go up, and then you add 208 and see if you can bring them back down. So we did that by co-administering our drug with the mediator, we did that by pre-administering the mediator with our drug. And either way we saw levels downregulated to basal or slightly below. So we were very happy that this happened in an inflammatory state, which would be the case in a human with cardiovascular disease. Finally, and so that data you can kind of see it over here, I don’t give you each of the components here, but these are MRNA expression changes in five of the complement components. You can see that anywhere from, so this one was not statistically significant, but you can see that from these we’re seeing 50 40, up to 80% down regulation of these at the gene expression level in primary human hepatocytes, which are what this is. Over here. So from our old days of looking at mouse studies with Apo-A1, we had a mouse that had a humanized liver. So one of the challenges of studying lipoproteins in mice is that their systems are very different from humans. So we worked with a group at the time on a chimeric mouse. So in essence, this mouse had hepatic cells of human origin. So you could use human probes and you could look at all of these proteins with human antibodies and such. And when we went back now and just had look at what happened in these humanized chimeric mice, again the factors we actually saw in vivo, and we didn’t, you know, we recently did this work, we realized that we were having these effects in vivo too. So in treating these animals, we were really seeing changes in their gene expression of these complement factors.

SLIDE 67

(Apabetalone (RVX-208) Downregulates the Coagulation Cascade)

So similarly to the Complement cascade, we looked at the same thing for coagulation. This was again, one of our top five or six pathways that we downregulated. The red arrows again demonstrate on the microarray where we saw gene expression changes, and of course to confirm that, you need to do each of these genes individually in the cells.

SLIDE 68

(Apabetalone (RVX-208) Downregulates the Coagulation Cascade)

And that’s what’s summarized here. Again so, this was done in multiple donors of primary human hepatocytes across multiple parts of the cascade. Here is the data. This is again from primary human hepatocytes. These are clotting factors. I haven’t told you which ones they are, but you can appreciate statistically significant that we really see cooling of a lot of these in the liver. In the mouse model I previously mentioned, same thing. We see decreases up to 20-50% in some of these factors. So we were very excited about that, because that helped bridge the gap we had identified with what we were seeing with MACE, with what we thought our drug was doing.

SLIDE 69

(Apabetalone (RVX-208) is Anti-Inflammatory and Anti-Atherogenic

So on to atherogenic and inflammatory mediators. So I just told you about complement coagulation, but of course, we were always interested in atherosclerosis and vascular inflammation.

So this data here is not now from liver cells but now from whole blood. So we took blood from three healthy patients. We took it out, we treated it ex vivo with our drug, and we looked at what happens to global gene expression changes in these cells. And what you see over here is these are all the pathways that we affect in whole blood. So these are monocytes, leukocytes, these are all types of cells that might be involved in plaque build-up as well as plaque inflammation. And you can appreciate that a lot of these pathways are involved in inflammatory signaling, endothelial activation, plaque stability, platelet biology, macrophage biology, so this was very consistent with what we had seen previously, probably about six or seven years ago, with our vascular inflammation work.

And then when we looked at our top, 64 in this case, genes which we downregulated, or upregulated in fact, in response to RVX 208, and we looked at what are these genes doing, what are their functions, we found that a vast majority of them were pro-atherogenic genes. And in blue, you can see that we really downregulate these, some of them as early as three hours, some up to 24 hours. The anti-atherogenic genes which you might want to enhance, we saw about a 50% increase in some of those, at least in the ones we looked at. Fifty percent (50%) of the genes that we looked at had an increase in those anti-atherogenic genes.

Now what was truly exciting to us also was that based on that, we identified novel biomarkers that were really new to us.

CCL2 (MCP1), that’s actually one that we had looked at before. That’s involved in attracting leukocytes to plaque, and we knew we downregulated it. So we were really potentially decreasing inflammation.

CCR2 is the receptor of that.

A new one for us was Parc. CCL 18. So Parc is produced in plaque. And I’ll show you in another slide here that Parc has been linked to, it’s actually known as a signature gene that goes up during acute myocardial infarction. So the fact that we were downregulating it in whole blood was really exciting. And we saw similar effects with other tissues that we’ve looked at.

Osteopontin (OPN) is another one I’ll mention in a little bit more detail. Osteopontin is also a predictor of MACE so it’s a biomarker known to predict MACE. Its levels are linked to MACE. It is also a marker of liver injury, which for us was very important, because we were still trying to figure out what’s happening with our ALT elevation. So the fact that we really downregulate osteopontin was a wonderful indicator that we were not inducting any kind of liver injury or tissue damage.

Fibronectin and some others are listed as well.

SLIDE 70

(Apabetalone (RVX-208) is Anti Inflammatory and Anti-Atherogenic)

So back to some of the ones I just mentioned. A recent study, well a few years ago now, by Muller et al. (EuroIntervention 2011) looked at sites of occlusion during an acute myocardial infarction. And they actually took the blood from these sites, and then compared it to peripheral blood, which was blood further away from the acute myocardial infarction occlusion. And they identified seven genes that were completely upregulated in those patients that were assayed for this. And when we looked at those seven genes, we inhibited four of those seven, and they were in our top ten genes affected. So that’s what you see here. Fibronectin was one of our top genes, that was actually the highest inhibition, was on Fibronectin, at three hours in whole blood. You can see MCP-1, PARC, and Osteopontin. So these are really biomarkers of occluded plaque, and the fact that we were downregulating them to this level in whole blood was very exciting for us. This confirmed the anti-atherogenic anti-inflammatory effect that we were starting to think is part of the big picture of what we’re affecting here.

SLIDE 71

(Apabetalone (RVX-208) Reduces Osteopontin Expression)

One slide on Osteopontin. So we went in of course and looked specifically, this is in human hepatocytes. This is actually in cells that are U937 cells that we’ve differentiated into macrophages, which are a big player in plaque. And you can see that we really downregulate osteopontin by 80-90%. And then here’s the data from the microarrays, and we inhibit it here 70-85%. As I’ve mentioned it’s a phospho protein, but it predicts MACE in patients with CAD. It has a role in biomineralization, potentially a role there with the ALP that Kam mentioned. And it’s a marker of liver injury. So when we did our work, which, I don’t think we’ve really talked about the safety too much, but when we did some work with safety expert Dr. Paul Watkins, he said to us, “what does your osteopontin look like in your patients that have ALT elevations”? And he was very concerned that if it’s high, then you’re seeing some kind of inflammatory response. And we did this work and we actually also looked at clinical samples in those patients. And we didn’t see the increases that you would expect if you were really inducing any kind of liver injury. So we were excited about that as well

SLIDE 72

(Follow Up Clinical Analysis)

So really, what’s the next step? What’s going to convince us that this is truly happening in cardiovascular disease? Well you need to look in the clinical samples. And we are so fortunate to have clinical samples archived from all of our clinical trials up to date, treated with RVX-208 from three to six months from these patients. So what we initially did is we went in and we took our best, our favorite patients, and we did a small subgroup analysis. And we looked at complement, we looked at coagulation, we looked at inflammatory mediators across the board. And we were happy to see that we saw the changes we saw in vitro in these clinical samples as well. But that said, these were small subgroup analyses. And so to really confirm is this really truly happening in our patients, we’ve actually embarked upon a large investigational study with a group out of Colorado. And they have a beautiful elegant assay to look at 1,300 plasma proteins. So not just the 40 or 50 we’re interested in, but across the board 1,300 proteins in our entire cohort from the ASSERT study and some ASSURE patients. And what we’re hoping to see is that we not only see these markers correlate to the in vitro work, but to see a dose-response in these markers as well. And hopefully to identify novel biomarkers that we haven’t yet thought to look at.

SLIDE 73

(Summary)

So in summary, mirco-array and gene expression analysis individually and in our cell work has demonstrated these anti-inflammatory effects and effects on complement coagulation. We’ve been able to do this in liver cells; we’ve been able to do this in whole blood as well. Our preliminary data from the clinical sample analysis is in line with the data we’ve observed in vitro, which has been really wonderful. As soon as you see that, then you know that this could be part of the biology that’s really driving the MACE reductions. It’s not just the reverse cholesterol transport but it’s these anti-inflammatory effects that are known to have a role in cardiovascular disease. And of course, the biomarker studies are really the way for us to move forward on that.

SLIDE 74

(Orphan Diseases)

And one or two final slides for me. Based on what I’ve shown you on complement, we got pretty excited because targeting complement in orphan disease, complement-mediated diseases in orphan disease – you know, that’s the holy grail of treating some of these very rare diseases. I mentioned to you Eculizumab. It is a drug that right now, it’s one of the most expensive drugs in the world at half a million dollars a year per patient. And it targets C5, which is one of those complement components I mentioned. So we believe that, if possible - if what we’re seeing in cardiovascular disease patients is any indication of what we could be seeing in patients that actually have an over-active complement cascade, such as in paroxysmal nocturnal hemoglobinuria, then we think we’re going to have an impact on orphan diseases that are mediated by an over-active complement. So our plan moving forward is to take 208 into a proof-of-concept trial in PNH patients, to first see if we’re seeing this translation into the clinic. And in patients that have too much complement activity, which results in hemolysis and all of the terrible complications of this very rare disorder. There’s reason to keep moving forward into particularly other indications, and some kidney ones, you know with the effects that we already see on the kidney. Hemolytic uremic syndrome is a mean one, and glomerulonephritis, which are both driven by complement.

At the bottom is just a graph just summarizing. You know, 208 is just the first one we’ll move forward but there are others. We do have a whole host of compounds that we haven’t yet moved forward into the clinic, because we had of course, 222 and we were so happy with it. Sorry, 208. But there are others, and we have set up screens for them now, more from an orphan perspective and of course cardiovascular disease as well.

SLIDE 75

(Orphan Disease Overview)

My final slide is just an overview of what an orphan disease is. You can see the low prevalence rates. PNH are the ones that we’re going after now. But if you can believe, 75% of these patients are not treated adequately because of the cost of Eculizumab and all of the tough adverse events and complications of taking it. There really is a space for us to try a drug like 208 that would potentially keep complement in check and prevent the kind of life-threatening thrombotic events from occurring that would put somebody onto the Eculizumab. So there are seventy-five percent of the patients out there with this disease that are not treated. They’re just treated with blood transfusions and platelet therapy and iron for anemia and all of that. So we really think that there’s an opportunity here. And hopefully if 208 does what we think it does, we would move that forward, but there are other molecules that are just waiting in the queue. So…

SLIDE 76

(Agenda Slide with items 7 and 8 highlighted: 7. Market Opportunity: Ken Lebioda; 8. Primary Market Research: Ken Lebioda)

…with that, I will pass off to Mr. Lebioda.

Ken Lebioda: Thanks Eva. Fantastic science. My name is Ken Lebioda. I’m the Senior Vice President of business and market development.

SLIDE 77

(Residual Risk in Vascular Disease: Pipeline Value)

So we’ve talked a lot today about the residual risk in high-risk vascular disease. It’s a huge commercial opportunity. Deutsche Bank put out a very good report a few years ago, focusing on just the residual market in cardiovascular disease. They stated that it was worth up to 90 billion dollars. A lot of good drugs are out there right now, but there still is this huge unmet medical need that has been outlined by the key opinion leaders earlier today.

So we are entering into Phase III within the next month or two months. And when you do comparators, it’s quite remarkable when you look at what are these assets worth. In the hands of big pharma, they’re worth a lot. These are just some examples where the, CETP class; Pfizer had one, Torcetrapib; the Dalcetrapib (Hoffmann-La Roche); Darapladib, which was GSK’s. Unfortunately, all of these drugs have failed, but at the time, they ascribed huge market value opportunities for these pharmas if they worked. So here were the pipeline values of those. So this is the reason why we’re so focused and so excited about what our opportunity is for reduction in these types of high-risk patients.

SLIDE 78

(Apabetalone (RVX-208) Value Proposition: Efficient Residual Reduction of MACE in Diabetes)

We think we have a very unique value proposition for physicians, for patients, and more specifically for payers. In diabetics, there have been a lot of studies out there. And there’s been a new one in SGLD2 inhibition from Lilly that appears to have had pretty good results for MACE reduction over a four-year period. But if you drill down into some of the data subgroups, it probably provides more questions than answers. But when you look at glucose reduction as it relates to efficient MACE reduction. A lot of these studies highlighted that there was really no effect. And that’s what we want to come in and change the paradigm. Our paradigm is to create a new MACE paradigm that in high-risk residual patients, we want to have an efficient MACE reduction, and our early data thus far illustrates that we have a very strong potential to do just that.

SLIDE 79

(Potential Target Indications: High Risk Vascular Markets)

So we are very target focused. When you look at the three big groups that we’d be focusing on, diabetes with low HDL, underlying coronary artery disease. That’s what BETonMACE is going to be focusing on. As a subset with the BETonMACE, we estimate based on our historical data, that we will have somewhere in the neighborhood of about fifty percent-ish CKD patients. That’s the bottom left. So in BETonMACE we could have up to three, four or five hundred CKD patients. We’re going to look at that very carefully as well. That’s why we brought Dr. Zadeh on. And then there are other opportunities in high-risk residual vascular disease, such as peripheral arterial disease and so forth. So in essence, this very enriched, very targeted group still represents close to eighteen to twenty million patients. So it’s a huge huge opportunity for us.

SLIDE 80

(KOL Market Research)

So what we’ve done, is we’ve done active outreach to KOLs (key opinion leaders), more specifically in the United States. We are going to do active outreach to now physicians in Europe and Australia. But we hired this one strategic consultant on numerous occasions. And we asked the question with twenty physicians, most were in the United States. Five were in the European Union. Cardiologists, endocrinologists and nephrologists. These are the focus groups that we’re focusing on right now. We also interviewed five payers in the United States who cover a lot of managed care lives, up to 170 million lives, so about two thirds of the population in the United States. And it was pretty clear what was coming back from them. There is definitely a significant unmet need. And they like the fact that we are really targeting on the patients that we will make a big difference. As Kausik had lain out earlier, we don’t want to treat everybody, we just want to treat patients who we think we can have a real impact on. So we just wanted to kind of highlight some of the findings from this.

SLIDE 81

(KOL/Health System Affiliations)

So here are the physicians that we spoke to from this first group of patients, sorry, of physicians that we spoke to. All key opinion leaders, cardiologists, nephrologists, and endocrinologists. Some with, you know, the past president of the French Cardiology Society, some from New York, North Carolina, etc. etc. And it was interesting. A lot of them really, before we started this process, they really didn’t have a good idea about BET inhibition and the potential to reduce MACE in these high-risk patients. So after this exercise was completed, 100% of all the physicians stated that whenever this clinical trial appears, they would love to be an investigator for the Apabetalone. So we were very pleased to see that.

SLIDE 82

(Endocrinologists and Cardiologists Unmet Need)

So when we asked some of the questions, and those are highlighted in the blue bars. The level of importance of MACE reduction in these target groups, type 2 diabetics, low HDL levels. It’s very consistent for both endocrinologists, cardiologists – this is just some examples - and nephrologists. And these are just some examples. They state that there’s definitely a very high level of unmet need, and they really want to see something there.

SLIDE 83

(Novel Approach to MACE Reduction)

And so another question was asked, where, the importance of a new approach to reduce MACE. So not LDL lowering, not sugar or glucose lowering, but a new approach. Which we firmly believe and the data suggests that BET inhibition is that new approach. And there was still a very high level of importance and a high level of voting that yeah, they really want to see that. That we want to have a new approach.

SLIDE 84

(Select BET Inhibition)

This just goes back to when we started this process. The current knowledge of epigenetics and BET inhibition was fairly low. So we’re a small company. We’re doing active outreach now. We’re talking to more and more people, such as yourselves and in the medical community to make sure that our story’s being known. And so it was nice to see that the level of interest after this exercise was very high. They said, OK, we think that the mechanism of BET inhibition was a viable mechanism to reduce MACE.

SLIDE 85

(Potential Prescribing Behavior)

So when we asked the question of also potential prescribing behavior, and this is based on the fact that they had reported data in here that there’s major gaps in current drugs that really aren’t doing an efficient job of reducing MACE. They said that I we can fill that gap, if we see what we hope to see in BETonMACE, a reduction of 20, 25, 30 percent in major cardiovascular events, these are the consistent results in nephrologists, endocrinologists and cardiologists as to how they would prescribe the drug. So by year two, you can see a pretty high level of prescribing, which indicates that these individuals are looking for a solution for these high-residual patients.

SLIDE 86

(Importance of MACE Reduction)

Now these are questions more specific to payers. And Kausik had lined out earlier that it’s important, that there’s the four Ps in the spectrum of pharmaceutical drug development. You have your patients, you have your physicians, your pharmacists, but you have your payers. So it’s great to have clinical data, but you’d better be efficient in lowering events. And that was the concept of the number needed to treat. I always like to say that the number needed to treat is like golf. You have to shoot below a 70. If you can shoot below a 70, and your drug is priced appropriately, the payers really like you and they start to pay attention. And reimbursement is much much easier. So that was very important because our, and you’ll see in subsequent slides here, that our current data on number needed to treat is very low.

We also basically asked the question, which is, “if you have good glucose levels that are managed, do you think those patients are still vulnerable to cardiovascular disease?” And these key opinion leaders said absolutely, yeah. Which kind of ties in the fact that you can modulate and control sugar levels, but however, we’re still seeing these large diseases, heart attack, stroke and death. That’s why we’re here. We want to lower that.

SLIDE 87

(Preliminary NNT Analysis: Modeling)

So this is our early preliminary number needed to treat analysis. And the way you have to look at this analysis, is you have to look at it as annualized over per year. And currently from our pooled ASSURE and SUSTAIN, we see about a 21 for NNT. So this is exceedingly great for us. We do have to try to replicate it, but in BETonMACE, this is almost too good to be true. But it’s a very good signal that if we see anything below 50-60 we’d be delighted. And that is represented by about a 25 to 30 percent relative risk reduction. This is just to highlight what we’ve seen so far.

SLIDE 88

(Potential Pricing)

So when we talked to the payers, and we said,” If you see 25 to 30% I mean, what are you thinking, or 20%”? How could we start to price model this? Which helps us understand much better, what is the value of this asset, RVX-208 at its current and in future stages of development? So here are the numbers that the U.S. payers said that they’d be very comfortable with. The four to five thousand dollar price point; if you can keep it below that, you get a preferred co-pay. And so our modeling right now is somewhere in the neighborhood of between three and forty-two hundred dollars per year. And if you see that with number needed to treat below thirty, below forty. $100,000 of drug to prevent an event is actually very very efficient. When you look at some of the data that is out there on other LDL lowering drugs, some of their numbers are coming in at about eight hundred or nine hundred thousand dollars. So that is a very important value proposition that we want to bring to the payer community.

SLIDE 89

(Prescribing Behavior – SERMO Survey Findings)

So this is a second outreach that we did, which covered almost two thousand physicians. We had 625 primary care physicians, 550 cardiologists, 420 endocrinologists, and 325 nephrologists. And we asked a series of questions, but this was a very important question. Where we said, “If select BET inhibition in a large Phase III prospective study illustrates this efficient reduction of MACE, would you prescribe? What’s your level of interest? “

And most of the physicians here stated that if you see 25 or 30 percent, with pretty much a high level of interest, eighty-five percent of these individuals said that they would start to prescribe. So this starts to tell us that these new approaches such as BET inhibition, if they truly make a difference in prospective studies such as BETonMACE, the value of this asset is very significant.

SLIDE 90

(Summary)

So in summary, high risk vascular disease retains a very high level of commercial interest and a high level of value for everybody within the pharmaceutical and life sciences industry.

Our understanding right now is that there is potential up to 18 million patients in the top seven markets. This doesn’t even include China or BRIC countries. We just closed one of the largest single molecule deals with a very good partner, Hepalink, in China. So we’re delighted by that.

Efficient MACE reduction is a very important thing that everybody is going to be looking for. And so our early market research illustrates that, if we see what we hope to see in BETonMACE, there will be a very strong pull into the market from these key opinion leaders. We are going to continue that effort with more outreach in physicians in Australia and Europe this year.

And we’ve also worked with leading individuals such as IMS and others on really starting to build very very accurate early pharmaco-economic models, more detailed than what you saw in our Numbers Needed to Treat. But they’ve done some early, and HEOR means Health Economics Outcomes Research, Number Needed to Treat and other different variables that look at the value proposition and the early reports that we’re getting from them right now has illustrated that Apabetalone looks very promising. And so on that point…

SLIDE 91

(Agenda Slide with item highlighted: )

… I will move it over to Don

Don McCaffrey: Thank you Ken. I’m just going to summarize a little bit here and then we can get right to the Q&A. As you can see, it’s pretty exciting data that we’ve compiled over the last two years and what we’re going forward with. So we have a lot to work with, and it’s getting pretty exciting.

SLIDE 92

(Financial Profile)

So just a quick financial profile. We are still Canadian stock listed only. We are looking at moving to the NASDAQ, and we hope to do that soon. We have talked to NASDAQ and everything seems to be in place. We have Board approval. So we’re excited. We’re also sitting on the most cash we’ve ever had, so that is a real plus as well.

SLIDE 93

(RVX-208 Additional Clinical Plan Potentials)

I’m glad that Ewelina had to pronounce all those words in the potential indications that we can go into in complement, but there are a lot of directions here for us. And this has been very well planned, because we knew that we were going to have about a three-year gap in data while the BETonMACE trial is in full function. So we’ve designed it so that there will be a lot of value and inflection points during that three-year period.

Chronic Kidney Disease is a huge potential for us. I think you can understand from Kam’s excitement that we really have something there, and we will build towards that.

Peripheral arterial disease. That’s very much a natural, especially with all the anti-inflammatory components going on.

Alzheimer’s. We’ve talked about Alzheimer’s for a while. We were waiting for some NIH funding, which is always in the process. But at the most recent international Alzheimer’s conference, the big study subject, the big breakthrough was the relationship to complement in Alzheimer’s. So we’re very excited about moving forward with that potential as well.

And then of course the orphan indications. Which orphan drugs seem to be very popular with pharma these days? Eight ten years ago everybody switched into oncology, now it’s orphan indications. So to be able to enter those indications with RVX-208 already as a Phase II B drug is fantastic. And to back-up molecules for that program for other indications is even better.

SLIDE 94

(Early revenue opportunities include regional licensing deals and orphan indications)

And we will continue with some of the plans that we’ve talked about over the past. The orphan indications, as we started rolling that out yesterday.

We will continue with regional deals potential as well. We are in discussion. We like regional components. We try to stay away from the main countries that would get you your highest value in global deals. But there are a lot of places where we can utilize regional pricing for bringing in revenues at a lot earlier point.

SLIDE 95

(2015- Milestone Check List)

And of course the final milestone checklist. We’ve had a good year. Proven MACE reduction. We’ve brought in $82 million in the last year, so that was pretty good. And clinical launch of the Phase III trial, the design is already done, the launch is imminent here. And presentations in just about every major event there was last year. We had, I think it was 12 accepted. I just list a few of them here. But it’ll be the same next year. You’re going to hear a lot more about us. Especially now that we’re rolling this data out. It’s really quite exciting. And the business development is ongoing in regional and other areas.

So on that, we’re going to break and…

SLIDE 96

(Q&A)

…go to Q&A. There will be two microphones floating around the room. Sarah’s going to hand them out. And love to hear your questions, looking forward to it. Thank you.

Test these mics, make sure they’re on. Yup. Alright do we have some questions from there? Look forward to any of them. OK. Sarah will bring you the mic.

Q: Hi Good afternoon. I’m going to ask a question about the clinical trial period. It’s a period estimated to be two years, one hundred and four weeks. Is that something by design, something particular to you, something you’ve been advised by the FDA? I’m curious about the background.

A: It’s an event-driven trial. So looking at the background rate in previous studies of the number of MACE events, we realized that we required 250 of them, and the average exposure to gain this based on previous studies is eighteen months So if you then have a year, year and a half to recruit the patients it comes to two or two-and-a-half or three years. So it’s actually designed as to include the period that we feel that we need to have the 250 events.

Don: Next question, please. Don’t be shy.

Q: Much of your data shows what happens when a person has diabetes. However, in the civilized world mostly, diabetes is under control for the patient with glucose control with high blood pressure etcetera, more or less. To what extent does your information therefore have to be modified in comparison?

A: So the problem with diabetes is that it is progressive and even when you have good glucose control that you actually still get progression of disease. So if you take somebody who’s had diabetes for about ten years or so, even, it doesn’t really matter what the range of HbA1C, the glucose control is, they will still have a high level of progression. Because the population that we are targeting particularly has the highest level of risk, they’ve had a heart attack you know, recently, and they’ve got a factor which is not going to go away. So even when you basically control blood pressure, glucose, lipids, etc. just having diabetes just accelerates this whole process. And then if you look at for example the complications, like if you develop renal disease or microvascular disease, it starts to go up like this. And so, if you like, the best way to actually not get those complications is not to have diabetes in the first place, but once you have it, you’re on this trajectory. And all you are potentially doing with glucose control is just slowing down the trajectory, but it’s still progressive.

DM: Yeah. I’d like to add to that. In the recent ACCORD trial, which was run by Henry Ginsberg here from New York, who also sits on a committee, our steering committee with this gentleman, he showed in that trial that no matter how well your glucose is maintained, that patient is still going to die from cardiovascular disease at a rate of about sixty-eight percent.

Q: Yes, your phase II data seems to be very encouraging, and you are about to start a Phase III study. I just wanted to get some sense of, besides the data you presented for the Phase II study, is there any other - what’s the differences really in terms of patient cohort between the Phase II and Phase III, as well as, was there any other data in the Phase II suggesting that the MACE outcome of the Phase III can be achieved or potentially be achieved?

A: You know in Phase III we have targeted that group of patients which did best in the Phase II, the ones that had the greatest MACE reduction. So whereas our Phase II was cardiovascular patients, usually with stable cardiovascular disease, our Phase III is going to focus on the highest-risk patients where we saw the highest benefit in Phase II. And that’s where our confidence is that we will meet the primary endpoint in Phase III. They are all patients with diabetes, low HDL, extremely high risk.

Q: I recall that you presented that the baseline for the Phase III MACE events was about 10 percent or 11 percent, is that for that particular cohort, or is there more to it.

A1: Initial answer from me is that it’s that particular cohort based on the examined study, but obviously, Professor Ray has got a lot more experience on this than I have.

A2: Yes, so if you look at the modeling that’s been done, there was a trial called, and it’s the only one recently that’s been done where you’ve had patients straight after a heart attack, and it was called EXAMINE and it was done with just a pure glucose lowering agent. And it just showed that the compound was safe. There was no benefit on MACE; there was no harm on MACE. It improved glucose a little bit and this is the FDA requirement. And so, because everybody in that study had to be diabetic as well, the event rate at one year is what you can predict from that. Now, what we will have is probably a slightly higher event rate, because we’re also going to be recruiting on the basis of a low HDL. So the event rate that we’ve actually picked is a more conservative one. And when you actually add to that the fact that you’ve got a low HDL, we would expect a slightly higher event rate. So when you apply the relative risk reductions, we actually have more chance of success, you know, along the lines that you’ve just asked, because you’re enriching for people who are more likely to develop cardiovascular disease in the eighteen months, two years of follow-up.

Q: Yes Don, I think you mentioned in your opening remarks, that to achieve 250 events, it will take about three years. I believe that’s what you said. But you also said that there would be many opportunities for interim analysis along the way; can you expand a little bit on that?

A1: Not interim analysis of that particular trial. The opportunities that I was talking about were new orphan indications that take much much less time. So being able to keep news flow going. We won’t be doing any interim sneak peaks at the BETonMACE, I think that’s highly frowned upon.

A2: There will be obviously safety data. As part of the charter for running this study, there will be safety data and the data safety monitoring committee will look at that. So I think that will obviously be important. And with any drug class that you have, any new one particularly, you need not just the efficacy but the safety. So the fact that as we go along, getting a positive sort of sign, that no, there’s actually nothing to worry about and it’s safe to continue, is actually going to be very encouraging for the study as well. All studies have an analysis plan like that, so we won’t be any different. But in general, we won’t be doing multiple looks, there will probably be one analysis that we will do based on a certain number of events.

Q: For a patient in the eighties who has no history of diabetes himself or in the family, and who has good blood pressure, lipid control, glucose properly, weight control, the question is how much of a danger is it to inflammatory, that is in the vascular can be have inflamed, as being a cause of a blockage? How much of a danger, I think there’s a test, what is it, C something can be tested, and what can be done based on present drugs?

A: So in terms of, all of us have some level of inflammation, and the more risk factors you have, the higher the level of CRP, which was the marker you’re referring to. It’s a non-specific marker. It’s not a target for treatment. So specifically in your patient population that you’ve just described, if everything is otherwise OK, but CRP is high, that is a marker of somebody who is going to die more readily or develop a cardiovascular event. We don’t have specific treatments that really lower that. There are treatments that are being developed, that will target inflammation. So our drug is one drug that would we know, we showed you some data in people with a high CRP the clinical event reduction was lower in that population (I think maybe he meant to say higher, as in clinical events were lower, and reduction was higher), so we know that that drug worked. There are two other drugs being tested currently. One is a monoclonal antibody, so it will be very expensive. The other one is a drug that’s used for arthritis, methotrexate. That’s an NIH trial that’s being done. But if you look at what happens in the monitoring, in terms of reducing the white cell counts, I’m not really sure that’s a drug that I want to be taking for the rest of my life, so you know, irrespective of what it shows on that benefit. So we do have an unmet need for inflammation. And that’s one of the things that really excites us about this compound, is that it actually reduces the genes that govern inflammation. It does it very very quickly. But it doesn’t completely knock it out so that you then are more at risk of infections, at least, you know, in the Phase II data we’ve seen.

Q: Based on these studies, is it more danger of blockage in the artery from inflammation than from higher lipids?

A: They are both complementary. So if you think about lipid levels, if you have a high cholesterol level and you have a high CRP, that’s a marker of the worst group. And if you have both low, that’s a marker of the best group. If you have one or the other, that’s the middle group.

A2: If I could also expand on this. There are studies that may suggest that other risk factors that our colleague astutely alluded to are even more important. Now, I’m not here as a kidney specialist to say that cardiologists were wrong for the past forty or fifty years targeting cholesterol. But we have already targeted cholesterol for the past forty or fifty years. And we are already doing this. And we are already lowering this in most patients. So yet, we still have cardiovascular disease burden and events. So therefore, that’s why there are studies that are showing that those non-cholesterol related risk factors are as important if not more important than.

A3: I think without doubt it’s that today they’ve become more important now. Because if you think about the biggest bang for your buck and you start here and you’ve already reduced a lot of the blood pressure and risks, well the law of diminishing returns states that if you keep targeting that particular pathway you’re going to get less and less return. And all of these treatments are going to be add-ons. So then, from a payer perspective people ask, hmmm do we really want for that NNT (numbers needed to treat)? Now on the other hand, if you target residual risk and what else is driving, as you very nicely said, those recurrent events, well actually they become much much more important now. And if you actually target those, now you actually modify something that you were never able to modify before. So, you know, in the present environment of best clinical care, these novel treatments, niche areas that they might seem, but they’re actually probably going to give you a bigger return.

Q: This question is probably for Don or Ken. It’s in two parts. You’re well-funded at the moment. Might you expect if all goes well that you will not, or might you need further funding to get over the line with your first product to the market? And secondly when might you expect if all goes well to get that first product to the market? Will it be two years?

A: The first product to the market could be two years with an orphan indication. And as far as the funding questions go, I always answer that the same way. We’re a biotech company; we’re always in funding mode. We’ve done very well. We’ve seen the price go up quite a bit. So it’s allowed us a little more free room, elbow room on the open markets. We will never say we’re not looking for money. We would like to at much higher rates do something. We’re also still in discussions with other regional licensing potentials. And/or we would even look at things like first right of refusals, which would put a lot of money into the coffers and allow us to really expand on some of these programs

Q: A follow up question here. In terms of the Phase III study, the primary endpoint is more narrow MACE instead broad MACE. What’s the rationale behind that and what kind of discussion did you have with FDA to get that. And another one for Don is what’s the cost for the phase III study?

A1: Well, the rationale behind it is that that was requested by the regulators. The regulators wanted the hard endpoints as the primary endpoints, with the broad as the secondary. And it’s really precedent in the regulators that we consulted, that that’s what they required in the past.

A2: And you asked about the cost of the trial. We’re not fully aware of it yet because it is event based, 250 events. I’m really hoping they get there way faster than they think they will. But we will keep the market updated on that cost as we go through the next three years.

Q: (About as close as I could get. May need some revision. Time 1:41:43)

Just wanted to comment on the conversation several questions ago. Statins as a class reduce C-reactive protein approximately 15%. And it’s thought that one of the ways that LDL-reducing medications work is that they reduce inflammation. The mere fact of lowering LDL has a potent anti-inflammatory effect. Also alluding to Paul Ridker’s c-reactive protein work in the JUPITER trial, there’s a group of patients that have a low LDL but they still have a high C-reactive protein. These people still have cardiac events. So perhaps it’s LDL and C-reactive protein. But statins as a class do modify C - reactive protein by approximately 15%.

A: I absolutely agree with that, that statins do reduce CRP. I mean you’ll have heard about the latest class of lipid-lowering agents, the PCSK9 inhibitors, they have as big an effect on cholesterol, but they don’t lower C-reactive protein. So that would probably suggest that the statins have an effect that is separate from the LDL lowering effect. And that might be, that the presumed mechanism is intrahepatic production of CRP. But we know that inflammation is definitely associated with adverse outcomes. So targeting both makes a lot of sense. This is why obviously there’s an interest. There is the Novartis compound in testing. There’s the NIH trial that I was talking about. And we’ll effectively be the third, but with a very different mode of action.

Don: Any other questions? Well, I really appreciate everybody coming today. It was very nice start to share some of this exciting data. As you can see, we’ve got a lot on our plate. We’re financed up for it, we’re very excited, we’ve got a lot of support from key opinion leaders around the world, and we’re looking forward to moving forward. Thank you.