SLIDE 1

So welcome to the annual meeting and as I said the weather seems to track us for this, I don’t know why, but it does.

SLIDE 2

We have a forward looking statement as usual

 

SLIDE 3

And this is Resverlogix at a glance.

We are a late-stage clinical biotechnology company with a leadership position in epigenetics

And that is starting to be recognized globally, so we’re pretty excited about that.  

Our lead product is Apabetalone, a first-in-class small molecule – we have about a ten year lead on anybody else, so. We have broad applications in cardiovascular, renal, and other disease indications, some of which we’ll talk about today.  

We’re a fully enrolled phase III trial

We’ve been fully enrolled since around February, so that happened quite fast for us

We kept some enrollment open in China to help speed up our process going through the CFDA in China

So we didn’t stop enrolling in China until about the end of June But the rest were fully enrolled by February  

We have a very attractive safety profile. We’ve now dosed over 1900 patients with this drug. And as I think you’ve seen in the past, the seven DSMB reviews have all been in our favor.

So that’s very positive news. 

And you pretty much know the exchange and outstanding shares and the market cap

    (Toronto, C 735m, US 550 m, 188.5 m shares outstanding as of Sept 10).

That was yesterday’s number so that was pretty nice.

 

SLIDE 4

And this is my favorite slide

We’ve had a good run here

From September 12 last year, our stock price is up 174%. (1.41 to 3.86)

So we have to figure out how to make that happen again between now and next September 12,

but I think we’re well on our way.

Also the market cap has increased even more, 348%   (162 M to 725 M)

So it is pretty good

And if you’re wondering what the stock price dilution has been, it’s only 39%.

So that’s pretty good numbers for us.

We look forward to seeing that increase again next year 

 

SLIDE 5

Now our pipeline plan is pretty solid.

We’ve bounced back and forth a little bit in the last year as to when some of these trials will get launched.

A lot of that was to do with financial reasons

and as you’ve seen over the last several months, that continues to improve for us.

But the ones I’d like to talk about the most –

Of course the acute coronary is in full gear, almost done. 

 

Chronic kidney disease is well on its way. It is approved and ready to go by the FDA.

But at this point –  –

The original plan was to try to slip that in there and get top line data before BET on MACE is done.

Clearly that’s not going to happen.

So the smart thing to do now is just wait on that BET on MACE data, the renal component.

see if we need to tweak that protocol any, or if it’s good to go the way it is

It would be a shame to launch it right before and then find out

some new knowledge in the New Year that could have made the trial even better.  

So that’s what we’re doing there 

 

Fabry’s disease – we’re pretty much ready to go now 

Pulmonary arterial hypertension – We don’t talk about that a lot, but there is a group out there that is intrigued about this. They’ve done a lot of work and publication on Apabetalone’s effect on PAH, and they also have applied for funding to pay for a trial like that – so we’ll see where that goes. It’s looking quite promising.   

Vascular cognitive dementia again, that’s going to be dependent on BET on MACE data that’s coming out shortly.        

SLIDE 6

So just the investment highlights.

We are a global leader in this area and are being well recognized for it at this stage.

As you probably know, all others in the BET bromodomain space are in oncology only

because they don’t have as full a grasp of the biology as we do.   

Apabetalone is a first-in-class BET inhibitor with broad potential in many diseases

Critical unmet need in our top markets is about 12 million people.

So when you start timesing that by the sales price of what this drug should go for,

it’s a pretty impressive number, and that is just in the eight top markets.

 

The lead program is fully enrolled as we’ve talked about. 

Well established safety profile, and that continues.

So I think we have one more DSMB before the trial is over,

but we have had no changes in those, which is really quite strong.  

Proven track record for funding, I think we’ve shown that over the years - 

Eighteen years of developing a drug and no revenue. It’s a bit of a trick and a half,

But we’re getting pretty close to some very exciting times.  

 

And a robust intellectual property position,

2034 is a very long time to be coming out with a patent life

after the length of development time we’ve had,

so we’re very pleased with that.

 

SLIDE 7

So addressing the unmet needs in the cardiovascular side

Where we’ve really focused over the years is this sixty to seventy percent unmet need

You know the thirty percent is taken care of by the statins.

Some of these newer drugs, the PCSK9s and some of the LDL modulators,

they’ll take up about another 10 percent of that market

But that 60 percent unmet need is an enormous market

When you consider that 30% used to have twelve to fifteen competitors in the statin market

And even with that Pfizer was able to obtain 14 billion a year in sales with a dozen competitors

So a pretty impressive market potential 

And on the Diabetes side, well it has reached epidemic proportions

According to the World Health Organization, over the next thirty years it will increase by 55%

And in certain regions like the Middle East, it will increase by almost 100%

So we’re getting a lot of attention about our drug in the Middle East

It will help us moving forward with some of our licensing and finance plans.

 

SLIDE 8

OK, now I’ll skim through this because I’ve probably shown some of you guys this slide

 like a hundred times by now,

But it is important to understand where we’re different and why we’re different.

We are an epigenetic mechanism.

And the first epigenetic mechanisms in the world were the writers and erasers

So histone modifiers, that kind of thing – but it’s a chemical to chemical interaction,

Where you’re adding a chemical on to or off of the end of a histone tail,

and that’s where you get a change in protein production.

We’re different. We’re a protein to protein interaction.  

Fully reversible.

These are not reversible, they’re permanent.

So they’ve ended up with some toxicology issues that they’re still working through.

But we’ve caught up and surpassed them with this newer technology.

It’s quite brilliant stuff.  

 

SLIDE 9

Our program is differentiated from the other BET inhibitors quite a bit, because we have selectivity.

We’re able to go in and really focus in on BD2.

How we did this was from early design, but also the knowledge of the biology here.

We’re about ten years ahead of the world because we have the only blood bank in the world.

When we were finished Phase II, no other pharma or biotech had even started Phase I.

So nobody had blood

We were able to go in and reverse engineer this through detailed proteomics, genomics, pathway analysis.

And really understand what’s going on.

So our follow-on program is really quite strong.

And after our BET on MACE trial we expect to be very active in

licensing and partnering some of these additional compounds as well

And we’ve come with a pretty clean toxicology profile as well

Because of our understanding of this.

Most of the BET bromodomains in the clinic are focused on oncology or GI stem cell tract issues or

And that’s because they can get away with some of the higher tox issues like thrombocytopenia, or GI stem cell tract issues or ? FERG ? We have none of those, so very positive for our program.

 

SLIDE 10

Now this is a slide that I think is really important, because it really distinguishes

Now, drug development for decades has taken place at the protein level.

And that’s wonderful if your disease is a single protein disease.

Cardiovascular, diabetes, and chronic kidney disease are not.

They’re multifactorial.

And to think you can go in and change one protein and cure heart disease is a bit of a stretch.

It worked a little bit with the statins, but it just isn’t going to happen

So trying to increase or decrease a certain protein for disease reasons, it’s a great approach

 If the disease is that type of disease

 

Whereas some of the newest approach is called CRSPR or genome editing

That too is a wonderful approach

I think it’s got a long way to go, ethically and proof of concept yet

But for a disease that is a one gene related genetic disease this is great

You’d be in there gene editing all day – there’s not a chance that CRSPR could be used to solve cardiovascular disease.

 

So where do we fall?

We fall right in the middle, in something called transcription.

So what happens here is you have your original DNA

And it has a message built in it

And what happens is through a process called transcription,

it duplicates into messenger RNA

Now the messenger RNA’s job is to tell the proteins what level to make – more or less of the proteins

So what’s happened in cardiovascular diabetes, chronic kidney disease, is in this transcription phase

There’s been corruption.

Whether that corruption happened from disease, from diet or environment,

It doesn’t really matter, the original DNA message is not being sent.

 

So I’ll used inflammation markers as an example.

The inflammation markers get turned on and the body cranks up the inflammation marker proteins.

Well what happens then they keep replicating saying more more and more

So you have this domino effect and it just keeps creating more inflammation markers, proteins.

And for us the trick was – shut it off. And we shut down bromodomain 4.

So by doing that, you now have your original DNA message being sent.

That is a huge advantage in medicine.

At the same time we’ve been able to do this, we’ve been able move from the very expensive biologic drugs (which mean they’re alive) to small molecule, the cheap drugs, the ones that are a few thousands a year not hundreds of thousands a year. So as we all know from whether you’re listening to FOX news or CNN or CBC, it doesn’t matter.

Pricing issues in drug development are front line, and it’s going to stay front line.

And they’re going to stay front line.

So the fact that we’re actually producing the cheaper version of the drug is a huge benefit for us going forward.

  

SLIDE 11

Now in learning about all of this, we actually in part of that reverse engineering that I was explaining, we went in and we learned a lot of stuff, particularly the main pathways in which this drug works in a cardiovascular patient.

So we started with reverse cholesterol transport, and that was great.

It is one of the top six and it is very important.

But what we learned along the way through some of these trials was that there’s a lot more impact than that. The metabolism pathway, the calcification pathway, coagulation, complement and inflammation pathways are all highly affected, positively by Apabetalone.

 And I’m going to show you some slides in a minute that are published now that really highlight that.

    (From slide)

      Vascular inflammation – Reduces mediators that promote inflammation of vasculature

      Reverse Cholesterol Transport – Increases ApoA-1, positive effects on lipid content of HDL

      Metabolism – Delayed and reduced oral glucose absorption and endogenous production

      Vascular Calcification – Reduces mediators that promote calcium deposition in the vasculature

      Coagulation – Reduces components of the coagulation cascade

      Complement – Reduces components and function of the complement cascade 

 

SLIDE 12

So our first three initial opportunities are really high risk acute coronary syndrome (ACS), high risk chronic kidney disease (CKD) and dementia with mild cognitive impairment (MoCA score <26).

So these are ones that I think we’re going to be ready for, right away with a successful trial. So you.ve got 12 million potential patients right there in just the eight top countries in the world.

So these are numbers that we use in pharmaco-economic studies that we go over with various pharmas, and nobody refutes our numbers. They agree with our numbers, and they’re actually conservative, very conservative. 

 

SLIDE 13

So we took some of that data that we learned from the clinical trials, the pathways.

And this is now published data I don’t think it was published last AGM but it is now. And it’s quite impressive.

So overall we have a 44% relative risk reduction in MACE events. Now this particular MACE is four point MACE, so it does include revascularization. So for each one of these you can take off about ten percent to get close to three-point MACE. That is above and beyond standard of care. So when we show placebo here, the red line, that’s patients on the top dose of statins, beta-blockers, ACE inhibitors, glucose management. There were 500 concomitant meds in those studies. So this is that much better than the best medications that are out there right now, which is fantastic for us. And if you take a look here at the percentage of patients who are diabetic, cause 40% of those patients are diabetic, we have a 57% relative risk reduction in MACE events. That’s heart attack, stroke, MI, and revascularization in this case. So pretty impressive numbers. And again, we looked at the inflammation marker CRP, huge reduction in MACE in those who had high CRP at the beginning of the trial. We were able to bring that down quite a bit and reduce MACE events. So that gives more ammo for our belief in what we’re going to see in the BET on MACE trial.   

SLIDE 14

OK let’s go on here.

So we designed the BET on MACE trial based on that information.

And we were very selective about the patients, because we wanted the sickest patient group.

We wanted patients who had diabetes, who’ve had a major even in 7 to 90 days, and who have low HDL. The reason for the low HDL is because it accounts for about 70% of patients with events.

And unfortunately, I am a bit of a ghoul, because I need to cheer for patients to have events. That’s a heart attack a stroke or a death. Who knew I’d ever cheer for that? But we need 250 of them and I’ll touch on that in a minute, where we are on those numbers. 

 

So everybody gets Crestor or Lipitor.

There are over 2,400 patients

Originally they were only going to stay on for two years, but all patients interviewed wanted to stay on longer, so I think that’s a pretty good sign 

So some of these patients have been on almost three years now.

And then we’ll take an average when we do our statistical analysis.

So it is a well-designed trial

 

And I think the most important part about it is that it included secondary endpoints, pre-specified secondary endpoints, like renal and cognitive function. It’s going to make a big difference in our read out.

 

SLIDE 15

Now this has been taking place all around the world.

It’s been approved for Phase III usage in fourteen countries already.

So this will go a lot faster when EMA or FDA do their final approvals.

So it’s pretty impressive.

The U.S. was a little slow, but as you know In June we got that approval.

So that was pretty exciting. And we’re moving forward with that.  

 

SLIDE 16

Now this slide is a little busy but I wanted to put it in

more as a leave-behind so you can go through it later.

It’s really our product profile.

And this is for Apabetalone in the high-risk ACS, and I’ll show you a similar one for the renal later on.

But - really the primary efficacy endpoints, just to be clear what they are in the trial.

The subgroups, which are the renal the GFR and the cognitive function,

They are very much an important part of this trial.

The expected efficacy outcomes, what we’re expecting in this trial

And the duration of treatment, originally it was going to be about 18 months, but it’s looking like it’s going to be 22 to 24 by the time we’re done.  

And our unique selling points over any other drugs on the market. 

 

SLIDE 17 

So the clinical trial analysis points and some time lines here.

It’s important that we maintain our existing safety profile up until the completion of the trial.

Everything is going very smoothly there.

And as I’ve stated, some of these people have been on the drug for as long as three years now,

And we have had seven straight DSMB approvals.  

It’s an adaptive trial, so we have some options.

And this is where I’m going to choose to be conservative.

We could run the trial for another month or two here and then just stop dosing,

and accumulation of events would happen up until 250.

So technically we could speed up the end-point read-out a little bit here.

I don’t think that’s the right way to go.

I think we’re going to wait until the end of the year, where we’re going to have 250 events.

And then by the time we get to the read-out, we should have around 270.

So this helps with our technical powering as well.

So instead of making a bigger trial, just let it run a little bit longer – thirty, sixty days, whatever.

Let it run a little bit longer and get those 270 events.

 

That could make the difference of hitting your primary endpoint or not hitting it.

And I think we’re in great shape on this, but boy I would hate to have to stand here next year and say

I wish we had done that. That’s not...

And for a short short period of time, I don’t think it’s worth taking that risk.

We’ve all been in this a very long time,

So I don’t think jumping for the finish line is the right thing to do 

 

And that also applies to this futility analysis, and the SSRA or whatever it was called after a while.

Neither appears at this point to have any benefit.

We’re already fully enrolled and we have been since February.

And nobody has seen this data. So it’s not being erased for any reason.

We haven’t seen it and the Data Safety Monitoring Board has not seen it.

The Clinical Steering Committee has not seen it.

Basically if we go down the route even of the SSRA, it will take ‘til December to get an answer.

Well It doesn’t matter what that answer is in December.

We’re not going to stop the trial. We would wrap the trial up and finish the trial.

There are cases, Amgen went through that, where a board actually recommended that they stop the trial and they did not stop the trial. And the trial succeeded. So I wouldn’t want to be in that boat.

 

But more importantly, and the biggest reason why I think it’s just easier to pass right now, is because

once you do this analysis, there is a statistical penalty on your endpoint.

So it only amounts to about one to two percent.

But if it has no benefit and you’re taking a two percent penalty on your statistical analysis

Why would you do that?

 

I mean, we have no reason to do it at this point in time.

And it’s not being changed because we’ve seen something.

Actually I think it would have been great if we could have gotten this done

before we were fully enrolled, which was February; it enrolled a little faster than we thought it would,

and then you can make a decision do you keep enrolling or whatever

But now that you haven’t been enrolling for eight months, well if I put more patients in now,

I’ve got to leave them in at least six months, so that means this trial is going to the end of 2019.

And I don’t think any of us want that. I sure don’t. I’m getting gray enough. 

 

So this is a three-point MACE. And we now stand just almost bang-on 200 accumulated events.

And we’ve been accumulating events at a rate of 10-15 per month.

And historically they’ve been slower in the summer and way higher in the winter.

So we are going into the winter now.

And you can calculate quite easily we don’t have very long to go until we’re at the 250,

And we will end up going over 270 at that point.

We’ve bashed this around with the Clinical Steering Committee, the Data Safety Monitoring Board,

the Board of Directors and no one can see a reason to go forward with the original plan.

And we’ve also informed the FDA and it was fully accepted by them. 

 

So adjudication of a full 270 severe adverse MACE events

will likely take about two months past the end of dosing,

which I’m saying I think we can still do by the end of the year.

So we’re only bumping it a little bit into -

 

We’re adding a nice little percentage here, about 10% in the numbers,

And we’re avoiding a statistical penalty, so I think that is important. 

 

Top line data will be announced immediately upon its availability,

And we’re trying to make sure that we not only announce the top-line data,

But we can give a yay or nay on the renal and the cognitive function as well.

Now what we do after that

Is there’s a lot of analysis to be done. 

We’re talking literally billions of data points here.

And throughout 2019, we’ll be doing full outcomes, pre-specified data end-points,

safety results, clinical implications.

So there will be a lot of publications and presentations at major podiums.

During that time of course we will still be moving full-force ahead

 to have this drug registered with the FDA and the EMA on the key data points. 

 

SLIDE 18

So the committees I’ve talked about – this is the main one.

This is the Clinical Steering Committee.

It says Clinical Advisory Board but it’s the Steering Committee.

And they are the who’s who from around the world.

They’re very excited.

They’ve been putting symposiums for us on around the world

And getting hundreds and thousands of new cardiologists up to speed on this drug

And how important it is moving forward and where we’re going 

 

And on the right side you can see we’ve had a lot of publications of late and a lot more coming

So it’s great to be ten years ahead of the world, but it’s also a pain at the same time.

Or at least it used to be, because people would say

well can you point to a publication and show me how that works.

Well before 2010 there were exactly twelve publications in the world on BET bromodomain.

There are now over 700. And ten percent of those reference us or are us.

So we’re pretty pleased with the acceptance of this technology.

And out of those publications, I have yet to read one that’s a negative against BET bromodomain.

So that’s pretty impressive. And five, six, seven years ago you couldn’t say that.

Everybody was waiting to see what’s in that black box.

So far it looks really really good.

 

SLIDE 19

Now let me talk a little bit about the kidney program.

because we’ve done a lot of extra work on that. 

 

SLIDE 20

We did a trial on it last year specifically.

But first this is one of eight slides.

It’s a busy slide.

All it’s really meant to show you is that we have

a reduction in a key component called alkaline phosphatase (ALP)

And an increase in glomerular flow rate    (Glomerular filtration rate [eGFR])

So for those of you who don’t know what a glomerular is,

it’s in your kidney, it’s kind of like a cow’s udder; it’s a filter.

So your blood filters through it.

When that gets plugged up, that’s when you have chronic kidney disease

There is no medication or exercise to reverse that - yet.

As we were highlighted at the keynote address at the American Society of Nephrology,

We actually had a very nice statistically significant reversal of that.

And we believe we’ll see that or more in this particular (BET on MACE) trial, because this trial is a lot longer.

This particular trial was only six months 

 

SLIDE 21

Now from that data we did the New Zealand study.

So we had eight patients who were really sick.

They had stage four chronic kidney disease,

So they were not on dialysis yet, but they were close.

And we matched them with eight healthy patients.

So these patients were same age, same gender, same weight, but they had healthy kidneys

So we dosed them both with our drug 

 

SLIDE 22

And the results, which are published now in Kidney International

The most important one out there

288 proteins in patients at baseline - these are the sick patients

288 proteins, we did a protein panel of 1,310 proteins

Some of these proteins were as much as 14-fold over producing

Those are inflammatory ones and stuff

So these patients were living in a constant state of inflammation

And remember what I told you is keeping them there?

Bromodomain 4

So our drug is a BRD 4 inhibitor

We give one dose of our drug

And we changed 152 of those proteins in one day

Now that’s pretty impressive

Are you going to take Apabetalone, or are you going to take 152 different single protein molecules?

I think I know which one you’ll take

So this is pretty exciting stuff, because this has never been shown in human medicine before. 

 

SLIDE 23

Now here’s a part of what was published, and it is pretty exciting

These are twenty of the upper end ones.

And they’re in categories here, inflammation, cell adhesion, calcification, and thrombosis.

Every one of these targets, these gene symbols here are protein names.

Every one of them you can go to ClinicalTrials.gov, look up and find a trial

For a single-protein approach to every one of those twenty.

And look at the result we have.

Highly reducing these in one dose.

Here are your healthy patients.

What happened? Pretty much nothing.

Not everybody’s perfectly healthy, so there are a couple little blue lines there.

But these patients, their original DNA message has not been corrupted.

Their original message is being sent through.

The ones that are being corrupted over here, we’re knocking out the bromodomain 4,

and the original messages come back.

 

Now in the future people are going to say this is an insidious plot by pharmaceutical companies

To make you have to take the pill every day,

and I guarantee you it is not, but it is convenient as hell for us.

You stop taking it and it goes right back to the corrupted state.

So you do need to stay on medication, It is not a cure

And of course that does look like a conspiracy theory plot here,

but none the less it is how the biology works

And we’re learning more and more about it as we go forward. 

 

SLIDE 24

Now this is a different way of looking at the same data, and I really like this.

So I talked about the six pathways that I showed you in the cardiovascular patients.

Here are the top five pathways involved when we did the proteomics and pathway analysis in the kidney patients.

They’re what you would expect, some inflammation pathways, acute phase –

This isn’t any big surprise to medicine.

But

 

SLIDE 25

These are these patients at baseline.

So anything in yellow means it’s cranked way up; it’s turned up.

Now I told you about the old protein approach

So the normal drug development approach here is pick a target guys,

this one or maybe this one, or maybe this one

And dose for that and see if you can cure the whole thing.

What do you think the odds are? Pretty low.

So dosing with Apabetalone, you go from this 

 

SLIDE 26

To that, in one day.

So these are all now highly down-regulated.

And I’m not hitting all of these

If I were hitting 152 proteins, I’d have probably 75 toxicology issues to be worried about

I’m hitting one. Bromodomain four causes all of this.

So being able to knock it out

Going from there to there that quick

Is pretty impressive

So this is published and it’s getting a lot of attention,

Especially from the global nephrologists.

There is nothing out there in nephrology for these guys to take

They just watch them go from CKD 1 to 2 to 3 to 4 to dialysis to death.

And it’s just a slow march. There’s not much they can do about it.

Our global lead nephrologists who are working on this are thrilled with having an option here finally. 

 

SLIDE 27

So this is the product profile for Apabetalone in chronic kidney disease

And I just put it up here again, not meant to go through or read it today but just as a take-away

So you guys understand what we’re looking for in the BET on MACE trial as we unroll this data 

 

SLIDE 28

Now I talked about some of the key people around the world in Nephrology.

Kam Kalantar-Zadeh has been fantastic.

He’s the head of Nephrology at UC Irvine.

And he is the gentleman who did the keynote address at the American Society of Nephrology and used eight of our slides.

And the rest are a committee that he put together from around the world.

These are the who’s who in Nephrology.

All he had to do was show them our data.

These guys are excited.

We are adding a seventh member.

She’s coming to us from Bei Jing University. She’s also a global expert in the field.

The reason we’re adding her is that we are planning to launch our kidney program first in China.

And that has benefits, it can move faster.

But also Hepalink is responsible for paying for that portion of the trial.

And I go there tomorrow to see if we can work out some of those details. 

 

SLIDE 29

Now, I went through the investment highlights already

This is just a wrap-up

But it is exciting

It’s a first-in-class drug.

That doesn’t happen very often.

When the PCSK9’s came out there were six or seven of them all racing for the finish line.

And then they stumbled on pricing and other things.

But we don’t have that behind us.

We have nobody behind us.

The next in this category will probably have the RVX initial on it.

So we’re moving forward nicely, and

Safety. Proven track record so far.

And we’re really looking forward to it. 

 

SLIDE 30

No words from this slide, nor any of the Q&A session were included in the webcast. 

Also included were four additional slides that were not shown in the talking portion of the webcast.