Jim Letourneau's Blog

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Alzheimer's Therapy Potential

This post is part of 12 of a 16 part series of posts taken from the transcript of an interview I (JL) conducted with Resverlogix (RVX.TO) co-founders Dr. Norman Wong (NW) and Donald McCaffrey (DM).

What follows is a lengthy and candid interview about the history of Resverlogix, recent events at the American Heart Association meetings, and future plans for the company.

I’ll be publishing two interview segments a day so not all of the links may be active if you are viewing this during March 28-April 5, 2011.

Part 12

This post is part of a 16 part series of posts taken from the transcript of an interview I (JL) conducted with Resverlogix (RVX.TO) co-founders Dr. Norman Wong (NW) and Donald McCaffrey (DM).

What follows is a lengthy and candid interview about the history of Resverlogix, recent events at the American Heart Association meetings, and future plans for the company.

I'll be publishing two interview segments a day so not all of the links may be active if you are viewing this near the end of March, 2011.

  1. Background of Dr. Norman Wong

  2. Early History of Resverlogix

  3. HDL Biology

  4. American Heart Association Meeting - 2010

  5. CETP History

  6. Importance of HDL Type

  7. AHA ASSERT Trial Response

  8. ALTs

  9. Investor Reaction

  10. The Next 2 Years

  11. David vs. Goliath

  12. Alzheimer's Therapy Potential

  13. Upcoming Assure Trial

  14. Volatility of Resverlogix

  15. Resverlogix is Expanding

  16. More on the sell-off

Part 12

JL: How about on the Alzheimer's side, what . . .

DM: I shouldn't say too much about it, because we are planning . . .

JL: But the mechanism . . .

DM: Well, the mechanism is simple. It's the same drug. And Alzheimer's plaque, albeit it's
a little different than the artery plaque, it's a plaque called beta amyloid 40. And it's a 40
amino acid chain. There's a lot of dissension in the research field. . . the smartest Alzheimer's
researchers can't agree on what beta amyloid 40 is. Good, bad or indifferent. Does it have
anything to do with it? The only way you can confirm a true Alzheimer's patient is a pathology
report. So there is no live patient test. A lot of the patients people think have Alzheimer's
don't even have Alzheimer's. They have some other disease.

JL: There's another company, called BiOasis, and they've got a marker, p97, that they think
they can have a pretty good chance of . . . it must tie in. It crosses the blood-brain barrier.

DM: Yeah. There's going to be a few of those. Amorfix is one of them. There's a few of them
trying to determine live tests. And there's a group out of the University of Texas now, Sid
O'Brien. Dr. O'Brien, who's doing a combination of gene studies and
protein . . .

JL: Oh, really expensive. Yeah.

DM: It is expensive. But one of the problems in an Alzheimer's clinical trial is how do you even
know if the placebo patient has Alzheimer's or not? And how do you know if your Alzheimer's
patient has Alzheimer's or Parkinson's or something else? You don't know. Some other form
of dementia? So, it's a lot better now. You can get pretty accurate on it. The scientific
community around Boston and Harvard are really hard core believers in beta amyloid
40 having something to do with Alzheimer’s.

JL: That's what causes the problems?

DM: Yes it may be. And the research community in New York really thinks it's a bunch of
bunk, in general. I'm sure there's crossovers and differences. But the beta amyloid 40 has
had a lot of news coming out on it in the last while. Much like ours and cardio, you always
get the news at a certain time of year. Cardio news always comes out in November and April,
because the American Heart Association and the American College of Cardiology take place
at those times. And the media go and write articles at that period of time.

JL: If you could do it over again, would you still present at that conference?

DM: No. No, I would not. Knowing what I know now, no, I would definitely not. But the
Alzheimer's conference is in July. So in July, there was a whole ton of new Alzheimer's data
coming out, and this week there was even more. But in July, beta amyloid was believed to be
the cause. So it's a plaque protein, 40 amino acids long, and its closest known entity is the
sticky side of the barnacle. You know how hard those things are to pull off rocks. So this stuff
is sticky. In patients who have died and autopsies done, they have an enormous amount of
beta amyloid. That's why some people believe beta amyloid is the problem.

So Alzheimer's programs, these $300 million market cap companies in the U.S., have gone
in trying to break down beta amyloid and cut it into smaller chains of 20 amino acids and to
try to destroy it. These trials haven't been going very well, and some research that came out
in July from Harvard show that beta amyloid appears to have a very important brain function.
It's part of the brain's internal immune system. Getting rid of it, stopping production of it, or
breaking it up may not be a good idea.

So this plaque, although a different type of plaque, has the same biological problem. The
plaque that is in us, in coronary arteries, is a result of too much LDL. Well, LDL, the
bad cholesterol, has a bad rap in its name, because it is cell food, organ food. Every cell and
every organ need those lipids.

JL: Just not too much of it.

DM: Just not too much. So the problem really is the excess. Same with beta amyloid 40. You
have the excess of too much, and this is where you have this sticky mass, and it's kind of
a nesting area for misfolded aggregated proteins that build up, and that's believed to be the
cause of Alzheimer's. Well, there's a new theory now. Because of the possible importance,
you don't want to destroy the beta amyloid 40, because you may be killing the brain's
immune system. Well, how about you just pull out the excess? What's our drug designed
to do? Pull out the excess of plaque, and we already showed in the Phase One study that
on treated versus non- treated, beta amyloid in the blood plasma was 14% higher. And that
means we're pulling the extra beta amyloid across the blood-brain barrier. And if a next trial
can show in a small group of patients . . . and you will actually go in, do spinal fluid tap, so
you will know those patients actually have Alzheimer's. It's a little barbaric, but people are
dying so . . .

NW: It hurts a little.

DM: So you go in, and you get a very good relationship as to who does and who doesn't
have it. If you can treat the sick ones and pull that beta amyloid plaque out, presumably
you're going to have a very profound effect on the further development of Alzheimer's in that
particular patient. There may be only one drug now that can do that. That would be RVX-208.
So we will get some additional material out on this. We've already shown we can do it. We've
already publicly announced we can do it. And we hope to go and show a reconfirm or not. We
hope to get that data out soon.

JL: So is that just by seeing in the blood more?

DM: Yes, that's correct.

JL: Okay. You haven't got monkey brains.

DM: No.

JL: You haven't done that yet.

DM: No. Animal models for Alzheimer's disease are just next to impossible.

JL: Oh, you can't do it, or it's not . . .

DM: It's a totally different disease.

NW: How do you assess the memory of a monkey or a rat? It's tough.

DM: Yeah. And the monkeys lie and the rats cheat. We already have a drug with Phase One
safety approval, so we can go right to a Phase Two human trial. There's none of this six
year build up for the drug like we've had with RVX-208. It is RVX-208. We can go right to
an Alzheimer's Phase Two trial. And we're talking trials that are way shorter and way fewer
people. So we're talking $1 million or $2 million for a trial, not $15 million to $20 million. So
for us, if we can show that we're removing beta amyloid plaque, that has some significant
value to the pharmaceutical companies, and it should eventually to the market as well.

JL: So, are you anticipating getting some board members, because it seems all of your board
members are really strong, world leading cardiovascular guys, but what about Alzheimer's

DM: Already being put together, clinical board members that is.

NW: That's right. There's one person, and we won't mention names, that has both.

JL: If I knew this field, I'd know the name, but I don't.

DM: We will follow the same routine, because I strongly believe in that approach, that we
show it to the best in the field.

JL: Yeah. Why waste your time?

DM: If they say that doesn't look good, then I'm not going to waste my time, like I said. If
they're on board and excited about it, I'm on board and excited about it. So that's what we're
doing. We do believe whether one side is right or not on the beta amyloid, whether people
are right that it's highly involved or not involved at all, it doesn't matter. Nobody has a tool
to study whether it is or not. A paper came out this week confirming that the beta amyloid
excess in the brain, excess production, is not the problem. It's the lack of excretion that's the
problem. So there was a paper that came out, CNN published about it, showing that if a drug
like RVX-208 can pull that excessive beta amyloid plaque out of the brain we would either
prove or disprove one or the other side of this theory, because if we're pulling it out and
these patients don't end up with Alzheimer's, that's pretty good. If we pull it out and nothing
happens and they continue on their course of dementia, well then it's not beta amyloid 40.

But nobody but us seem to have a tool that can do that.

JL: So at the worst case, it's pretty interesting science.

DM: You want to look at your age level and your buildup of Alzheimer's, your rate of
Alzheimer's. It's called the doubling rule. Basically, at 60, 1% of the population will have
Alzheimer's. At 65, 2%. 70, 4%. 75, 8%. And then it gets ugly. Doubles every five years. So
guess what also happens from 60 to those later years. Exact opposite curve. Your body starts
producing less and less apolipoprotein A-1. So there's a direct correlation between the drop
in ApoA-1 and the increase in Alzheimer's.

JL: Wow.

DM: So, we're increasing ApoA-1 and we're seeing this plaque coming out.

NW: Coincidence? No.

DM: You have to market RVX 208 to one company. Otherwise, you end up with a
cannibalization issue. So that's basically how our whole option concept came forward with
potential double digit royalty hopes. If a second indication comes along for RVX 208, the
buyer would take over, but we would get the royalty off of it. So it could work very
well. It would avoid a very big problem. Johnson & Johnson and Amgen have been in a
20-year lawsuit over EPO, which is a growth hormone. They each have a very different
indication, but doctors in the U.S., a doctor can give you a Alzheimer's drug for a heart
problem. So they have all of the rights for one indication, but Amgen selling for a different
indication. But that doesn't help JJ if they're not getting all of the revenues from patients
truly using the drug for their indicated use. Not Amgen’s fault but very problematic for both

JL: Exactly.

DM: So this potential structure was designed to avoid that problem, because that's a big
problem for pharma.

JL: Yeah, absolutely.

NW: You have to understand a little bit, Jim, about what Don has said, saying there are two
sorts of fundamental hypotheses about 208. The one is that the Alzheimer's disease in which
the beta amyloid 40 will come out of the brain. The second is the ApoA-1 effects on HDL
and reversing heart disease. That hypothesis has been around for three decades. We're the
only ones brave enough to go into answering that question. CETP won't. CETP, you're going
to block the synthesis or block the removal of these big particles. That doesn't increase the
production. We're increasing production. That really is exciting.

DM: Yeah. Another thing is, over the years, all of these different pharma studies that we've
done, there's one question that they've always asked us that we didn't have an answer for
because we were busy. We don't have all of the deep pockets that they have. I'm trying to
find a particular slide back here. That question was let's see your animal model that shows
plaque regression.

Well, we went straight from monkeys with great numbers to humans, because our clinical
advisors told us to do that because the data was so good. These animal regression studies
studies cost millions of dollars. So for us, it didn't seem to make sense to keep working on
animals. But over the last year, we've gone back and done these studies.

JL: So you went back to do those studies . . .
DM: Over the last year.

JL: . . . at the behest of big pharma?

DM: Yeah, and also our own comfort level. So what this is, is a regression study. You fatten
up two groups of mice. The ApoE knockout mice, specially genetically modified so that they
get fat really quick. You fatten them up. You do that for about ten weeks. Then, for the next
several weeks you give one RVX-208. Now remember, we're trying to reduce plaque in
humans by 1% or 2%. That could make us a $20 billion a year drug. Well, Norman's mouse
model presentation shows 41% plaque regression. So does our drug work? Does our drug
reduce plaque? Well, apparently yes, and apparently very well. Now, you can't equate that
41% to any percentage in humans. You can't say 41% equals 10% in humans or 1%. You
can't. But you can say, "Does this drug, in a living biological system, reduce plaque?" The
answer is yes, and very, very well.

So are we comfortable going forward? Hell yes. Is safety an issue? Hell no. I would way rather
have our safety profile than this one, than Anacetrapib. I mean it's a scary drug actually.

NW: They stopped 142 patients out of . . . what was the number they had? I've forgotten.

DM: Eight hundred and something.

NW: Yeah. So that's quite a bit. That's like 20 some odd percent.

DM: 17.6%.

NW: Yeah.

DM: That's a pretty big number and then to list it as not a safety issue.

DM: . . . does RVX-208 work? Is it safe? This is exactly what we continued to prove all along.
Then if you show those numbers where you've got 1 versus 85 in the ASSURE population, we
shouldn’t even see the safety issue going forward. Later we can try to prove that those guys
have so much plaque going through the liver that the liver is just turning on its signal saying,
"Wow, what is this?"

JL: Well, it seems a lot of the comments were made kind of on the spot, on the fly.

DM: Yeah. Many didn’t understand the data.

JL: They probably didn't . . .

DM: Media comments were made before our data was presented.

NW: Before 11:00. How could they know what we were going to present?

DM: That Bloomberg article came out three hours before our presentation.