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Executives

Stan Crooke - Chairman and Chief Executive Officer

John Kastelein - Chairman of the Department of Vascular Medicine, Academic Medical Center with University of Amsterdam

Joseph Witztum - Director of the Atherosclerosis Research Group at the University of California, San Diego

Rosanne Crooke - Vice President of Cardiovascular Research

Richard Geary - Senior Vice President of Development

Sam Tsimikas - Director of Vascular Medicine, University of California, San Diego

Analysts

Andrew Goldsmith – Canaccord

Isis Pharmaceuticals, Inc. (ISIS) ISIS-APOCIII Rx Conference November 19, 2013 8:15 AM ET

Stan Crooke

The purpose of the event this morning is to review the Phase II data on our novel Triglyceride drug ISIS-APOCIII Rx and to discuss how this drug could enhance the treatment of patients with severely high Triglyceride and FCS. We’re obviously very pleased with the data on ISIS-APOCIII Rx and look forward to initiating our Phase III program in the first half of the next year. We hope that after the presentation today that you will be as excited as we are about the potential for ISIS-APOCIII Rx for these patients who have very high Triglyceride and of course are in desperate need of new treatments. Before I begin let me note that we will be making forward-looking statements and you’re cautioned to keep that in mind. Joining me today are Dr. John Kastelein, Professor of Medicine, Chairman of the Department of Vascular Medicine, Academic Medical Center with University of Amsterdam, Dr. Joseph Witztum, Professor of Medicine and Director of the Atherosclerosis Research Group at the University of California, San Diego, Dr. Rosanne Crooke, Vice President of Cardiovascular Research at Isis, Dr. Richard Geary, Senior Vice President of Development of Isis and Dr. Sam Tsimikas, Professor of Medicine and Director of Vascular Medicine, University of California, San Diego.

This is our agenda for today’s events. I’m going to get us started and then Dr. Kastelein will discuss the challenges, situations faced today and treating patients with very Triglyceride’s and why new treatment ISIS-APOCIII Rx are needed. Dr. Witztum then will outline the current therapeutic treatments options for patients with severely elevated Triglycerides in FCS and then after Dr. Witztum, Rosanne will give the presentation (indiscernible) with the American Heart Association’s meeting. In this presentation Rosanne reviewed the data from all of the Phase II studies reported this year including a complete efficacy data for the monotherapy Phase II study in patients with very high to severely high Triglyceride.

After Rosanne, Richard will provide more detail on our Phase III plans for ISIS-APOCIII ISIS-APOCIII Rx. Richard will also provide a quick review of the Phase I data from our drug design to reduce Lp(a) for which we presented data at the AHA event this weekend. Lp(a) it's another atherogenic lipid that is an independent cardiovascular receptor and we’re certainly very pleased to advance this drug in the Phase II trials. There is another recent that our lipid franchise is so exciting to us and finally I will briefly review the commercial opportunity for ISIS-APOCIII Rx. As you know we plan to move ISIS-APOCIII Rx into Phase III on our own without a partner. We view this program as one of the most important assets in our pipeline. By the way was Lyn was going to cover the commercial opportunity today but she is off busy doing something else today. So you will have to hear from me. We will then open up the event for questions. At this point all of our panelist will be available to answer your questions and we will also have Dr. Sam Tsimikas who will be available to answer your question. Sam is an interventional cardiologist who treats patients with severely high triglyceride as well as patients with high Lp(a) and is an expert in all of these areas.

Today our primary focus is on triglycerides. Patients with extremely high triglycerides are at a significant risk for many serious health conditions including frequent episodes of pancreatitis which can be life threatening and require hospitalization. High levels of triglycerides often resolve in insulin resistance which itself is an important risk factor for peripheral cardiovascular disease stroke and coronary artery disease and of course triglycerides are an independent risk factor for cardiovascular disease. I’m particularly excited about the profile of ISIS-APOCIII Rx in that it produces an optimal change in lipid profiles and improves measures of glucose control.

Slide 6 shows the lipid franchise that we’ve created. We believe that this pipeline represents the most comprehensive approach to treating dyslipidaemias in the industry. One goal of this program is to provide lipidologist and other physicians a toolbox of drugs that can be used in combination or a single agent to help manage dyslipidaemias. Much of the industry is focused on LDL cholesterol, there are several other lipid targets that are independent risk factors for cardiovascular disease and other significant health problems.

There are few therapeutic interventions that effect to reduce these important lipids. The LDL cholesterol is today well addressed with drugs on the market and in late stage development, yet lipid related health issues continue to grow so lipid related health issues go well beyond LDL cholesterol and there is a need that continues to be there for these other opportunities and these other risk factors focusing on these other lipid targets provides us the opportunity to create additional therapeutic opportunities that we think are badly needed.

Kynamro was approved this year to treat patients with Homozygous FH because of the mechanism of Kynamro treatment with this drug has been shown to have a positive effect not only on LDL cholesterol but on all other atherogenic lipid as well. ISIS-APOCIII Rx is of course the topic of the discussion today. This is a drug that has been shown to reduce ISIS-APOCIII Rx both as a single agent and in combination with fibrates does so equally well in every patient population we have studied and it worked equally well irrespective of incoming triglyceride levels.

So we’re hopeful that ISIS-APOCIII Rx could be used in patients who are currently taking triglyceride lowering drugs as well as those who are not taking any of the currently available medicines. And in all of our clinical trials to-date, our ISIS-APOCIII Rx has been very safe and very well tolerated. ISIS-APOCIII Rx is the next drug in the franchise, patients with Lp(a) elevated Lp(a) have an increased risk of cardiovascular disease and when Lp(a) is severely elevated it is often the primary driver of the cardiovascular disease because elevated levels of Lp(a) are primarily genetically determined. Lp(a) levels are stable over a lifetime, they are unresponsive to changes in diet and they are unresponsive to changes in physical activity. There are no effective treatments available to-date to lower Lp(a).

We just completed a Phase I study with ISIS-APOCIII Rx and we’re very encouraged by the activity and safety of the drug that we’re seeing so far. These data were presented Sunday at the AHA and Richard will be showing you some of these data little later on and then finally the newest entrant in our franchise is ISIS- apolipoprotein C-III [ph], this is a drug designed to reduce apolipoprotein C-III. This is another genetically validated risk factor for cardiovascular disease and we expect that this drug will be able to reduce both triglycerides and LDL cholesterol and other lipid risk factors as well. So you can see we have a very broad and very comprehensive pipeline of drugs to treat dyslipidaemias because (indiscernible) drugs we expect them to be highly efficacious to have no drug-drug interactions and work equally well as a monotherapy or in combination with other lipid drawing drugs.

So that is a big agenda for us over the coming years in the management of dyslipidaemias and with that I’m going to pass the baton over to John Kastelein now. John you’re up.

John Kastelein

The triglycerides that are mostly associated with coronary artery disease and severely high elevated levels of triglycerides which are associated with other conditions such as pancreatitis and sometimes as I’ve seen in my own patients premature death. I will also show you that in fact in the current climate lowering in the lower range is expected to have a greater benefit than going down to very low LDL levels.

Third, I think that the existing therapies that we have for triglyceride lowering are inadequate and what we have learned with some very exciting biology and we’ve actually also learned it APOCIII (indiscernible) inhibitor is that APOCIII is pivotal in the whole physiology of triglycerides per say.

So let me remind you of this graph and then please concentrate with me on the grey lines indicates the risk in a group of diabetic patients with coronary artery disease going down the line of LDL and when I started medicine and started lipid lowering drugs it was about 1988 when the first statins were there. In those days as you can appreciate on the right hand corner LDL levels in these individuals were 200. We moved all these individuals down to about 80 now and as you can appreciate that line is extremely steep so the absolute benefit that we have gained in the last 15 years or so is immense and every clinician is witnessing that today with the lower event rates.

In the next 5 to 10 years what we now have to do is to nullify other risk components of this lipidemia and as you can appreciate moving from 80 to 40 is going to be associated with a much less greater absolute benefit, so that is very important observation and that is one of the reasons that’s for example the PCSK-9 monoclonals have trials that are well over 20,000 people because they have very, very efficient LDL lowering but since they lower LDL from 80 to 40 they don’t need very many people to show an effect.

We all know that current patient that we see in our clinic does not only have LDL as a sole abnormality, in fact with all of the diabetes and obesity we see increase in patients that have both elevated LDL as well as elevated triglyceride levels. And the question of course is if we give them high potency statins or high efficacy statins do we get rid of the risk of triglyceride. You see here three very large statin trials, our protection study on the left, care and lipid on the right and you can appreciate from the brown graphs that individuals that are on statins with high triglycerides in fact still are at much higher risk than those individuals that just have lower LDLs. This is well known and in our field we call it the lipids triad because these individuals very often have high triglycerides, low HDL, elevated LDL. So there is a specific constellation in which statins do not take care of all the risk. In fact in the proven data this was beautifully illustrated by Chris Cannon from Harvard Medical School where on the left hand panel you can appreciate as we all know that those with an LDL of above 70 do worse than those with an LDL below 70. So moving LDLs from below 70, sorry from above 70 to below 70 we will be associated with benefit but exactly the same on the right hand panel was in fact published and reveled on the triglycerides those with trigs over 150 did worse than trigs below 150 and in fact as I will show you in the next slide moving from triglyceride over 150 right hand side to triglyceride’s below 150 is associated with a greater benefit than moving from an LDL above 70 to an LDL below 70. Now of course we’re not the only one that have appreciated this and there are a number of novel strategies in development and in my opinion the APOCIII inhibitor is the most promising of those.

Now this was basically to give you an introduction on this very frequent atherogenic lipid triad, what is in terms of health I mean health concern for us clinicians even more important is that there is an increasing number of individuals with extreme or severe hypertriglyceridemia.

There are approximately 50,000 patients in the U.S. and there are an approximate number also like that in the EU and they have severe hypertriglyceridemia. So we now are no longer talking about over 150 which is in the moderate range, we’re now talking above 80 and these individuals already are on all sorts of existing triglyceride lowering drugs and on the low fat diet.

Interestingly what can be seen is those individuals also very often about 1/3rd have diabetes so there is this I would say conjunction of sever hypertriglyceridemia, insulin resistances, metabolic syndrome, diabetes and dyslipidaemias and these individuals have a risk of a disease that has nothing to do with heart disease, this is acute pancreatitis and as you can appreciate that acute pancreatitis very often leads to admission in an intensive care unit and can even be associated to premature death but it's definitely because it's often recurring leading to more hospitalizations, surgery and if the pancreas is fully destroyed after 4 or 5 episodes you buy definition have no longer insulin and now you’re a diabetes mellitus type 1 patients.

Interestingly and this is something that cannot be stressed enough, they have also a high risk for cardiovascular disease and this is thought to be linked to APOCIII. The standard therapy that we have for these individuals was very severely elevated triglycerides include nicotinic acids for example, fibrates and fish oils and although they all lower triglycerides none of these therapies is capable of bringing patients back to the level where the risk of pancreatitis is basically zero and then on top of that of course there are side effect issues with these drugs not with the fish oils but definitely we think nicotinic acid and the fibrates that often make them very difficult to combine with the statin which is something that we do not want because these individuals have high risk for cardiovascular disease so very, very often they have statin therapy as baseline. If you look at the risk and it's difficult to express this but we’ve a very large clinic in Amsterdam of individuals with the severe syndromes and we used to call them when I was young Type 1 and Type 5, I’m no longer allowed to say that but in fact if you follow these individuals over a life time almost all of them get a pancreatitis or two. So it's difficult to express it overtime but in my clinic I hardly have patients that have not experienced an episode of pancreatitis or severe upper abdominal pain.

And we also know that if we can bring those folks down to trig level below 500 in the moderate range then there is still the remaining cardiovascular issue of course but there is no longer the pancreatitis issue. Now why on earth has this something to do with Apolipoprotein C-III. Now not to make your morning too complicated, I will be brief APOCIII is one of the Apolipoprotein’s. It's a protein like APO-A1 associated with HDL and that’s good for you, Apolipoprotein B associated with LDL, supposedly that for you and this one APOCIII is a small protein produced by the liver that we have understood and this is very recent data that it's absolutely key in the regulation of triglyceride levels and it is key because it inhibits enzymes that breakdown your triglycerides and in fact it also inhibits the uptake so it actually inhibits the whole triglyceride breakdown and removal pathway at different points at multiple points and that’s why it's such a crucial protein. Very interestingly at the same time very large studies have established that it's also an independent risk factor for cardiovascular disease and therefore we call it a genetically validated targeted and as you know in drug development these days we would like to see that a target is genetically validated first before we decide to move it into a preclinical animal models and into human development because we have seen many failures with targets that were not genetically validated in humans and why do I use the word genetically validated? Now what’s very interesting is that there are always experiments with nature where you and I have a 100% levels of APOCIII.

If you’ve a mutation in one of your genes by definition you lose half because you’ve two genes for one trait so you lose 50% of your activity that mimics a drug, that’s like inhibiting it with 50%. So studying those individuals is like studying individuals on drug therapy and it's so interesting because people that have mutations in CIII in fact have lower triglycerides, lower heart attacks, improved insulin sensitivity and in fact from studies they are just simply in better health and they live longer and it's also interesting is that we’ve individuals in our clinics that have higher levels of APOCIII and in fact they show the exact opposite of the picture. Higher triglycerides the clearance [ph] is impaired and they have an increased incidence of heart disease, insulin resistance and liver steatosis or a disease called MESH.

So these are rare family so you will yeah that’s a lower numbers and show me something better, well the Broad Institute in Boston has done something better, they have done these very large wide genomic studies and we now have data from over a 100,000 individuals that unequivocally link CIII quarterly [ph] to lower CIII and lower risk of coronary artery disease. So that is in fact what we call a genetically validated targeted and for example if you will take the example of LDL cholesterol familial hypercholesterolemia would be the ideal genetic validation for LDL as a target and you can basically do that with all of those Apolipoprotein’s.

So with that I would now like to give the chair to Professor Witztum because he will share with you what our current options are for the management of these individuals.

Joseph Witztum

Good morning what I would like to do today is share with you little bit about how difficult it is for patients with these very, very high triglycerides and then I would like to explain to you the path of physiology why these patients have high triglycerides and get in trouble and then example to you the role of APOCIII and this disorder and we have learned now it's those central in their control. So this is a cartoon to try explain to you what’s happening and Erlenmeyer flask represents the plasma pool or the plasma circulating volume of triglycerides and as you can see there is a normal level of triglycerides it's toward the bottom of our flask and as where most of us hopefully have our plasma triglycerides it's low, it's relatively constant. Now we have two inputs into the plasma pool of triglycerides, one comes from the liver in the form of VLDL particles, they are triglycerides rich like [ph] proteins and the other source is from the intestine where the diet absorption of triglycerides which is the main fat we eat comes into the plasma in the form of chylomicrons and so these are the input sources.

Now at the bottom of the flask we have, there are two output sources and on the left side of the slide you can see there is an enzyme called Apolipoprotein (indiscernible) that you just heard about and this is always thought to be the rate limiting step in the clearance, breakdown of triglycerides and we will call that the LDL dependent pathway and on the right side you see that there is another pathway which summed up probably a variety of pathways we will call the LDL independent pathway. Now after the triglyceride which is called a triglyceride because it means it's a glycerol molecule with three fatty acids and so what happens is when they are broken down by the lipases is that you create fatty acids and the fatty acids are the fuel that the body uses and so if you’re exercising the muscle takes up the fatty acids, uses it as a fuel source and is a very good way and that’s why exercise is so important and so efficient for example and so effective in triglycerides and normal people.

If you’re a couch potato or you’re a postprandial then the fatty acid is going to the adipose tissue where they are (indiscernible) back to triglycerides and stored for later use.

And the third source uptake is that the fatty acid will go back to the liver where it can be used by variety of sources but can actually even be resynthesized and come back out and again it's the LDL. Now we made this cartoon to have a Erlenmeyer flask to emphasize the fact that the normal person has low triglycerides, there is actually a large buffer capacity to if you say you go out you’ve a big McDonald in French fries full of fat you have the capacity to absorb that, your triglycerides will only go up a little bit and so that’s an important point and then the other important point I want to make is that the work started here it was thought that the main mechanism by which APOCIII caused triglycerides to be elevated was that inhibiting the Apolipoprotein LPL dependent [ph] pathway. So the idea was that if you could inhibit APOCIII you would relieve that, you would make the LPL dependent pathway more effective and then you would triglyceride clearance. Now there is a special syndrome that you heard about called familial chylomicronemia syndrome we will call it FCS which is a very rare condition and in this what happens is the patients or homozygous for a deletion or a mutation in the LPL gene which causes both copies of their LDL protein to be defective. So in a homozygous patient as shown on the left, they really have no LPL activity. Well what happens as you can see is that the plasma pool fills up very rapidly and because it's narrowed the very top is essentially a very low buffering capacity. So now the patient goes out and he has a high fat meal once or twice and you see there is no capacity so the triglycerides really become very elevated or they drink some alcohol which stimulates the liver to make more triglycerides among other things and again you fill up the blood pool and the triglyceride is very rapidly go up.

Now when we started this one would have predicted that if you give a drug that inhibits APOCIII the APOCIII Rx of ISIS it really should not work in these population of people because they don’t have LPL but one of the beauties of first of all this kind of technology is that you’re directly inhibiting APOCIII you’re not see the chance of having any kind of other reactions are almost nil and people went ahead at ISIS and I think it was a wonderful experiment and now we know that in fact it was very effective at lowering triglycerides in patients with FCS and so that’s taught us a whole new level of biology and that is that APOCIII is also involved in this LPL independent pathway as well and so you can see why APOCIII appears to be so central in the clearance of triglyceride rich lipoproteins.

Now patients with FCS really have a lot of clinical symptoms and on the lower left you can see that their plasma actually looks milky and that’s because milk really is solution with a lot of chylomicron like and VLDL like particles that’s what milk is. In fact when you’ve cream those are all of chylomicrons and that’s what these patients get but you can imagine that’s not very good for you as it circulates and blow [ph] it. Many problems with this, the most feared problem is that they get very severe pancreatitis and as you heard from John patients who all have high triglycerides are at great, great risk for that but they have many other complications for example they can get these erupted [ph] them it's almost on the skin. Their eyes look, if you look in the background you can see they have this milky retina and actually they have all kind of mental symptoms, they can have trouble hearing, they can become forget and all kinds of other complications. (Indiscernible) clear by giving you two quick, two patients that I’ve seen in the last couple of years, the one was a 21 year old female college students who presented to the emergency room with severe abdominal pain and she had been out partying the night before at a fraternity house and obviously drinking and she should have known better she had a history of recurrent episodes of pancreatitis but she was young.

Her triglyceride levels were 4500 and her diagnosis was pancreatitis. The other patient is a 46 year old biotechnology executive who presented to the emergency room not only with severe abdominal pain but he actually was in clinical shock and that was because he was having hemorrhagic pancreatitis and he had to be admitted in emergency basis to the ICU. His history that had been depressed and drinking and not following a low fat diet which he knew he should be on and his wife assured us that he had been his fibrate every day though. He had some milder episodes of abdominal pain since youth and actually had an episode or two of pancreatitis and he has a brother who has a very similar history. His triglycerides were actually 15,600.

When his plasma was taken out and just put on the test tube literally on the bench, it actually you could see cream on after a couple of hours, you can just see it settles out. I mean that’s an extraordinarily high triglyceride level and he really did have life threatening pancreatitis and hyperlipidemia.

So I want to switch gears now and talk about not patients with these, there are many, many thousand triglycerides with triglycerides at 880 or greater. So these patients have a really clinical syndrome much like the others except their triglycerides are lower and importantly almost all of these probably have a genetic component to their disease. These were formerly categorized as Fredrickson Type 5 which means of lots of VLDL and lots of chylomicrons and really the symptoms and risks are similar to those of the FCS particular when they do something that raises their triglycerides but these patients as John mentioned also appear to be a much higher risk for cardiovascular disease and for diabetes. So using our cartoon we can kind of see the pathophysiology, so their baseline triglycerides you can see are not as high the Erlenmeyer flask is not quite filled up but the capacity observed new triglycerides is very limited. So they have triglycerides of 880 and so they now have some kind of indiscretion it very rapidly can fill up and they actually achieve the same kind of high levels as in the FCS patient. So again they can’t, they have to watch their diet and they have to watch for example if they are overweight and the liver makes more VLDL or they drink alcohol then you have both source of inputs again.

Now the etiology at the bottom, the output is more complicated. Many of these patients in fact are heterozygous for the LPL dependent pathway that is one of their genes is normal and so it's able to handle some of the triglycerides, particularly if they watch all the inputs but the other LPL gene is defective and so they can’t handle an excess. But they also appear to have defects in the LPL independent clearance pathways as well and as we have just seen that APOCIII is a very clearly involved inhibiting these pathways and that’s really you can see then why inhibition of APOCIII protein by the antisense approach really is an ideal way to treat these patients. So in addition to all of the other symptoms that patients can have, they can have Type 2 diabetes, they have cardiovascular disease and so it's a very complicated patient to take care of.

Now this slide which represents a slide from the (indiscernible) study looking at what kind of drugs patients who have very high triglycerides are on and basically the point to make but not to go through it is that they are really very little, very few patients on drugs and the reason is that physicians know that very high triglycerides like this they don’t respond. I don’t even use them in these patients by and large and most of us don’t find that they are not useful and that’s the problem. So finally let’s just ask what would be an ideal drug that would work in such patients with severely high triglycerides and we would like it to of course and must have substantial triglyceride lowering. It should work for triglycerides at all different levels and we think for the reasons I’ve outlined to you that it should lower APOCIII. It would also be nice to have a drug that improved glucose control, improved the lipid profile, increase HDL cholesterol and had of course safety and tolerability and I would suggest we really do not have any drugs that meet these criteria for the reasons outlined from understanding the path of physiology. We think that the APOCIII Rx is going to be a medication that will in fact beat this very important niche.

So with that I’m going to turn it over to Rosanne who is going to actually tell you something about the data.

Rosanne Crooke

Thanks Joe and good morning everyone. We conducted a broad Phase II program in patients with high to very high triglyceride levels, this slide shows the treatment design and the patient population evaluated. We have reported data on each of these patient population this summer. Today we’re reporting the final set of data for the monotherapy study. This study evaluated three different doses 100, 200 and 300 mgs of ISIS-APOCIII Rx dose weekly for 13 weeks.

However essentially we believe the first indication for ISIS-APOCIII Rx will be in patient with FCS I will show a bit of a data from our FCS trial first. While we’re thrilled with all of the data we have reported the most impressive of these were the effects of ISIS-APOCIII Rx on APOCIII and triglycerides in patients. In this open label study the three FCS patients treated had incoming triglyceride levels on average of 1844 mgs/dL.

Treatment with ISIS-APOCIII Rx produced significant rapid and profound reductions in APOCIII in all of the three patients as shown on the slide. Now in this graph we show the effects of APOCIII Rx on fasting triglyceride levels. After treatment with our drug we absorbed an average reduction in triglycerides of 69%. More importantly two or three patients achieved triglyceride lowering a greater than 1500 mgs/dL and all three patients experienced triglyceride levels below 500 mgs/dL.

This is an important milestone because as John discussed earlier below 500 mgs/dL a patient’s risk of pancreatitis drops to nearly zero. Now let me review the final data from the monotherapy study. As I mentioned this study evaluated 100, 200 and 300 mgs of ISIS-APOCIII Rx dose weekly for 13 weeks. In this slide and then in the next several slides we show the time course effect of our drug. In each graph the shaded areas which are on the left hand side of the graph represents a dosing period and the right triangles at the bottom of the graph represents a weekly doses. As you can see in this slide our drug produced a rapid, profound statistically significant reduction in APOCIII at the two highest doses with a less but still positive effect at the lower 100 mg dose.

Here we show the effects of ISIS-APOCIII Rx on fasting triglyceride levels. Similar to the observations for APOCIII we have robust statistically significant reductions in triglyceride. These reductions were observed early in the treatment and were maintained during the entire treatment period. In the 300 mg dose group there was a 71% reduction in the main fasting triglyceride levels. Now this graph shows the actual reductions in triglycerides, it is particularly important that in the 300 mg dose cohort mean fasting triglyceride levels dropped into the normal range that is below 150 mgs/dL by 857 and remained under 150 mgs/dL through the end of dosing.

Here you see some wonderful model (indiscernible) showing percent change in triglyceride for all patients in the monotherapy and fibrate studies. Note that all the patients in the 300 mg dose group displayed substantial triglyceride lowering and respond to 200 mgs was similar. Given the long half five [ph] of ISIS-APOCIII Rx we would expect to see additional triglyceride reductions in all treated patients with continued dosing.

Similar to our earlier studies, ISIS-APOCIII Rx caused a rapid profound and prolonged increase in HDL cholesterol which is the good cholesterol. Again the significant increases were apparent early in the treatment in similar for the two highest doses tested.

The magnitude of (indiscernible) increases at all doses are actually quite remarkable and represent another important benefit of ISIS-APOCIII Rx. So to summarize we absorbed improved lipid profiles in all of our Phase II studies and in the study we presented that some are in patients with high triglycerides and Type II diabetes we also absorbed improvements in measures of glucose control consistent trends and improved insulin sensitivity indicating that our drug could provide benefits beyond an improved lipid profile.

This slide summarizes the overall clinical safety profile of our drug across the four Phase II patient population studies. We’re very encouraged by the safety profile to-date. There has been no drug related elevations of liver enzymes greater than three times upper limit than normal even when the additive statins by rates or metformin.

There are no changes in renal function, there were no clinically meaningful changes in other biochemical or hematology lab values and there were no flu like symptoms associated with the treatment and the drug has been very well tolerated. The most common AE has been in frequent injection side reactions that were predominantly mild in nature. In fact ISR [ph] has occurred in less than 10% of the injection and there were no discontinuations due to ISRs.

And now I would like to introduce Dr. Richard Geary to review our plans for the Phase III program for ISIS-APOCIII Rx.

Richard Geary

Thank you Rosanne. So we have now demonstrated that ISIS-APOCIII Rx has an ideal profile and it produced unprecedented lowering of lowering triglycerides, improvements in overall lipid profiles including greater than 50% increase in HDL which of course has never been seen with triglyceride lowering therapy.

Added to all of this we have seen improved glucose control and Type 2 diabetes in turns and improvements with insulin sensitivity and no identified tolerability or safety issues to-date. So we believe this is a remarkable profile and sets the stage for our Phase III program.

So just to remind everyone ISIS-APOCIII Rx is a wholly owned drug that we plan to develop for both FCS patients and for patients with severely elevated triglycerides greater than 880. We plan to pursue FCS as our initial indication which we believe will provide us with a rapid path to market. We plan to conduct a two phase three programs, we plan to evaluate ISIS-APOCIII Rx in patients with FCS and in parallel, we plan to evaluate our drugs in patients with triglyceride levels greater than 880 mg/dL.

The Phase III programs should get underway in the first half of 2014 after we have our U.S. and EU regulatory inputs into the plan. This schedule puts us in line to potentially we have Phase III data in 2016 to support a regulatory filing for FCS.

So to summarize our Phase III plans for our next step in our Phase III plans is to conduct our end of Phase II meetings with both U.S. and EU regulators. We hope to conduct our end of Phase II meetings in early 2014 or we had hoped to very early in 2014 or even late 2013 but the FDA has asked that we schedule our end of Phase II meeting after the submission of our completed chronic toxicology studies.

We also plan to have our EU meeting in the same time frame. Once we have these meetings we will be finalizing our Phase III plans with the goal to initiate the Phase III program in the first half of 2014.

We’re optimistic that we will be able to file an NDA for this drug in 2016. Before I turn the podium back over to Stan to discuss the commercial potential I wanted to spend just a few minutes reviewing the other set of data that we presented this weekend today at AHA and this is a Phase I study with the Lp(a) lowering drug ISIS-APOCIII Rx.

Lp(a) has produced in the liver when combined with LDL it creates a lipid particle that is very atherogenic. As Stan [ph] said earlier APO(a) is genetically validated risk factor for cardiovascular disease and in some patients severely elevated Lp(a) appears to be the primary driver for their cardiovascular disease. Lp(a) levels in the blood can vary greatly between individuals due primarily to genetic variances. As a result, Lp(a) levels remained constant throughout the life of an individual and diet and lifestyle changes have a little impact on Lp(a) and current therapies are not able to adequately reduce Lp(a) to acceptable levels.

So as this slide detects Lp(a) is a bad actor for many reasons including a number of factors that are known or believed to be a prothrombotic as well as proatherogenic. In our Phase I study in healthy volunteer’s treatment with ISIS-APOCIII Rx produced dose dependent robust and prolonged reductions of up to 82% in Lp(a).

These reductions were independent of baseline Lp(a) levels. In fact this normal volunteer study in this volunteer study we did have subjects with very high Lp(a) levels for example we had a subject with an incoming Lp(a) of 98 mgs/dL that we can substantially lower Lp(a) even in patients with very high Lp(a). It's quite important because our focus in on treating patients with extremely elevated Lp(a). In this table we have compared the effects of ISIS-APOCIII Rx on Lp(a) and oxidized phospholipids. In this study subjects treated with our drug experienced mean reductions in oxidized phospholipids of up to 38%. Oxidized phospholipids are very atherogenic and many believe that oxidized phospholipids loaded on Lp(a) are a proximal cause for atherosclerosis. We’re obviously very encouraged with these early data and we plan to begin a Phase II program on ISIS-APOCIII Rx next year.

And now I would like to turn the podium back over to Stan.

Stan Crooke

Thanks Richard and thanks to all of our other panelist. I’m going to just spend a minute on the commercial opportunity that is represented by ISIS-APOCIII Rx but before I do that I want to address one comment that Joe Witztum made. I want to make it very clear that the 46 year old biotech executive who was depressed, drank and had a bout of pancreatitis was not an ISIS executive. We don’t allow depression and more over we don’t allow people to take off work. If you’ve pancreatitis you come to work. I’m concerned about our reputation. So I think the Phase II experience that we have had with ISIS-APOCIII Rx is really remarkable and I think it demonstrates a unique and ideal profile for drug for patients with very high triglycerides and while we have summarized all of the effects on lipid parameters today I do want to remind you once again that we did demonstrate significant improvements in glucose control and trends toward enhanced insulin sensitivity, that is an extremely important added profile on the commercial side of things for ISIS-APOCIII Rx because so many of these people have Type 2 diabetes.

Each of the two patient populations that we’re targeting with ISIS-APOCIII Rx represents to us an important and very accessible commercial opportunity. Treating these very rare patients with FCS provides us with a rapid initial path to market and a small focused patient population that means it should be possible for us to handle the initial commercial launch for ourselves if we choose to. The larger but also rare second indication in patients with triglycerides greater than 880 mgs/dL provides us an opportunity for the initial expansion of the commercial opportunity for ISIS-APOCIII Rx. So let me now just focus a bit more on these two distinct populations. Firstly FCS patients, there are about 3000 to 5000 FCS patients worldwide, so it's a very rare disease. FCS patients has you heard from both John and Joe are often identified because of the symptoms of the high triglycerides and that typically is abdominal pain and pancreatitis.

Overtime the pancreatitis recurs and these patients can in fact lose fully the function of their pancreas and become Type 1 diabetics. Most of these patients are identified today and they are typically referred to lipid specialist. In the United States we now know that there are about 600 to 700 physicians who specialize in the management of severe lipid disorders. In Europe FCS patients are often found in geographic clusters because it is genetically determined but both in the U.S. and in Europe and this I think is really quite important and it's been demonstrated at the AHA here this year, there are increasing efforts to raise awareness of FCS so that these patients can be correctly diagnosed much earlier and get cared for by the lipid specialist.

One of the stimuli for these efforts to bring Lp(a), FCS into the light is it's a they are drug into the development of FCS. For example Novartis’s Phase III program for DGAT1 inhibitor in FCS patients. It's gone a long way to increasing awareness of FCS in both the U.S. and EU and of course as we begin our Phase III program we benefit from the work that Novartis has done.

Of course the most important stimulus for early diagnosis will be truly effective treatment for FCS and we believe in ISIS-APOCIII Rx for the first time physicians may finally have a treatment that could really lower these people’s triglycerides and bring in real benefit. So we think that commercial opportunity represented by FCS is substantial and very attractive for us. And we’re certainly thinking about both U.S. and ex-U.S. markets as possible opportunities that can be addressed by very small, very focused and very well trained sales force.

Now let’s look at the second indication for ISIS-APOCIII Rx, seizure patients with severely high triglycerides or patients whose triglycerides are greater than 880 mgs/dL despite the fact that they are complying as well as they can with diet and taking whatever available medications they can tolerate. So they are about 50,000 of these patients in the United States and Europe but unlike FCS patients these patients are treated by wide-range of physicians and of course many of these people do have Type 2 diabetes so they are very often treated by endocrinologist. They may also have a cardiovascular branch, so some of them will be treated cardiologist and then still others will be treated by lipid specialist. So this is a very different set of physicians and a much more commercial opportunity and commercial challenge and so it will represent a different type of launch. So given these factors this second indication which is rear disease opportunity but I think it will require a sales effort that’s different and broader than the sales efforts that would be needed in FCS.

So as we said patients with elevated triglycerides are in desperate need of new therapies and we think current therapies are not effective sufficiently in these patients. So clearly drug that can reduce triglycerides by 70% or more, would provide patients with a level of therapy that no existing drug can come close to providing and importantly ISIS-APOCIII Rx can be used in addition to other triglyceride therapies that these patients may be taking. So, and again bringing added benefit. What patients with severely elevated triglycerides need is drug that works, that really can lower the triglycerides in these people at least below 500 mgs/dL and substantially lower than that if possible. And we also think that these people need a drug that improves their overall lipid profile and brings benefit with regard to their Type 2 diabetes that they are very frequently have and if you look at that table you can see that we think that ISIS-APOCIII Rx is demonstrated as everyone of the attributes that you would desire to have if you were thinking about this as an opportunity.

So now back to the pipeline, we continue to believe that Kynamro was an excellent drug but we are well focused well beyond just the management of LDL. We think that these drugs in this pipeline will change the management of dyslipidaemias and create a remarkably valuable franchise for lipidologist and the patients they take care of. So with that what I would like to do is thank everyone for their participation and we will now open it up for questions.

Question-and-Answer Session

Unidentified Analyst

(indiscernible) are they lower in your more recent products than compared to the Kynamro product?

Stan Crooke

I think we have discussed that quite a number of times in various presentations. If you look at if you think about Kynamro is having been discovered now 13 years ago of course we have continue to make progress and understanding the technology and during that time we have learned a lot about how to predict locally inflammatory sequences and we have put screens [ph]. In addition we screen much deeper and the old (indiscernible) from small molecules that the more you screen the better your drug applies to antisense and so we just have significantly more potent drugs and I would say we’re about 50% to 100% more potent than Kynamro with all of the same chemistry just better screening. So we’re seeing activity, you will know we’re not we don’t go to 400 milligrams anymore and we have activity of 100 that we used to see, that we saw with Kynamro 200 so we have more potent drugs and they are also better tolerated thanks to better screens but there will be variation from drug to drug but we have now looked at all five or six of these recent vintage [ph] second generation ASOs and all of them have dramatically less injection side reaction and much less almost no (indiscernible) syndromes with this drug (indiscernible) and glucagon and all of those. Perhaps a little bit more with the Lp(a) so it's probably a little less perfect than say the APOCIII or glucagon or some of the other drugs that we have recorded.

Before I leave Lp(a), did I answer your question?

Unidentified Analyst

Yeah but I’ve a Lp(a) question. Do you expect to have to do outcome studies to get approval for that?

Stan Crooke

No. We don’t expect to have to do outcome studies, well we focused on patients who had extremely high Lp(a) levels and we’re just working with KOLs [ph] to finalize that number now but certainly north of a 100 probably.

And these people they have an extreme cardiovascular risk and they also have a very high risk of aortic valve disease and that disease is driven people think it's almost entirely by the Lp(a) that they have. So think about the way we managed Kynamro and the way we’re managing APOCIII, the initial indications would be these quasi orphan like diseases in these people with genetically really high Lp(a) levels. I might add that with Lp(a) we’re still in the planning process but I think we have pretty much decided that what we will do is an intrapatient dose titration to a desired Lp(a) level. I think in this very rare patient population I think it's probably the way to go with that drug. Any other comments, Richard or Rosanne or John?

John Kastelein

So these patients and we definitely look through our clinic in Amsterdam about four times a year, they did want a cure who gets a heart attack and no one understands it as a local cardiology or GP level and they measure LDL to normal you know diabetic, you haven't smoked, you’re thin. There is nothing wrong with you so nobody understands why you’ve a heart attack and you just got a PCI and then they referred him us and we do a screen and the only abnormality we find is an Lp(a) of a 170, makes for destiny [ph] to which is like very, very, very high. So this is almost like an inherited disease in itself, so we call it isolated severely elevated lipoprotein(a). So what we now need to do in order to get orphan indication for this you need to determine what the frequency is in the EU Union you have to be less than one in 50,000 but that’s not hard because all the data that were shown by Rich are in fact European. So we can exactly see where on the graph you’re and then say, so individuals that have nothing else have high disease, isolated Lp(a) are occurring at a frequency of 1 in 50,000 in UK and then you don’t need APO trials [ph].

So it's for us very interesting but it's very nasty population because we had nothing to treat them with.

Unidentified Analyst

And the regulatory authorities concurred on this or are you just assuming/hoping that given the severity and the mechanisms attractiveness they will go for it.

John Kastelein

As you well know regulatory authorities never agree on anything so this is work in progress.

Stan Crooke

We have a lot of experience some of it positive but not all in metabolic divisions of regulatory agencies today probably we have as much experience in some of the metabolic divisions and regulatory agencies of any company with the pipeline that we have and we are while we haven't met with the regulatory agencies and Lp(a), we’re very confident that there will be an opportunity that won't require an outcome study. And we’re just beginning to learn about this aortic stenosis and all of that and I think that represents another real opportunity, Joe you’re agreeing with that, with the aortic stenosis opportunity?

Joe Witztum

So one of the and then (indiscernible) the cardiologist, one of the thing that’s really become very, very interesting is that and this is originally came out of QI [ph] studies that when they did a scan across the genome to look for aortic classification and aortic stenosis that the gene that came up with Lp(a) and that’s now being confirmed in a second study and actually was talked about ate American Heart Association Meeting and actually (indiscernible) had just written an editorial about when that article is making comments but it appears it's just a very, very strong independent Lp(a) in addition to cardiovascular disease it's very strong risk factor for aortic stenosis. We have the hypothesis that at least as far as some of that maybe with oxidized phospholipids which is associated with Lp(a) and have been preclinical data and I support them.

Stan Crooke

This meeting has been a significant focus on Lp(a) as a risk factor for both disease and Sam gave the lead off a lecture on that yesterday or day before, Sam do you want to add anything?

Sam Tsimikas

Sure I think aortic stenosis, cardiologist have been looking at echocardiograms for 40 years now and very few have thought that would be a risk factor you know Lp(a). So it's really opened our eyes into etiology of aortic stenosis, it's a very common disorder so in patients over 65 the incidence is about 10% to 15% for any aortic stenosis and for severe aortic stenosis about 3% and with the aging of the population this has become very serious problem. About a 1/3rd of the patients don’t have opportunities to get surgery because they are too sick, this is why percutaneous aortic valve has been developed which are very expensive, each valve is about $35,000 not including the hospital cost. So this is going to be a huge burden on society in terms of how to deal with these older patients that are very sick and having aortic stenosis. Now that I will have only the genetic determinant which is Lp(a), we have the opportunity to really you know I have diagnosed these patients early in the disease and with the therapy that can lower Lp(a) 80% it should be very easy to do a trial that doesn’t evolve morbidity or mortality but look at echo end points for example or classification with CT and look that if you can delay the progression of aortic stenosis. If you can do that it would delay the need for your valve replacement and I think it will make a huge impact in some of these patients. So it really represents I think aortic stenosis are very unique opportunity because there was nothing that we have right now to delay the progression. You just echo’s on patients or you just watch the valve get narrow and narrow and there is nothing you can do. So I think this is a very viable future indication for valve (indiscernible) therapy along with the other treatment that we mentioned keep in mind that Lp(a) unlike hypertriglyceridemia is very common, about 30% of the adults have levels that we consider atherogenic which is over 30 mgs/dL so if you do the math you assume there are 7 billion on earth that’s 1.5 billion – 2 billion people that have what we consider atherogenic Lp(a) levels.

So out of that subset there is going to be some patients that are going to need to get those levels lowered of course you need to prove it they are going to benefit it from it but now at least we can pretty much get about 99% of patients to normal with the ISIS-APOCIII drug, so it really allows us a very important tool to get those Lp(a) levels down and prove that doing that it will be important with the trial. And it's remarkable in our normal volunteer study how many of these young people had very, very high Lp(a) levels. So it's a big opportunity, I do want to emphasize that we’re just very early in our thinking about the aortic stenosis opportunity but we think it's very real. And by the way for the webcast participants just in reference to John’s comments you said he spoke about the (indiscernible) question, just to tell you that he is young, he is handsome and he manages a lot of money, he is also thin. Other questions?

Andrew Goldsmith – Canaccord

Just a question on the commercial strategy, you’re talking about maybe taking forward an FCS and then partnering later on. Mechanistically how would that work? Would it be a timing thing?

Stan Crooke

Was everyone able to hear the question? You know the question is whether the mechanics of handling one indication ourselves and perhaps a licensing a later indication, yes we’re thinking through that and we think there are some very straightforward ways really have to do with the differences in the physician population that we would be addressing. So we’re looking at all of those various options on how to slice this so that we generate the greatest return to shareholders with this drug yet retain our commitment to the kind of company we want to be with which is a small research focused innovative company and so just state tuned, we’re working through all of that over the next few months. We’re looking at all the options, so sometime in the next 12 months or so we will provide a lot more clarity about what that is going to be.

Andrew Goldsmith - Canaccord

And then just a follow-up on the FCS population about 3000 to 5000 worldwide, do you think it's closer to three, do you think it's closer to five and what’s your conviction level of that? What’s your conviction level on, where does that come from and I know there is out of literature out there.

John Kastelein

We have done very extensive work in the Netherlands to precisely define and strategically [ph] because Holland has 16 million in the size of Rhode Island. So you can do, you can very precisely determine frequency of disease and the prevalence of the homozygous Lp(a) efficiency in an open western societies 1 in 250,000. So 4 in a million, so you can simply take the population of the U.S. and multiple it by four and in European we have 400 million people so you can multiply by four and that’s just us. We know there are pockets of these individuals in French Canada, in Lebanon, in South Africa and especially in the Netherlands, so in Tahiti. So for example in Riyadh there is physician taking care of a very large proportion of Lp(a) efficient patients. So next to this prevalence of one in a quarter million there are pockets across the world where it's not hard to get because everyone knows these individuals in our community. So that’s a precise prevalence.

Andrew Goldsmith - Canaccord

Quick follow-up, if the pocket-

John Kastelein

No the pockets are strategically out of that. So when you determine the prevalence of a genetic disease you go to an open western society, you know that has no in-breeding and no continuity and you buy large scale screening programs, you determine the frequency.

Stan Crooke

Let’s go back there.

Unidentified Analyst

It's interesting that inhibiting APOCIII may prevent the progressions in diabetes in these patients, do you think it might affect progression of diabetes in patients with less severe forms of hypertriglyceridemia?

Joe Witztum

Yes we do. In fact the study was done in patients with less severe forms of hypertriglyceridemia. If I remember correctly the average triglyceride and assay was about 250-255.

Unidentified Analyst

Do you got diabetes patient or?

Joe Witztum

I like to focus on our first indications. I think if you think [Audio Gap].

Unidentified Analyst

In case the regulators would require some clinical end points ambition to your lipid levels. We’re on Plan B and in case you’ve to use pancreatitis as end point especially for the 800 level trial how big a sample size would it become?

Stan Crooke

We probably look at the current pancreatitis. So people who have had a bout or two so if you look at the available data and we have done quite a bit of work on this, you can find people with incoming triglycerides are greater than 880 who had pancreatitis and then the incidences of the current pancreatitis is fairly high. So it's a feasible study. But I think everything we know from Europe and U.S. is that strategy with APOCIII for FCS and (indiscernible) is going to be regulatorily accepted strategy. Stay tuned with if we finally get one you know. You might want to add to that Joe?

Joe Witztum

I was just saying that in my presentation and John you know it's such a totally unmet need that when we actually when this is presented at the American Heart Association when I presented this, the place was packed. I mean every lipidologist and to treat these patients there is no therapy and we not only it's difficult for patients it's difficult for doctors because we can’t help them. I mean don’t, my cartoon you could say we (indiscernible) extremely low fat diet. You can keep those chylomicrons from coming and you can control their triglyceride to 600 but there is so little tolerance and you know they all slipped and so I think the regulatory people will know that. I mean there is such a uniformity of physician about that, you know physicians who are expert in this area.

Unidentified Analyst

If I can ask another question outside of your lipid portfolio. On 2014 what how that’s been few drugs, candidates emerged like APOCIII emerged this year.

Stan Crooke

Yes that’s ISIS-NRX 2014 is going to be a very important year for us in ISIS-NRX and we’re looking forward to the additional most of those data, TTRS [ph] is going to have a very important year that Phase III program is going very well, back to ’11 been here in 2014 and the metabolic pipeline. Glucagon, glucocorticoids and P2B1B [ph] they are all in meaningful trials now and for at least two probably all three will report important Phase II data and those drugs are again a product of the improved screening and other things we’ve done so their performance we think is going to be very good. I guess we shouldn’t forget OncoGenex OGX-011 they will be reporting the Phase III data there, what if I missed through (indiscernible), you’ve got 30 drug and development there is news almost all the time and we have been very pleased off late that the news has been predominantly very, very good and we think 2014 is going to be another very positive year for us and it goes well beyond lipids and the cardiovascular program goes well beyond lipids. We haven't had a chance yet to tell you about some of the things that are just behind these that are coming such as our drugs to treat severe and RECLAST with hypertension and other things. So this pipeline continues to expand and the neuro pipeline is tremendously exciting. I mean ISIS-NRX looks like it's working, the HTT program it's often running with Roche. The myotonic dystrophy drug we think has a very good chance of working and working much better than the other drugs that have been trialed and you will be hearing a lot more about that. So our problem is really answering the question what should I focus on tomorrow and I think there is quite a bit to focus on. Did I answer the question or did it just make it worse? Okay. I think we have probably worn everyone out. Any other final comments from our panelist? If not I want to thank everybody here and of course everyone on the webcast. We look forward to an exciting rest for the year and certainly 2014 is going to be another important year for us. Thanks.

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