Isis' CEO Hosts Conference to Review KYNAMRO Data Presented at the ESC 2012 (Transcript)

Aug.29.12 | About: Ionis Pharmaceuticals, (IONS)

Isis Pharmaceuticals, Inc. (ISIS) KYNAMRO Data Presented at the ESC 2012 August 29, 2012 10:00 AM ET

Executives

Dr. Stanley Crooke - Chairman and CEO

Dr. Klaus Parhofer - Professor, Metabolism and Endocrinology, Ludwig-Maximilians University, Munich

Lynne Parshall - Chief Operating Officer

Rich Geary - Senior Vice President, Development

Walter Singleton - Vice President, Development and CMO

Wade Walke - Executive Director, Corporate Communications and IR

Analysts

Nicholas Bishop - Cowen & Company

Stephen Willey - Stifel Nicolaus

Carol Werther - Summer Street

Chad Messer - Needham & Company

Sam Colin - First Manhattan Company

Operator

Good day, ladies and gentlemen. And welcome to Isis Pharmaceuticals' Conference Call to Review KYNAMRO Data that was recently presented at the ESC 2012 Meeting. As a reminder, this call is being recorded for replay purposes.

I would now like to turn the conference over to Dr. Stanley Crooke, Chairman and CEO. Please proceed.

Dr. Stanley Crooke

Good morning, everyone. And thanks for joining us today. As [Donato] indicated the purpose of this call is to have Dr. Parhofer to review the additional results or some additional results on KYNAMRO that were presented at the European Society of Cardiology Meeting this morning in Munich.

Joining us on today’s call are Dr. Klaus Parhofer, Professor of Metabolism and Endocrinology at Ludwig-Maximilians University in Munich; Lynne Parshall, Chief Operating Officer; Rich Geary, Senior Vice President of Development; Walter Singleton, Vice President, Development and Chief Medical Officer; and Wade Walke, Executive Director, Corporate Communications and Investor Relations.

Wade, would you please read the forward-looking statement.

Wade Walke

Thanks Stan. A reminder to everyone this webcast includes forward-looking statements regarding the development activity in therapeutic and commercial potential and safety of KYNAMRO. Any statement describing Isis's goals, expectations, financial or other projections, intentions or beliefs including the planned commercialization of KYNAMRO is a forward-looking statement and should be considered an at-risk statement.

Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use of human therapeutics and in the endeavor of building a business around such drugs.

Isis's forward-looking statements also involve assumptions that if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements.

Although, Isis's forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements.

These and other risks concerning Isis programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2011 and on its most recent quarterly report on Form 10-Q which are on file with the SEC. Copies of these and other documents are available from the company.

Now, I'll turn the call back over to Stan.

Dr. Stanley Crooke

Thanks Wade. Let me begin by saying how pleased we are with the progress being made by the Genzyme sanofi Isis team. We are well along in preparations for the FDA Advisory Committee panel in October and the review of the European application is progressing. We look forward to KYNAMRO being approved in Europe this year and in the United States early next year.

Earlier today, Dr. Parhofer presented a poster at the ESC Meeting in Munich. In our call, Dr. Parhofer will review these data with you. Dr. Parhofer is as I mentioned Professor of Professor of Endocrinology and Metabolism at the University of Munich in Germany and he has a major focus on metabolism of apolipoprotein.

Dr. Parhofer has made significant contributions to the cardiovascular community with more than 130 published papers. Dr. Parhofer is currently conducting an investigator-sponsored study evaluating the use of KYNAMRO in patients who are undergoing apheresis.

Apheresis is a dialysis like procedure in which blood is filtered through a machine to remove excess cholesterol. Although, apheresis is the only option available to patients with severally elevated LDL-cholesterol levels, many eligible patients are not treated with apheresis because of the lack of availability, the high cost and the negative impact on their quality of life.

Analysis presented today focuses on the potential of KYNAMRO to reduce the need for apheresis by lowering LDL-cholesterol levels below the thresholds for apheresis eligibility in patients with severe heterozygous FH.

So, with that, I’m going to turn the call over to Dr. Parhofer. Dr. Parhofer, please.

Dr. Klaus Parhofer

Thanks Stan. Thanks also for giving me the opportunity to discuss this data today just presented earlier here in my hometown at the ESC Meeting. Well, what we evaluated in this study was basically the potential of mipomersen to reduce the need for apheresis in severe heterozygous FH, thus the hypothesis was mipomersen may delay, elongate interval or eliminate the need for apheresis by reducing LDL-cholesterol level below the threshold for apheresis eligibility even when employing eligibility criteria more stringent than in the U.S. guideline.

On the next slide, you can see my disclosures and I work as a Consultant for Mipomersen especially for that study.

Let me now turn to the introduction. Next slide please, and you probably know that LDL-apheresis is weekly or biweekly applied and it’s actually the only non-transplant treatment option for patients with severe heterozygous FH if maximum lipid-lowering therapy fails to lower LDL-cholesterol to target levels.

And also it’s quite expensive and with limited access in the United States, especially LDL-apheresis is appropriate for heterozygous FH patients if they despite maximum lipid-lowering therapy do not achieve an LDL-cholesterol below 22 milligram per deciliter in persons with coronary heart disease or below 300 milligram per deciliter in the absence of CHD.

And there is actually some difference to other countries where less thresholds are used or most thresholds are used. For example in Germany, a lot of patients are even eligible for apheresis if the LDL-cholesterol is above 100 milligram per deciliter or 130 milligram per deciliter.

Now mipomersen is an investigational ApoB synthesis inhibitor, which can reduce LDL-cholesterol by 25% to 47% when added to maximally tolerated lipid-lowering therapy in Phase 2 and Phase 3 clinical trials, and the question now is here is does this allow to avoid apheresis in a significant number of patients.

Next slide. On this slide you can see the typical course of LDL-cholesterol during LDL-apheresis. And as you can see, if you follow those lines, you start at the high level and then with each apheresis drop and after certain point you will reach a new steady state when you do readily apheresis.

Now that is as mentioned before and as extra-corporeal form of therapy which requires venous access, which requires the patient to be in the hospital, it’s quite cost expensive and therefore, there is a need for meditation that may avoid such expensive and waste of therapy. So that’s background about the apheresis.

Now let’s move onto the next slide and for this analysis we use data extracted from mipomersen Phase 3 clinical trial, safety and efficacy of mipomersen in patients with severe hypercholesterolemia on maximally tolerated lipid-lowering regimen and who are not on apheresis. Thus an hypothetical evaluation in how many patients apheresis can be avoided if the cohort of apheresis patient is such in the study and if we apply different LDL thresholds.

So for this analysis, the primary efficacy parameter was the percentage of patients who achieved a LCL-cholesterol level below the thresholds for apheresis eligibility and we used different type of values, we used 300 milligram per deciliter, 200 milligram per deciliter and 100 milligram per deciliter, with the addition of mipomersen compared to placebo, and the date we evaluated two weeks after treatment completion and I will show later that was 26-week trial.

The study design which is shown on the next slide, as shown here and you can see that patients with severe heterozygous FH were randomized in the 2:1 fashion to either 200 milligram mipomersen subcutaneously weekly, these were 39 patients or placebo 19 patients for 26-week. And you can see here that 104 patients were screened for the study, 58 were finally enrolled and then after screening period of four weeks patients were randomized either for mipomersen or placebo, they received the treatment then for 26 weeks and two-week after the last dose their end point data were collected.

And eligible patients had a pre-treatment screening LDL-cholesterol of equal or above 200 milligram per deciliter if they had coronary heart disease or above 300 milligram per deciliter if they does not have coronary heat disease and that’s basically the definition of severe heterozygous FH based on the U.S. apheresis criteria.

On the next slide you see the baseline characteristics and there is actually not much surprise here. The placebo group and the mipomersen group are quite similar. They were approximately 50 years old. There were about 40% males, BMI around 29. Almost half of them have metabolic syndrome and more than half of the patients in both groups have taken statins plus ezetimibe. And all patients I should mention were on maximally tolerated lipid-lowering therapy, including of course, stable statin dose for more than eight weeks.

Next slide, here in the primary study, the weekly treatment with 200 milligrams of mipomersen, when given to patients with severe heterozygous FH resulted in slight dramatic reduction of LDL-cholesterol, which was significantly stronger compared with placebo.

And as you can see here, LDL-cholesterol fell by 36% in the mipomersen group and increased by 13% in the placebo group, which then added up to almost 50% difference between the two groups.

On the next slide, you can see these in absolute values and you can see that in the placebo group from a baseline value of 250 milligram per deciliter that increased 264, while it was very dramatic 100 milligram per deciliter decrease in the mipomersen group from 276 to 275, which then corresponds to the mentioned 36% decrease in the mipomersen group and the 13% increase in the placebo group.

As seen in previous studies, there was some heterogeneity with respect to the response to treatment and that’s shown here and that waterfall plot and if you can see, while in placebo there were some patients who had a decrease, some patients who had an increase, one patient actually had quite a dramatic increase of cost of rates with vast majority of patients in the mipomersen group had a decrease of approximately 40% to 50%.

But, well, as you can see some patients with -- we saw very good response with -- which went almost up to 100% and the few patients who did not respond or even had a small increase in LDL-cholesterol.

We go now to the next slide you and that’s one of the key signings now. You can see that 41%, that’s seven out of 17 patients of the mipomersen group with a baseline LDL cholesterol of above or equal to 300 milligrams per deciliter and 61%, 22 out of 36 with a baseline LDL-cholesterol of above 200 milligram per deciliter, achieved levels of below 200 milligrams at end point that’s June mipomersen therapy, while there was 0% or only 14% in the placebo group.

And overall, in patients with a baseline of plus LDL-cholesterol of 100 milligrams per deciliter, 15% and remember these were patients with very high baseline LDL-cholesterol and they reached level below 100 milligram per deciliter, thus with 15% in the mipomersen group while that was none in the placebo group.

I will discuss this in a bit more detail in the next slide, which at first glance looks like a bit of a complicated table but let me go through it and I think it’s important to focus on the last column on the mipomersen column.

As you can see, 17 out of the 39 patients at baseline had an LDL-cholesterol level of plus 300 milligram per deciliter. At the endpoint, only three that’s only 18% was still above 300 milligram per deciliter. While 82% were below that threshold, some of them only below 300 but above 200, some of them at 29% between 200 and 100, and 2% thus 12% even below 100. But 12% of the patients from -- starting from above 300 came down to below 100.

Now, when you use a different kind of value the 200 milligram per deciliter and that’s now the next block and again just look at the mipomersen column, you can see that 36 of these -- of the 39 patients were above 200 milligrams per deciliter at baseline and 39% at the end were only above that base, still at the baseline, while 61% were been below 200 milligrams per deciliter.

So if the cutoff value for apheresis would be 200 milligrams per deciliter than of 36 patients been above the level at baseline, only 14 would be still above that baseline, above that level at the end of the study.

Now when you go further down the threshold, namely 200 milligrams per deciliter you are not surprised that all of the patients 39 out of 39 were above that threshold at the beginning of the study and so six patients in the mipomersen profile none of placebo group went below that threshold at the end of the study.

In the next slide, this is shown a bit more graphically and the first two columns represent the placebo group and the second two columns represent the mipomersen group. And you can see placebo baseline to placebo endpoints that was only a few patients that were not anymore above 200 milligrams per deciliter, while this fraction was much, much higher in the mipomersen group shown in the second pair of columns where you can see that more than half of the patients that of those that were above 200 milligram per deciliter at baseline were not anymore above 200 milligram.

And if you look at the pink part of the column, you can see that some of these patients despite the fact that they were above 200 milligrams per deciliter at baseline now are even below 100 milligram per deciliter.

Now on the next slide, you will see a similar picture with respect to the threshold of 300 milligrams per deciliter and again you can see very little change in the placebo groups in the first two columns while there is a dramatic change in the second column, a pair of columns which represent the mipomersen group.

The vast majority, 82% of those patients who were above 300 milligram per deciliter at baseline are below that threshold when using mipomersen. And as mentioned before, even of those patients being above 300 milligram per deciliter at baseline, some will reach the levels below 100 milligram, which is shown again in the pink column.

Now on the next slide I would briefly comment on the safety and as it is well-known mipomersen treated patients have higher incidents of injection site reactions and flu-like symptoms. And but you would have to acknowledge that most of this injection site reactions were mild to moderate in severity and did not occur with every injection, plus also most patients experienced injection site reaction at some point of the study thus by far not occur with every injection.

Now with respect to ALT and AST elevations, they occurred more frequently in the mipomersen than in the placebo patients, and interestingly and also as observed in previous studies, these elevations and liver functions are correlated with LDL-cholesterol and the ApoB response to treatment.

On the next slide, there are some limitations shown. Of course, this was not the primary intention of the study. So this is a sub-analysis and it was actually not designed to treat patients to an apheresis goal.

And furthermore and that’s actually the first point on that list, although apheresis criteria typically include patients with diagnosed coronary heart disease, but less elevated LDL-cholesterol, stratification of patients according to CHD versus non-CHD was not possible for that sub-analysis, plus we don’t know exactly which patients responded well and which did not responded well.

Now let me conclude. On the next slide, the unique mechanism of action of mipomersen, combined with other maximally tolerated lipid-lowering therapies, may minimize the need for LDL-apheresis in patients with severe heterozygous FH.

In the cohort studied here, of the 36 mipomersen patients with a baseline LDL of above 200, 22 about 61% attained an LDL-cholesterol below 200 milligrams per deciliter and would no longer require apheresis using the U.S. apheresis eligibility criteria.

Of course, further studies are warranted to prospectively evaluate the clinical impact of combination therapy and to evaluate the need for apheresis with the availability of other new therapies that are also on the horizon as we say.

Whether or not mipomersen will replace apheresis in a significant number of patients will then of course ultimately depend on the risk, benefit of effectiveness, long-term safety and cost.

And with this, I would like to turn to the next slide and thank my co-authors, Dr. Anja Vogt also here from the University in Munich and Mary McGowen for her support and I would also like to acknowledge the help of Genzyme, which allowed me to use the data to analyze this -- to do this analysis.

And on the final slide, there are some references which were mentioned during the poster, which were also mentioned during my presentation.

And with this, I would like now to turn the call back to Stan. Thank you very much.

Dr. Stanley Crooke

Thanks very much, Klaus and I think this presentation highlights the potential of KYNAMRO to meet the unique needs of patients with severe heterozygous FH. There is no approved treatment other than apheresis that addresses the big challenges faced by these very sick patients and we think we look forward to meeting these unmet medical need with our partners at Genzyme, Sanofi and look forward to bringing this important new medicine in marketplace.

So, with that, I’m now going to open it up for questions. [Donato] if you can set us up for questions, please?

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) Your first question comes from the line of Nicholas Bishop with Cowen & Company. Please proceed.

Nicholas Bishop - Cowen & Company

Yeah. Thanks for taking my question and thanks for reviewing the data with us today. I wonder if you could comment clinically on two things. I guess one is, for those patients who improve on mipomersen but perhaps don't quite disqualify themselves for apheresis, they are sort of close to goal. But we expect those patients might nevertheless have the opportunity to discontinue apheresis. Is that clinically justified?

And secondly, could you speculate perhaps on what percentage of patients you might expect in Germany, for example, who are currently in apheresis to convert mipomersen if its approved?

Dr. Klaus Parhofer

Well, I think it’s a very interesting question. Of course, it depends very much on the baseline value whether you will or will not basically pass the threshold level or not. And of course, even if you still above threshold level, even with the most modern form of combination therapy, it is still a benefit right because the overall level is much lower.

And it might actually lead to the fact that you will not require apheresis as often or that you might require shorter forms of apheresis, which also would then translate into a benefit for the patient and would reduce the cost for apheresis. So that’s the first part of the question.

The second part with respect to, on how many patients that really would translate into less apheresis. In Germany, it’s very difficult to answer because in Germany the apheresis population is quite heterogeneous. It’s not only patients with heterozygous FH, there’s also other forms of severe hypercholesterolemia and there is patients which that apheresis for elevated lipoprotein a.

So it’s difficult to predict in how many patients that would be the case. But let’s assume from this and from other analysis, I would assume that something between may be 30% or 50% of patients on apheresis would benefit to an extent that apheresis maybe even not any more necessary or necessary in reduced form either less frequent or shorter.

Dr. Stanley Crooke

Thank you. Just a couple of points to add hopefully verification, remember that this study is an ITT analysis, what you’ve seen. So that includes all the people who discontinued the drug in, for example, in that waterfall plot. And second that we know that as people continue to take the drug, drug continues to work consistently for a long period of time, up to four years now.

So if a person were a somewhat slow responder, looking a little later, you’d probably see a little greater response as well. Obviously, these are fixed dose studies. We did a 200 mg only and clearly we know that higher doses reduce LDL even more.

The final point I’d make is that KYNAMRO is the only drug that lowers all estrogenic lipids including Lp(a). And we believe that lipidologist in the world really understand how important Lp(a) is as a risk factor and we look at that as significant benefit from KYNAMRO.

Nicholas Bishop - Cowen & Company

Okay. That’s great. Thank you very much.

Operator

Your next question comes from the line of Stephen Willey with Stifel Nicolaus. Please proceed.

Stephen Willey - Stifel Nicolaus

Thanks for taking the question and thanks for hosting the call. Dr. Parhofer, may be just a little bit of insight as to what percentage of patients you treat. Who you think would qualify for apheresis, actually end up receiving apheresis?

Dr. Klaus Parhofer

I think there is on hand very much heterogeneity within or between different countries. You probably know that Japan and Germany, let’s say are high frequency apheresis country which probably also reflects the fact that several of these apheresis devices are developed in those countries.

So in Germany -- I mean, still there is undertreatment, right, with respect to apheresis but it’s probably very different from other European countries where you have much, much more severe form of undertreatment with respect to patients of severe heterozygous FH. It’s difficult to say, in Germany, there’s approximately 1,200 to 1,300 patients treated with regular apheresis but if you calculate the numbers of patients with heterozygous FH, that should be several -- should be more than 10,000, right. So there is obviously quite a undertreatment.

Stephen Willey - Stifel Nicolaus

And in terms of a disconnect between those patients that actually receive apheresis and the 10,000 patients that don’t. Those patients are getting routinely treated within physician office and are just choosing not to undergo the apheresis procedure?

Dr. Klaus Parhofer

No. I think most of them are not offered the option of apheresis.

Stephen Willey - Stifel Nicolaus

Okay.

Dr. Klaus Parhofer

I mean, they process also some patients who do not -- who decide against but that’s a minority.

Stephen Willey - Stifel Nicolaus

And then may be just a question for Stan, I guess, if you take into account some of the lower thresholds for apheresis eligibility that are presumed to be standard within Germany. As you kind of think forward to maybe the pricing and reimbursement discussions that could ensue here with AMNOG. Would you suspect that they would essentially choose something like apheresis as comparative arm and determine, I guess, the clinical benefit on your ability to reduce LDL relative to, I guess, what is a bit of a institutionalized process at all?

Dr. Stanley Crooke

Well, I don’t know and I don’t want to pretend that I understand modern day pricing and marketing, I don’t. That’s why we have Genzyme and Sanofi. But what I will say is that as I look to pharmacoeconomics, they are stunningly obvious and stunningly in favor of the drug. And I think there are two ways to look at that. What is the cause of the heart attack?

Remember that in this study, I think the average number of previous cardiovascular events was about three. And when I last looked, it’s real difficult to get numbers but survived heart attack in the U.S. is certainly hundreds of thousands to a million dollar and even if you die, it costs some money.

So if you think about the potential of reducing the risk of cardiovascular event by more than 50% and you consider the slight increase in HDL and the substantial reduction in Lp(a), you can really think about a very dramatic reduction in cardiovascular risk. And that will translate directly to pay your dollars that are saved in a five-year timeframe, that would be relevant to players.

And the second way to look at it is what is the alternative. And the price of apheresis is high but of course, the cost of apheresis is much higher than the price. It includes the lost work. It includes the need to go to the clinic in the U.S. that’s a real challenge, in Germany, it’s a lesser challenge.

So as I look at this drug, it’s benefit risk is marketably positive in the patients that were focused on in the pharmacoeconomic justification for a price that recognizes that value I think is very, very well defined. Did I come close to answering your question?

Stephen Willey - Stifel Nicolaus

You did.

Dr. Stanley Crooke

Any one who want to add anything to that? Klaus, did I say anything that you disagree with?

Dr. Klaus Parhofer

No. I agree with all you say. I think especially health economics part you cannot just look at the apheresis part itself. I mean, as you mentioned all the impact on traveling, on work, on all the secondary aspects.

Dr. Stanley Crooke

Even just having lines, it’s been long time since I took care of patients but I took care of cancer patients. And just keeping those lines open and making sure that they don’t get infected. As you all know, all of those things are problem that no one wants to deal with. You don’t have to.

Stephen Willey - Stifel Nicolaus

Thank you.

Operator

Your next question comes from the line of Carol Werther with Summer Street. Please proceed.

Carol Werther - Summer Street

Thanks for taking my question. I was wondering if you could elaborate a little bit more about the safety of KYNAMRO in terms of the patients drop out due to adverse events and what were the patients response to the injections reactions and possibly the flu-like symptoms, I mean, was this that they considered improvement in their life given these issues? Thanks.

Dr. Klaus Parhofer

I did not perform original study which we used here to analyze the data but to my knowledge there were six patients discontinuing their study due to basically side effects or events. But may be, Stan, better know their data, the original data of the trial because we basically use the lipid values to perform the analysis on the threshold study of apheresis.

Dr. Stanley Crooke

Carol, these are the -- the data from this trial and all those trials have been reported in gruesome detail, as you know. And as you also know we had very rigid stopping rules for ALTs. So we had patients who were forced to stop because their ALTs got above the rigid stopping rules we had and there were dropouts and overall in the phase III population, I think the total -- the percentage dropout was like 12%, 14%. I can’t remember the exact numbers, which is really rather remarkably good when you think about it in the six months study, dropout, average dropout in the statin study in six months to a year are somewhere between 8% and 12%.

So, of course, this is a drug like any other drug that has safety things with safety effects you have to watch. ALT’s are clearly associated with rapid and profound reductions in ApoB and LDL. Our studies didn’t allow does adjustments. Obviously a rational management of patients would -- if you saw someone responding suit super fast and super large and you saw slight increase in ALT you might adjust the dose, might hold the dose.

So, all of those things that contribute to the dropouts in rigidly controlled trials will be certainly in my estimation much, much better in the real practice of medicine. And very clearly, patients once they are unblinded and no what their LDLs are are very happy. Remember these are blinded studies. So the patient doesn’t know whether he is getting benefit or not.

Clearly, this is a situation in which you don’t have a physical symptom or sign that drives you to take your drug. It’s taking a drug to prevent an event, it’s not -- not at all like arthritis, for example, where you know if you don’t take the drug, you can have pain. And so patients being able to see their LDL level, know that their cardiovascular risk is reduced.

I think it will be a powerful motivation that we couldn’t provide those patients in a randomized, double-blind, placebo-controlled trials. But they didn’t know their LDL’s and neither did their doctor. So no new -- there are no new data here and we continue to believe that the drug is as in appropriate risk benefit profile for the patients that we are focused on.

We continue to believe that it is going to be adequately tolerated and we are confident that continuing studies that we are -- that are in progress will allow us to continue to assess its tolerability and safety profile in an ever-greater number of patients.

Carol Werther - Summer Street

And in this study did you do any subset analysis on measuring liver fat?

Dr. Stanley Crooke

We did. All of those data have been published and reported. And remember that the liver fat increases occurred in the small fraction of patients. They were associated with rapid and profound reductions in ApoB and LDL. And we already reported that the -- that overtime the liver fat increases that occurred in a small fraction of patients return to baseline level in the open-label study. Richard or Walter may want to add to that, but there is all -- there is no new information with regard to that and other than the material that we presented several times then it all continues to be very encouraging.

Carol Werther - Summer Street

Thank you very much.

Dr. Stanley Crooke

Richard, do you want to add anything.

Rich Geary

No. The only thing I would add is in the pooled data to kind of go to your question about ISRs. Actually only 5% of patient discontinue due to ISRs. In the entire Phase 3 placebo-controlled database and less than 3% for flu-like symptoms. So these were not events that were causing patients to get of the drug.

Carol Werther - Summer Street

Thank you.

Dr. Stanley Crooke

Next question?

Operator

Your next question comes from the line of Chad Messer with Needham & Company. Please proceed.

Chad Messer - Needham & Company

Yeah. Thanks for taking my question. Dr. Parhofer in your presentation you kind of have a slide where you gave a sense of what a typical response to apheresis looks like. I was wondering if you could maybe elaborate a little more. I mean is there a specific treatment and goal with apheresis and how many patients would reach that goal. In other words, how good is -- we know there is a lot of problems with that but how effective is apheresis?

Dr. Klaus Parhofer

Well, actually apheresis is quite effective and we usually try to get an average LDL-cholesterol below 100 in our patients and that could mean in some patient that we do it bi-weekly and some patients where do it weekly and that also basically affects the apheresis time, because obviously the longer your apheresis, the low your post apheresis value will be.

The rebound curve, they are quite typical and quite consistent. So it’s always like -- almost like a mono financial curve where you obviously in the first few days have a much stronger rebound, much stronger increase than in the days before the next apheresis.

But it also of course depends on whom you select for apheresis right. If you only select homozygous FH, you will only in a minor fraction achieve such strict goals. If you have a mixture of patients consistent of homozygous, heterozygous and other severe forms of LDL hypercholesterolemia, you reach within a much higher proportion. In our hands you probably be tend to reach that goal and maybe around 60% to 70%.

Chad Messer - Needham & Company

Okay. All right. Great. Thanks. That’s very helpful.

Operator

(Operator Instructions) Your next question comes from the line of Sam Colin with First Manhattan Company. Please proceed.

Sam Colin - First Manhattan Company

Hi. Thanks for taking my question and congratulations on these results. Can you just remind us what the cost does in Germany and if you know what the costs in Japan for apheresis?

Dr. Stanley Crooke

I only know the costs in Germany and its about €1,200 per session.

Sam Colin - First Manhattan Company

And the average patient would get it frequently in Germany.

Dr. Stanley Crooke

Either weekly or bi-weekly, so then it translate -- and let’s say most patients say do not step, even if they are on a weekly schedule, they probably do not data track 50 somewhat time free about more something 40 to 45 times so some translates into €50,000 to €60,000 cost per year.

Sam Colin - First Manhattan Company

Okay. So that would be the rough benchmark of about $60,000 just a direct costs from the apheresis.

Dr. Stanley Crooke

Yeah.

Sam Colin - First Manhattan Company

€60,000.

Dr. Stanley Crooke

And Lynne can probably give you a better number but I think in the U.S. it runs €100,000 to €130,000 a year.

Sam Colin - First Manhattan Company

Okay. Thank you. And can you comment on -- I was just curious with respect to the baseline characteristics that only about 50% of the patients are on statin plus ezetimibe and I was just curious if you could comment on that whether these patients were really push to maximal medical therapy.

Dr. Stanley Crooke

They were required to be at maximum tolerated dose. And there is just a lot of variability in what people will put up with. The doses of statins will vary but -- and some people will take ezetimibe until they get benefit, others don’t. What wasn’t included in the slide is all the other things these people are taking.

So the answer is every study we’ve done is maximal therapy but there is quite a bit of very -- more variability in what people consider maximal therapy than we expected when we did the study.

Sam Colin - First Manhattan Company

Okay. That’s very helpful. Just on the final note, I understood you to say that none of the patients in this sub-study met the U.S. criteria for severe heterozygous FH. I was wondering if you could just confirm that and also just review what the U.S. criteria are?

Dr. Stanley Crooke

No. All the patients in this study have severe heterozygous FH.

Sam Colin - First Manhattan Company

There were -- and in the U.S. that’s defined by what?

Dr. Stanley Crooke

200 or greater with coronary heart disease or 300 or greater without coronary heart disease on maximum therapy.

Sam Colin - First Manhattan Company

Good.

Dr. Stanley Crooke

And I think what Dr. Parhofer was referring to was the various criteria for apheresis that tend -- in the criteria for apheresis vary around the world. I think that’s what you were saying, is that right, Klaus?

Dr. Klaus Parhofer

Yeah. That’s right. That’s right. And in the U.S. that’s -- its close to the definition of severe heterozygous FH, when you can use apheresis while in Germany and Japan different guidelines are used?

Sam Colin - First Manhattan Company

Again, I may have misunderstood but I thought what you were saying was that because these patients were on apheresis which obviously marks down the LDL that if their baseline LDLs would not have qualified them to the definition of -- that their substantial portion didn’t qualify for severe but I may have misunderstood that point.

Dr. Stanley Crooke

Yeah. Sam, all these patients into the trial have severe heterozygous FH and none of them could be on apheresis in the trial. But what was -- what Dr. Parhofer is referring is what the -- what -- how many of those patient would no longer meet criteria to have apheresis. But all of the patients were severe and none of them had apheresis in this trial.

Sam Colin - First Manhattan Company

Very good. Thank you.

Dr. Stanley Crooke

You bet. I think we are just about out of time, are there any -- is there any more questions, [Donato].

Operator

We do have a follow-up question from the line of Nicholas Bishop with Cowen & Company. Please proceed.

Dr. Stanley Crooke

We will take this and then we will have to bring it to close.

Nicholas Bishop - Cowen & Company

Okay. Thanks very much for letting me squeeze in a follow-up. I just want to follow-up on the remark that you made earlier in the presentation, Stan, which was that mipomersen, one of its pharmacoeconomic benefit could be a reduction in the risk of cardiovascular events. And I am wondering in the pooled Phase 3 data, have you disclosed what the rate of serious cardiovascular events on or after treatment in the Mipomersen and placebo arms are. I’m not sure if you have seen that number?

Dr. Stanley Crooke

We have and obviously in 2006, we with the small that we have treated there isn’t -- there is no analysis to make sense to ask whether you reduced incidence of cardiovascular event.

Nicholas Bishop - Cowen & Company

Okay. Thanks.

Dr. Stanley Crooke

I mean that’s why they do outcomes studies that are five years, right and 5000 people.

Nicholas Bishop - Cowen & Company

But the numerical data is available?

Dr. Stanley Crooke

It’s been -- we reported all of those things in all of the presentations we made about the data and they are also present in the publications and so each of the Phase 3 studies is either been fully published or is about to published. But probably isn’t available in an easy access form to be uncontrolled of open-label study that continues. Obviously that’s not fully published yet because they are ongoing.

Nicholas Bishop - Cowen & Company

Okay. Thanks very much.

Dr. Stanley Crooke

Bet. With that, are there other -- a lot of other questions in the queue.

Operator

We just had one more question in the queue.

Dr. Stanley Crooke

Okay. We will take this and then really have to go.

Operator

Yeah. We do have a question from the line of Mark Schoenebaum with ISI Group. Please proceed. Sir, your line is open. I believe he has his line on mute.

Dr. Stanley Crooke

Okay. Well, Mark, if you have an additional question just give us call and we will try to get the answer for you. With that, I want to thank everyone for your interest and appreciate the attention to what we are trying to accomplish with KYNAMRO and certainly appreciate the questions on this presentation. And with that, we will bring it to a close and we will keep you posted as we progress in registration of this important new medicine.

Operator

Ladies and gentlemen, this concludes today’s conference. Thank you for your participation. You may now disconnect. Have a great day.

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