Stanley T Crooke – Chairman of the Board & Chief Executive Officer
B Lynne Parshall – Director, Chief Operating Officer & Chief Financial Officer
C Frank Bennett – Senior Vice President, Research
Richard S Geary – Senior Vice President, Development
Isis Pharmaceuticals (ISIS) Analyst Day January 5, 2012 12:00 PM ET
B Lynne Parshall
Good afternoon, everyone and welcome and welcome to those of you who are on the webcast. Also we have an interesting next couple of hours planned to presentation and we also hope that you enjoy listening to them as much as we enjoy putting them together for you.
We will be making forward-looking statements during the course of the presentation, so we ask that you simulate those precautions.
I’m going to be starting out today talking about the year that we’ve just finished 2011. And we think we have quite a number of accomplishments in 2011, so I’m pleased to be able to go through those with you.
I’m very happy to be joined today by Paula Soteropoulos from Genzyme Sanofi. Paula is the Vice President and General Manager, who is responsible for putting Mipomersen or Kynamro on the market later this year and so she will talk about Genzyme’s plans for and the activities that they’re undergoing to prepare for a successful launch as we get through the year.
Following Paula, we have three interesting presentations, Sanjay Bhanot, Richard Geary and Frank Bennett are each going to be presenting on three drugs that we’ve just recently announced clinical data on; our Factor XI drug, which we think has the opportunity to prevent clotting without bleeding, our APOCIII inhibitor, which targets two different independent cardiovascular risk factors, APOCIII and triglycerides directly, and the most advanced drug out of our GlaxoSmithKline relationship, a drug to treat transthyretin amyloidosis, which we think has a very rapid route to the market. Following those presentations, Stan will wrap up with a look into the future for the rest of 2012 and going forward.
I can't start any presentation about Isis these days without beginning with Kynamro. Of course we think Kynamro represents a very significant commercial opportunity for us and our partners, and we’re making tremendous progress over the course of this past year. We filed our MAA in Europe for both homozygous FH and the severe FH patient population, and our NDA is planned to be submitted this quarter.
Commercial launch preparations are well underway and you'll hear more about that as I said from Paula but this is just the beginning. We and Genzyme are continuing to invest in expanding the patients for whom Kynamro represents therapeutic alternative by investing in our FOCUS FH study, which is underway.
Beyond mipomersen, our pipeline is maturing. We started Phase I clinical trials this year on eight different drugs, and these drugs are in a variety of therapeutic areas to treat a variety of different indications. In addition to Phase I trials on three different type II diabetes drugs, we've expanded our metabolic disease portfolio by starting clinical trials on our first anti-obesity drug, and this is a peripherally acting anti-obesity drug, which we think distinguishes it significantly.
We started Phase I clinical trials on three different severe and rare disease drugs. And we’ve expanded our cardiovascular franchises well by starting Phase I clinical trials on our first antithrombotic drug, the Factor XI drug that you’ll more that later today. In addition, we and our partners have initiated Phase II clinical trials and the different drugs in cancer inflammation and in ocular disease.
Our pipeline has grown significantly this year as well with an addition of six different drugs, again in a variety of different indications. Our first two generation 2.5 drugs, our step III drug and our Factor VII drug. A new drug in our metabolic disease franchise to treat NASH, a drug to treat yet another independent cardiovascular risk factor or Lp(a) drug, so our pipeline is maturing, expanding and growing.
But most importantly, we’ve had clinical data both activity and safety data in multiple drugs in multiple indications. Of course, mipomersen leads the way with 20 positive clinical studies on mipomersen; it represents a host of positive therapeutic data. But beyond mipomersen, just this year we had positive clinical data on seven additional drugs, three of which we're going to be highlighting for you later in the presentations today.
Our business strategy is working. We’ve had numerous partner successes this year with our GlaxoSmithKline program leading the way. That’s the program that less than two years old and already we have two drugs in development, the most advanced being the TTR drug, which will go into late stage clinical trial this year. We've achieved numerous financial milestones for that program and as the drugs move forward, we expect to achieve more and we've expanded the relationship to move from five to six targets.
Pfizer’s recent acquisition of our satellite company, Excaliard, not only provides us with significant financial benefit, but also gives us an experienced partner to move the EXC 001 across the finish line to patients.
And of course just yesterday, we announced our newest collaboration, which I'll talk about a little bit later in more detail, which is a preferred partner transaction with Biogen Idec on our drug to treat spinal muscular atrophy.
Our strategy from the beginning has been to innovate. To use that innovation to create a novel technology platform antisense drug discovery that has the opportunity to revolutionize drug discovery. To use that technology platform to create novel drugs and to build the unique business strategy around that technology platform so that we can exploit the technology platform, our goal is to create as many different drugs, as the technology will support to treat as many different diseases as we can, so that we can provide benefit to as many patients as possible to help them lead healthier and more productive life.
We are the leader in RNA therapeutics. We have created a new platform for drug discovery and we've shown over and over again the second generation antisense drugs work. And we control the technology platform that we’ve created through continuing innovation; in fact, we’re one of the largest patent holders in the United States with over 1500 issued patents and a broad portfolio of patent applications following behind that.
We’ve utilized the technology platform to create a very broad and expanding pipeline of 28 drugs in development and we expect to add three to five new drugs every year to this pipeline. And we’ve done all of this with a company that has fewer than 350 people. That means that we can be innovative, be flexible, maintain our cost structure, and yet be extraordinarily productive.
What allows us to have that kind of productivity at the later stages of development of course is our unique business strategy where we engage partners to work together with us both large and small partners to maximize our long-term return and minimize our risk. And this partnership strategy has also made us well-financed as a biotechnology company and we believe it will continue to provide sustained financial strength, our partners of course are key.
We have partners to help us leverage and move forward many more drugs that we could move forward as a single company. We have strong partners in the cardiovascular arena with Genzyme and Bristol-Myers. In the cancer area we’re adding to our partnerships in the severe and rare disease area and of course we have numerous partners in a broad array of therapeutic areas beyond that. And today I'm going to focus just a little bit on our newest partner Biogen Idec.
We announced yesterday a transaction with Biogen Idec for our drug ISIS-SMNRx to treat spinal muscular atrophy. This is a transaction that has a potential value of nearly $300 million and of course the important component of it is commercial up side we participate in, in the form of double digit royalties. In this transaction, Biogen Idec has gotten an option to license SMNRx in the future.
They get to keep that option by paying us up to $45 million in pre-licensing development milestones as the drug move forward. Once we have clinical proof of concept or clinical proof of benefit from the program, they have the ability to license the program by paying a substantial license fee and then traditional milestone zone regulatory achievements and royalties when the drug is commercialized.
This is a drug that’s in Phase I clinical trials in SMA patients. Those trials started just about a month ago and we plan an expedited Phase II/III program to get this drug on the market for children with this devastating disease.
The preferred partner’s structure is the same structure that we used in our collaboration with GlaxoSmithKline. And we think it’s a structure that suites our stage of development and our business strategy. We provide the partner with an option early on in the history of the drug, which allows us to partially de-risk the program get some money early. But because the partner doesn’t license the drug until we have clinical proof-of-concept or clinical proof-of-benefit, we get the benefit of having much large licensee’s milestones and royalties in terms of commercial participation.
So we get some cash upfront, but we preserve the ability to have late stage licensing terms, economics. We develop the drug through proof-of-concept, which means that we can avoid a lot of infrastructure and potential delays in a partners infrastructure and provide efficient development aside benefit of that is because our program we are able to be much more transparent with all of you about data and stage of development what’s going on with the programs than maybe a large pharmaceutical company would be.
And because our partners work very closely together with us on the development of the drug through the licensing stage, we have a knowledgeable invested partner at the time they have the opportunity to license the drug.
We think Biogen Idec is the ideal partner for this opportunity, obviously they have global development commercial capabilities and our recognized leader in commercializing specialty neurological products. The transaction is a perfect fit for us. And most importantly both we and Biogen Idec are committed to very expeditious path to the market for this drug.
ISIS-SMNRx is the first drug in our pipeline to treat splicing disorders and you remember from the human gene sequencing project, one of the interesting things that came out of that was that we had a lot more diversity of protein level than we have at the gene level and that’s a result of splicing.
When you have spinal muscular atrophy, the body is preferentially making a truncated dysfunctional protein where the full length functional part of protein, form of the protein is necessary for a normal neuromuscular development and function.
ISIS-SMNRx alter splicing to cause of the gene to make the full length functional form of the protein rather than the truncated dysfunctional form of the protein and we’d hope that that treatment will help produce normal neuromuscular function and development in children with this devastating disease.
SMA is the leading genetic cause of infant mortality. But it’s a common rare disease so it’s a similar in size as cystic fibrosis or Duchenne's muscular dystrophy or sickle cell anemia or about 5000 children a year in the United States die from this disease and there are no treatments currently available.
We have very substantial pre-clinical data to support both the mechanism of action and the therapeutic benefits of ISIS-SMNRx in mouse models of severe SMA. And just to give you one piece of data after a single ICV bolus injection, you can see the increased longevity or survival of the mice in this SMA model. These are placebo treated mice and you could see these are the mice they got the benefit of a single dose of ISIS-SMNRx.
The drug has been granted orphan drug status as well as test drug status by the U.S. FDA. And as you would expect with a novel unique therapy for really a terrible disease like this. We have a very large group of high-profile, medical advisors, collaborators, as well as support from all of the different patient advocacy groups. So this is a program that has a high level of visibility and excitement around it.
We’re in Phase I clinical trials right now. After the Phase I clinical trials, we plan to do two parallel Phase II, III studies, but first in the most of here form of SMA type1, SMA and this is the form of SMA where children die frequently in infancy. And the second Phase II, III study will be on the II, III SMA patients who are children, who live much longer, but frequently with the significant disabilities.
Beyond our large pharmaceutical company partnerships, we have a unique part of our business strategy, which our satellite company strategy, with our satellite company strategy, we work together with smaller companies typically by our technology companies that have particular areas of therapeutic focus outside the areas that we’re working in.
This enables us to create drugs in areas outside our areas of focus, working together with the knowledgeable partner using their funding to develop the drug, it allows us to broaden our pipeline and to do it with very little risk; it preserves cash. But in fact an important thing about this part of our business strategy is actually generated significant cash.
We received over $450 million from our satellite company partners today. And for these drugs that our satellite company partners are moving forward, in addition to equity in some of these companies, we also have milestones and royalties.
So these are all opportunities in which we’ve made very little investment financially, but in which we have significant commercial upside.
The most recent success in our satellite company’s strategy has been Pfizer’s recent acquisition of Excaliard, as an equity holder in Excaliard we have the opportunity to get up to $14 million for our equity, but of course now we have experienced partner with the deep pocket moving this drug forward rapidly into Phase III clinical trial and we get milestones and royalties as that drug moves forward.
EXC 001 is the drug that we talked to you about quite a lot before. They completed three positive Phase II clinical trials with this drug, which is intended to locally treat scarring and a picture is worth a thousand words, so I have a picture here. I think you would all agree that following surgery you would much rather have this scar than the one below and that’s what EXC 001 can do. We think it has an opportunity to really be a significant commercial success.
Today, most of what we are going to focus on is the pipeline. Obviously, we are maintaining our leadership position in the technology; we are the leader in RNA therapeutics. We are broadening and expanding the pipeline and we are controlling development of our drugs through key value inflection points to ensure that when we partner them we get significant benefit from the licensing transactions. Because the pipeline is so big now, I’m not going to spend much time on this, because it’s really getting hard to read. But I am going to break it down and talk about our key therapeutic area franchises.
In cardiovascular disease area, our goal is to treat cardiovascular disease from numerous different directions. Obviously, cardiovascular disease is the largest cause of death in developed countries. And we started off by trying to look at all of the different atherogenic lipids and have drugs to inhibit all of the, methods to inhibit all of the different atherogenic lipids.
In addition, now we have drugs to treat thrombosis. We’re looking at the inflammatory components of cardiovascular disease, we are looking at atherosclerosis, we’re looking at heart failure, we’re looking at hypertension. So, our goal is to build a broad franchise with drugs that combat cardiovascular disease from numerous different directions.
And if you look at just the drugs that we have right now in the cardiovascular area, I think we’re being very successful in doing that. And we've got a lot of activity coming up in the next year. We'll have data from our CRP drug this year. We'll have two drugs, both our APOCIII inhibitor and our Factor XI inhibitor, going into Phase II clinical trials this year. While two drugs going into Phase I clinical trials, our second anti-thrombotic drug or Factor VII inhibitor and our Lp(a) drug, will both go into Phase I clinical trials this year.
In metabolic disease, again we’re branching out beyond type II diabetes, which has been the core of our metabolic disease program. We now have drugs, peripherally acting drug to treat obesity as well as our new DGAT inhibitor to treat NASH, and we’re treating, looking at various different components of metabolic syndrome, which is a growing health issue, again in the developing world.
Lot of activity coming up this year in our metabolic disease portfolio as well, with our PTP1B inhibitor going into Phase II clinical trial, data on four different drugs in this franchise coming up during the course of the year, and our DGAT inhibitor going into Phase I clinical trials later this year.
In the cancer area, we also have a multidirectional strategy to look at both solid and liquid tumors, metastasis, tumor vascularization, cancer thrombosis where our Factor, new Factor VII drug comes into play as well as drug resistance in cancer. This year we expect to have data from Lilly’s survivin program and our first generation 2.5 drug STAT3 drug will go into Phase I clinical trial.
Our newest franchise, which is our severe and rare disease franchise, is also extremely active. Of course our Biogen Idec partnership and our GlaxoSmithKline partnership are both focused in this area and it’s an area that we have a lot of interest from the pharmaceutical company. Here we’re focusing not only on splicing disorders like SMA and neurodegenerative diseases like ALS genetic diseases, but also on severe pain.
In 2012, we’ll have two different drugs go into later stage clinical trials both our TTR program, as well as our partners at ATL, their acromegaly drug. We’ll have two drugs from which we plan to have data this year, our (Inaudible) I program as well as our Spinal Muscular Atrophy program. And we plan to take our alpha-1 antitrypsin drug into Phase I clinical trials and that’s the second development candidate in our GlaxoSmithKline collaboration.
So, in addition to starting with Kynamro of course I need to end with Kynamro. We do believe that Kynamro has the opportunity to be a transforming therapy for a fatal cardiovascular disease. We’ve made tremendous progress. We completed the MAA application and the NDA is nearly ready to submit. This is a drug that we really think has a unique competitive profile. It doesn’t just lower LDL. It uniquely targets all atherogenic lipids and so we believe it has substantial therapeutic benefit.
The NLA has recently recommended early diagnosis and aggressive treatment of FH patients by lipids specialist and Genzyme’s commercial focus is right in line with that to improve diseases awareness and treatment of these severe FH patients.
Genzyme is of course very experienced in the rare diseases market that the global commercial infrastructure to support a successful launch of this drug. Of course that’s added too by the commercial infrastructure that Sanofi brings to the table. So, we think in Genzyme we’ve picked a perfect partner for a successful Kynamro launch.
And with that I would like to turn the podium over to Paula.
Thank you, Lynne and Stan. And first I want to thank you for asking me to join this very important day for Isis. I personally am very excited to be part of commercializing Isis’ innovative antisense technology through Kynamro.
Just a quick word on a little about me, I am 20 year veteran at Genzyme in various areas from our manufacturing operations through developments and commercialization and various businesses including our rare diseases, renal transplant oncology in addition to my current responsibility in cardiovascular.
This is an exciting time for Kynamro and just to reemphasize some of the things that Lynne mentioned, we’ve had significant accomplishments. We are already in the middle of a review for our European filing very close to our U.S. NDA filing. We’ve made tremendous strives already in terms of raising awareness about the urgency of this disease. We have very focused efforts in global markets around the world. We have brought forward significant programs to understand the true burden of this disease and begin to outlay the ground works for market access and reimbursements. We’ve also accelerated bringing forward a prefilled syringe for Kynamro, which will be available for launch. And so we are quite excited by the things that we have done this year. And so if, I would like to start again emphasizing four of the patients that we are going after. Kynamro is specifically focused on patients with familial hypercholesterolemia and the most severe of those patients.
Patients with homozygous FH, basically the defect is from both parents, are the patients who are most at risk. All of these patients have a deadly disease. But this manifest in homozygous FH at a very young age even as early as 18 months. Patients with homozygous FH are likely to have a heart attack in their teens and if left untreated they are likely to die in their 20s.
What we call is severe heterozygous FH are patients who essentially have LDL levels that are extreme, that is greater than 200, if they have cardiovascular, evidence of CHD or above 300 without. These patients are equally at risk as homozygous FH patients just two or three decades later. The same types of disease manifestation happen in these patients.
They are likely to have a heart attack in their 30s just when they are in the middle of building a family, a career. Many of those patients actually never know that they have this life threatening disease.
In all cases of severe FH these patients on naturally tolerated lipid lowering therapy and yet they are still so far from goal in their extreme reps. Their only alternatives are apheresis or in some extreme cases liver transplants. Apheresis is a treatment (Inaudible) to dialysis where a patient is sitting for three to four hours on a machine to clear the LDL from their blood. It’s quite an older therapy. In many cases people have to take out a full day, there aren’t many. Apheresis centers around if you look globally of all these patients that are severe FH that are eligible for apheresis. Only 2% of them actually undergo Apheresis partially because it is a life changing therapy that does affect normal daily living but also because there aren’t many Apheresis centers available.
And if I just take the metropolitan area of San Francisco for example there isn’t one Apheresis center and we see that around the world. So these patients are in dire need of a new alternative that addresses their unique needs.
In the case of patients that undergo Apheresis, they are lucky. There are patients like (Inaudible) who I showed here, who actually did not know that she had been exposed to the toxic level of lipids from the day she was born and at 40 years old her arteries look like an 80 year old. And so it is very important to treat these patients early and aggressively.
I want to back up. Well, there is it is. This is (Inaudible). So, if we look at the risk level of a person getting coronary heart disease, a normal person would actually be at about the age of 65 where they start to show evidence of coronary heart disease in the homozygous patients that is more like 15 years old. And then the heterozygous patients, not even severe that is actually 4 years old, so again importance of aggressively treating these patients.
So what’s happening in FH? FH is caused by genetic mutation in the LDL receptor, which is important for clearing LDL from the blood. And so what happens is the defect causing this mutation in the LDL receptor it doesn’t allow the LDL to be cleared from the blood and therefore there is an accumulation in the bloodstream.
What compounds with FH and professionally in severe FH is that, if there is not only a defect in the clearance, but there is basically [ambitious] cycle, where there is an excessive overproduction of apoB containing lipoprotein, so not only LDL but another atherogenic lipoprotein such as Lp(a).
So if you think about FH, again not only a problem of overproduction, it’s a problem of not only clears that overproduction as well and so most of the therapies today – so all the current therapies today actually focuses (Inaudible) focus on up regulating the LDL receptor.
And so FH patients for a patients that are the broad FH patient that may be good enough for them but these severe patients homozygous, severe heterozygous patients, it isn't enough on that ability to just up regulate the limited LDL receptor activity they have is not enough because of the over production of lipids. Right, so we will correct this technical difficulty for a moment. Slides are advancing on their own.
So, as Chris is kindly fixing that, I’ll just keep talking. So, we do believe as well as I just said that Kynamro represents a significant opportunity in this initial patient focused group that we’re looking at severe FH, thank you.
So, again in homozygous and severe we have files in Europe for the homozygous and severe heterozygous into patient and for the U.S. our initial filing will be in homozygous FH with a study that is initiating to further expand that as well. So, we believe that because of the unique aspects of FH that Kynamro is the right medicine for these patients.
It offers a personalized approach to the exact issues with their disease and we’ve done that on a foundation, executing the right clinical program. We have executed very robust studies that have been randomized double blind placebo control. And in fact our study is the largest clinical study ever done in the most severe of these patients. In all of our clinical studies, Kynamro has consistently demonstrated significant reductions not only in LDL but all atherogenic apo-B containing lipoprotein such as Lp(a), which is an independent risk factor, not only atherogenic but thrombogenic as well. And this is a drug that is actually delivered in subcutaneous injection once weekly.
It is well tolerated in our homozygous study. We had only one patient who discontinued for injection site reactions and in our severe study only two patients who discontinued for injection site reactions and flu-like symptoms.
So, a well tolerated therapy, a convenient therapy once a week. We’re hearing from patients in fact, it’s basically once (Inaudible), they don’t have to think about this drug on a daily basis, a reminder of their disease that can really get on with their lives. So, it’s an important delivery and that’s why I had mentioned earlier that we will be ready at launch with prefilled syringe and that is something that’s important for us to include in our initial filing.
This data has been published after the homozygous study in Aventis as we are very much in a launch mode. We are getting ready in all of our markets, so I show here various ways of our launch. The first countries that we are launching are U.S., Germany, UK, Netherlands, the Nordic regions.
We see their markets that we already have a premise with Cholestagel specifically targeted for FH patients, so we have the infrastructure in these markets. Subsequent launches are countries that have longer time to reimbursements or in some countries such as Japan and China require local clinical programs, which has already actually, plans have already been moving forward for those. We also have built in a very experienced launch team. We have seasoned professionals that not only have deep lipid experience but also experience in delivering products in the way of disease market space.
So we are quite excited that we’ve actually got a full team not only from a global commercial organization but even locally deep into the countries, really understanding their markets and so we have been working over the past year and a half to raise the level of awareness about this disease. This is a disease that really is not well understood. Many people think it’s just cholesterol. It’s so much more than high cholesterol.
This is genetic disease. This is the disease that causes people to fear, going to bed at night that they may not wake up the next morning, they are basically walking around, like a ticking time bomb.
And so that’s raising the awareness level even if it’s clinicians who don’t come across these patients everyday that there is an urgency to treat. We’ve also help facilitate increase awareness in doing family screening and provided tools around that. We’ve also increased our commitment to engaging with the healthcare community trying to understand, how we can open up early access for kind and rough for the patients who needed most and we’re also advancing our investment in the future with our FOCUS FH study, which is for severe heterozygous FIRST HALF.
And we’ve also done slight a bit of work with regard to prepared for reimbursement and access. There is so little data on patients outcome in this particular spectrum of LDL-cholesterol, there is an incredible wealth of outcome data for LDL levels at the lower range, but really not much have been studied in above 200 mg per deciliter.
So we have done extensive work looking at databases across the world and understanding the true burden of disease for patients with FH and to capture what the economic value and relative medical value of a drug like Kynamro will bring to these patients.
An important thing that we have been doing and that’s been our focus at Genzyme is really listening to the voice of patients. FH is a disease where there are no patient communities or there were no patient community. There were no foundations like we have in other diseases like cystic fibrosis. These are grass root efforts. An important effort that we do is bringing these patients together to share their stories and to actually begin to create a voice for themselves to actually demand urgent care and more education.
And so some of these patients, their stories in some ways are so different, but the same. Of these 13 people, you see in this patient (Inaudible) 11 of them have FH. I doubt you can take out the two that don’t.
Most FH patients look very healthy, young, lean, they are not your typical face of cardiovascular disease. All of the parents in the picture not only have FH, but they have children that have FH as well.
And every single one of us has talked about the guilt that they feel passing this genetic disorder on and they have stood up and they have come together to actually try to make a difference. And two of these patients have (Inaudible) are the founding leaders of a new FH patient foundation that we have just established at the end of this year, but and those two particular of very similar stories where they both have their first heart attacks in their late 30s.
In both cases, returned away by their physicians, by emergency room saying, go home, you have anxiety, there’s nothing wrong with you. They have since had subsequent in rise stents, in the case of Cathy here. I’ll do this. In the case of Cathy here, she only had a several heart attacks herself.
Her son had an MI at the age of 24. And anecdotally here in the corner, the little son also has FH, he – his brother actually died of a heart attack at the age of 27 and that’s when he had his cholesterol check.
And so this isn’t just one patient, this is a family. And the family you’re seeing in the center, all four, have FH. The little girl Canady when she was two–years–old went to a dermatologist, because they thought she had skin rash, it turned out to be xanthomas which is basically accumulation of lipid down her skin and she is diagnosed with homozygous FH.
If she wasn’t, her family would never have been tested, so her mother, her father and her brother all have FH, all now have the opportunity to get more aggressive treatment earlier than they would have. But these patient stories are absolutely important because they tell us what is missing and what we need to do to provide for these patients.
And so I’m very proud of what our team has done and shows on to already advance the understanding an FH; these are examples of some of the works regarding awareness. We have delivered the source FH patients with that provides education and this has been published on the National Lipid Association website.
We've done numerous continuing medical education programs to further the understanding and urgency of this disease and treatment. We have YouTube videos that describe the disease that can be publicly accessed. We have an iPhone App that helps physicians actually diagnose FH, because FH is easily diagnosed due to clinical manifestation.
And further, we have partnered with all of the major stakeholders in all of these initiatives from the NLA to the American Academy of Pediatrics, and we have some exciting programs moving into this year with women's heart and [men] hearts where they have significant bodies on the ground that can actually help educate and provide some of the tools that we have developed for FH.
So all of this is a part of what we do at Genzyme, and what we have significant experience around. We don't just deliver a therapy, we actually deliver all of the needs in understanding that's required for treating a disease. So we’re building a therapy around a community, and a community around a therapy.
And so that includes making sure that we offer the right education material, assistance with financial, any financial requirements and barriers to treatment, supporting patient foundations, and bringing those patients together.
And that we will lay the foundation for how we will organize our field sales force or our sales force, so the business that will just have a sales rep. In addition, we have nursing support, patient education support, case management, and medical education. So this is where we have already begun to structure our organization and separation for the launch.
And we continue to invest in the future with our FOCUS FH study, which is a study that is important for expanding our approval in the United States to severe FH patients. It will also support our post approval strategy for Europe.
It is a study that also allows us to look at alternative dose regimens, and importantly looking at dose escalation regimens, which we believe will help support the management and mitigation of some of the (Inaudible) effects that we have seen with the product.
This is the study that actually is underway with 480 patients in 27 countries. We already have approval in three countries, seven centres up and running and we have our first patient screening hoping to give randomize next week, so that study is well under way.
So we do believe that Kynamro is the transform therapy will add significant value for the FH community as well as significant value for Genzyme, for ISIS and Sanofi, we are very much into our regulatory process with our MAA files of July, and very close to filing our U.S. NDA this quarter. We have made significant progress in raising awareness, establishing or launch preparation.
We are also in a wonderful position, I think as a company as you know we are part of Sanofi and so we also have the opportunity to leverage and we’re taking advantage of that opportunity to leverage expertise as a broader organization, especially in markets where we didn't have as much presence.
And also in fact, because a program anti PCSK9 antibody, which is focused on broader FH and a very complementary product to Kynamro, it’s a great position to be in and to be able to address the full spectrum of FH with these two complementary products and really highlighting the commitment of the company to really do something for this disease.
So with that, I thank you again for your attention. And again, Stanley, thank you for asking me to join.
Stanley T Crooke
At least, dare to try this one time and see, hopefully it’ll work. Thank you, Paula. What I’m going to be doing in the next few minutes is sharing with you a novel strategy for the treatment of thrombotic diseases. It’s a very exiting program and as the title shows the compound ISIS-FXIRx has consistently shown efficacy in preventing clotting pre-clinically without causing bleeding, which has the potential to revolutionalize treatment for these disease indications.
As Lynne pointed out earlier and I’m sure you all know, cardiovascular disease remains the bleeding cause of death. And you can look at numbers expressed in different ways, but it doesn’t change the fact that over 2000 Americans everyday die of cardiovascular disease.
And primarily the disease manifests itself as two major aspects. The first is thickening of the blood vessels in the arteries, a process that is called atherosclerosis, which then decreases the blood supply to vital organs such as the heart leading to heart attack and complications and death. The second process is thrombosis or blood clotting, which then results in the clot moving and from sometimes its primary place and then moving on and causing the decrease in blood supply as well.
So what exactly is the process of the block formation, that’s depicted in this cartoon. It’s a very highly and tightly regulated process as would imagine. However, if you break it down simply and to some of the major steps, what really happens is once you see the tear in a blood vessel as shown on the second slide here, initially the platelets come to the site. And the first part of the process is called the initiation phase where factors such as Factor VII that represent in the blood interact with key proteins such as tissue factor and initiate the process.
Once the process get initiated, then has to propagate or amplify and this propagation or amplification of the process is where Factor XI, which is the drug target that our drug is designed for is critical, it’s critical for the amplification of the thrombus and once the thrombus amplifies and propagates, it then stabilizes the fibrin clot forms and it seals the tear. So clotting basically is a process that involves primarily the propagation and stabilization once it gets initiated.
So what exactly is the evidence that Factor XI is an important target to go after? As it so happens, we have majors experiment in patients who have both high levels of Factor XI as well as low levels of Factor XI activity. And it’s been reported that patients who have high levels of Factor XI are more prone to myocardial infarction, stroke and cardiovascular events.
In contrast, patients who have lower levels of Factor XI activity have been demonstrated to have a decrease thrombotic risk. So the experiment of nature already points to that as an attractive target. Very importantly, these patients even though they have big reductions in Factor XI activity do not have spontaneous bleeding, in fact when they have major surgeries these patients do not bleed as well.
So looking at Factor XI as a genetically validated target, it has two key attributes. Very good effectiveness based on the data from these families and secondly no bleeding. And we have over the last two years actually generated a tremendous amount of data in various animal models of thrombosis, which we’ve shown exactly the same phenomena, very robust efficacy without any bleeding.
A couple of points to keep in mind for this program before I get into some of the preclinical summary, first of all, because Factor XI is an effective target for both venous and arterial thrombosis, the commercial opportunity is very big, because it will work for diseases that occur either due to a venous plot or due to an arterial plot.
Secondly it has a unique mechanism. The mechanism is distinct from all available treatments that are available are in late stage development. And we have shown in preclinical models that when you add the Factor XI antisense drug to these existing therapies, you see very good effects in combination without further increasing the risk for bleeding versus the therapy alone.
So as we think about these compounds moving forward for both venous and arterial thrombosis it will be very complementary to existing therapies. And patient convenience which is a once a week injection as you all know with most of our drugs, if you compare it to some of the existing drugs which is warfarin and others where you have to give daily treatment and being the commission it is a challenge, because you have then have to monitor for the bleeding risk on a regular basis and adjust the dosing.
If you don’t have bleeding, which we hope will happen in this drug as we move forward in the clinic, there is no clinical monitoring need as well, so really very key and very attractive features for this program. Due to the ability of antisense drugs to very specifically reduced targets in the liver, we have had the advantage to knockout every single key gene target in these plotting cascades. And what this picture shows you basically is the approach where we’ve taken several factors some of them which you maybe familiar with, because Factor X inhibitors and others have been worked on the past few years by pharmas,
But what this shows you is that, if you inhibit very specifically each factor, if you do not cause the reduction of any of the other targets. We then compare the therapeutic index both the safety and the efficacy of each one these targets and Factor XI has really emerged as the top as the most promising target to move forward with, so compared to all the other compounds that we have evaluated to-date.
So what are the key data pieces that we’ve looked at – we’ve looked at numerous mouse models. And what we’ve shown is that we can reduce Factor XI activity by greater than 90% in almost all cases. The treatment is very well tolerated. We have not seen a single incidence of bleeding, spontaneous bleeding in any of the models. When you compare it to the standard of care agents, we see comparable or better efficacy with Factor XI antisense inhibition with the antisense drug. And like I said before, we can combine very well with drugs including the anti-platelet inhibitors.
Having done a lot of studies in mice, we then moved on to primates, non-human primates. We, for initial work, we started with normal monkeys, and we demonstrated that treatment with the antisense drugs up to 13 weeks, we reduced Factor XI activity by greater than 90%, and once again we saw no spontaneous bleeding throughout this study.
We then tested the compound in a baboon model of thrombosis with two primary objectives. The first being what is the level of Factor XI that can meet, reduce, to see efficacy. And we were able to demonstrate that reduction of Factor XI activity greater than 50% causes a robust antithrombotic effect.
And secondly, we confirmed once again in another non-human primate that there was no spontaneous bleeding. So just to give you a flavor of the data, this is a drug that I’m sure you’re all very familiar with that’s used in the clinic, it’s being used for the last 100 years, and when you look at it in this case, the tail-leading model in a mouse, what you see is a robust antithrombotic effect. But very soon, you start seeing the bleeding come up with warfarin. And so this is a drug for past centuries being very, very helpful and useful in patients, but again a very small therapeutic index.
This is an example of a drug that we evaluated that is Factor X inhibitor. These compounds have been worked on over the past five to 10 years. And the point is you again see an antithrombotic effect, so these drugs do work very quickly in this animal model, you start seeing an increase in bleeding, something that have been replicated now in the clinic as well.
So how about treatment tomorrow and what is that that makes us so excited about Factor XI? This is exactly the same model and what you see once again is a very robust antithrombotic effect; very comparable to the other drugs and absolutely no increase in bleeding. So this is what excites us about the program.
This study actually shows you the same kind of a study, but this time what we did was, we actually made surgery happen in these monkeys. So we used two models of surgery and as the evaluated and compared the Factor XI antisense drug with Enoxaparin, which as you know is a form of heparin and is used extensively in the clinic.
And two key points from this slide, first of all if you focus on the blue bar, what you will see is that in a tail surgery model, you see no increase in bleeding with the Factor XI antisense drug and even at clinical dose you see an increase in bleeding with heparin or the form of heparin here.
When you then look at a gum laceration model in these animals where you simply cause a laceration in the gum and look at the increase in bleeding, the same trend is repeated or increase bleeding with Enoxaparin and no change in Factor XI. So again both in mice as well in primates, you see a vastly improved therapeutic index with the Factor XI antisense drug as compared to, in this case, heparin.
So we then wanted to look at this in our Phase I study. This shows you a schematic of our very typical design that you are very familiar with. The study was six weeks in duration with once-a-week dosing, looking at both the safety as well as the pharmacodynamics of the drug, because these were normal volunteers we had to add a few stopping rules.
In this case and a aPTT prolongation greater than two times the upper limit of normal, if there was any major or clinically not other than major bleeding and of course we did not want to take Factor XI reduction in these patients to undetectable levels for prolonged periods of time. And as you will see that we actually did not of course got any change in either the aPTT or the bleeding risk because there was no bleeding, but we did due to the pharmacology hit the stopping rule of Factor XI activity, which was a great demonstration of efficacy in these subjects.
This slide shows you the Factor XI reduction as part of the study as three things that you will notice right away as I walk you through this. First of all, the effect is very robust with about 80% reduction observed at a highest dose tested 300 milligram.
Secondly, the effect is very dose-dependent and as you can see even at doses of 100 milligram, the effect is highly statistically significant and thirdly the effect is very prolonged. So if you look at when treatment was stopped, which is shown by this grey area here, you see a sustained effect because of the long half life of the drug in the liver.
I should also point out before moving forward that at the 300 milligram dose it seems like the effect is (Inaudible) at the – about an 80% reduction in activity. That's because we had instituted the stopping rule like I told you. And there were several subjects who actually have undetectable levels of Factor XI and they have that for several weeks, but we stopped the dosing. And even then there was no bleeding observed. So indeed very comfortable data in the Phase I study that was very consistent with what we had seen preclinically.
If you look at each individual subject, as shown on this slide the point is that there is a very consistent effect of the drug with each subject showing a very robust reduction. If you compare this for example with the drug that is warfarin, there is very varied response in fact that is one of the big clinical challenges in managing patients that they respond quite differently to the same dose of warfarin.
In this case very, very consistent response and the same trend was seen in the other cohorts as well. When you look at an increase in aPTT, which in this case is a measure of PD for our compound, as we saw in preclinical studies and as shown on this slide, you see about a 1.6 to 1.7-fold increase in aPTT. So we've exactly replicated what we saw preclinically. And please do keep in mind that this amount of an increase in aPTT does not amount to an increase in bleeding risk, which is where you have to hit a two-fold or a higher level at which we have placed a stopping rule in the study.
So when you look at the statistics, as you can see, the first important thing is at the dose as low as 15 milligram, there is a very statistically significant effect, only with an [NF9 per] cohort.
Secondly, if you look for Factor XI protein as well activity reduction, you have a very good dose response effect, with the maximal effect at greater than 80% in this case, and that is accompanied by an increase in aPTT, despite the fact that is placed here that dosing had to discontinued at the 300 milligram dose in four of the nine subjects because they had almost undetectable levels of Factor XI. And of course, we never went to the 400 milligram dose in the study, which we had to because at 300 we had already caused undetectable levels of Factor XI.
So the first and most important safety dataset slide here for any antithrombotic compound, what about bleeding? Like I said before, we never hit the stopping rules for either major bleeding, non-clinical relevant bleeding at all, but we looked very carefully for hematomas, any increase in bleeding time, and the good news is there was absolutely no change in any of the bleeding parameters in the study.
In fact, at the highest dose of 300 where we had greater than 80% reduction of Factor XI activity, there were no drug hematomas that were even observed, so very good safety profile and very encouraging for us. In these multiple dose cohorts, there were no SAEs, the AEs were mild, the incidence of injection side reactions was low and they’re very mild in most casing lasting a day or two. There was no change in any lab chemistries, no lab parameters and basically a very boring safety profile, which is what we had hoped for going into the study.
Where are we going with the compound after Phase I and what is that that you’re going to hear from us. We are going into a Phase II study that is going to get started this year in which we’re going to look at the effects of the compound in patients who undergo total knee surgery, that is our first proof-of-concept study and that will give us efficacy and proof-of-concept for venous part of the efficacy and we will then move on to patients who have atrial fibrillation for prevention of stroke and then in parallel with that, we’re planning to go on to the arterial end of things, which would be patients who have coronary artery disease in which you want to prevent secondary cardiovascular events, because remember I told you that the drug should work very well for both arms, both the venous and arterial arm.
And so just, what is that that we expect from the product profile. I think I’ve listed here a very effective drug for both arterial and venous thrombosis, no bleeding, therefore no monitoring needed doing therapy. We do not interact with on a not metabolized by the P450 system. So there should be no drug-drug interactions, a very key advantage in many of these patient populations. We would add and we actually work very well in addition to platelet inhibitors.
And so in people who are resistant to drug like Plavix, we should work very well as single agent and we should increase efficacy as our combination treatments and we definitely do not expect to see any rebound effects which we have shown very nicely pre-clinically. And so indeed, this seems like our drug based on our early data that is replicating our pre-clinical findings of a very efficacious antithrombotic that does not cause bleeding.
Thank you and with that I will hand it over to Richard.
Okay. Thank you, Sanjay. Thank you, Sanjay and good afternoon. And you can see why we are so excited about the Factor XI drug. I want to turn your attention for the next few minutes to our ISIS-APOCIIIRx, drug which is the first targeted drug for hypertriglyceridemia, second drug in our dyslipidemic arm of the cardiovascular franchise, following mipomersen and again directly targeting triglyceride levels.
So APOC3 as a target is a glycoprotein that synthesized principally in the liver. So it makes for an ideal antisense target, plays a key role in regulating it’s actually at the nexus kind of like the holy grail for targeting directly triglyceride lowering. It’s very difficult to target with traditional therapeutics and therefore again ideal for an antisense approach. It provides for us kind of a unique position and directly targeting triglycerides that is not possible with other therapies.
Serum triglycerides of course are an independent risk factor for cardiovascular disease and APOC3 importantly is also an independent risk factor and as Lynne said earlier, this is like a double whammy. The reason this is such an important target for us, is not only because it directly lowers triglycerides, but also because it's taking down the apoC-III, which is [proven inflammatory] itself, it's a test to lipid particles and proven inflammatory and its activity. So a simple cartoon here describes how apoC-III regulates triglycerides in the bloodstream.
The LDL is the particle that is synthesized or produced within deliver, its get loaded up with triglycerides and then is released into the bloodstream. The VLDL particle is then process to intermediate density and then low-density LDL. And in that processing then nutrients are provided to for energy use and tissues and ultimately VLDL is [screwed] to the LDL receptor. In the normal case this then regulates triglycerides to a normal level, provides nutrients to the tissues and eliminates the LDL particle.
It is in fact, the [lipase enzymes] in the blood they control the digestion or the clearance of the triglycerides of the particles and provide that nutrient. apoC-III then is produced and deliver attached on the particle and released into the bloodstream along with the particle really travels down to the life of the particle and functions as a break on the lipase enzymes. So if you have a particle released into the bloodstream with the apoC-III attached to it, it slowing down triglycerides clearance and that's the triglyceride levels in the blood are elevated. If you have a lot of triglycerides – if you have the [heart] of the LDL particles with apoC-III on there you have very or hypertriglyceridemia.
So, APOCIIIRx then blocks the synthesis of apoC-III at the liver. And therefore takes it out of the circulation essentially removing it so the particles that are released from the liver now do not have the apoC-III break on the lipase system and you go back to a normal lipase digestion and clearance of the triglycerides.
So the National Cholesterol Education Program and the ADA or the American Diabetes Association recommend lowering triglycerides because triglycerides of course an independent risk factor for cardiovascular diseases. And again apoC-III itself is an independent risk factor. The high triglycerides are also associated with increased risk in strokes so there is thrombotic component, very high triglycerides greater than 500 milligram per deciliter are associated with high risk of pancreatitis.
So, there is a number of populations with an unmet medical need in high triglycerides. There is the familial component of hypertriglyceridemia which have genetically been broken down into types and are very well defined, routine hypertriglyceridemia in patients who have high cardiovascular risk components and type II diabetes, a population which have often high triglycerides or out of control triglycerides as well as high cardiovascular risk.
So, again as in the Factor XI story this is a genetically validated target. There is an experimented nature out there. The (Inaudible) for example has been published, have a polymorphism in their apoC-III which makes them actually make much less apoC-III and have very little apoC-III in the blood, have reduced blood pressure, improved insulin sensitivity and its reported to have exceptional longevity in humans with very low rates of cardiovascular disease.
The old world Amish population, similarly have very low levels of serum triglycerides due to a no mutation in the apoC-III gene, they have reduced cardiovascular disease and enhanced health and extraordinary longevity. So these are the lucky guys. On the other side of the equation are the apoC-III gene variance in the eastern Indian males who have an increase in apoC-III circulating levels and a tremendous increase in their fasting triglyceride levels as a consequence reduced triglyceride clearance and an increased incidents in cardiovascular disease as well as reported in this paper nonalcoholic steatohepatitis of the liver and insulin resistants. So pre diabetic and pre disposed to diabetes.
So in our pre-clinical work once again we did a number of studies in multiple species. Some of these species were arthrogenic species that develop Atherosclerosis. We were able to show the amount of reaction of Atherosclerosis in the rodent models. But this is just showing you here an experiment that we ran in the non-human primates.
Now it’s important to understand that monkeys have extremely low triglycerides. So in this case we fed the monkeys Kool-Aid and we gave them Kool-Aid prior to treatment and during treatment and what the Kool-Aid does is of course raise their apoC-III and their triglycerides and that’s why you see a never increasing level of triglycerides as these monkeys are on diets more like humans I guess.
apoC-III stand lowered their messenger RNA expression dramatically to market to 85% of the highest dose and that resulted in apoC-III protein reductions that were robust and essentially taken to non-deductable levels, at the lowest dose tested in the monkeys and we saw this reversal of the triglyceride elevations with significant lowering of triglycerides and a good profile in the lipoproteins with rising actually of HDL or the good cholesterol if you will.
So on the basis of these data, we moved into Phase I. Phase I healthy volunteer study, which is a randomized double-blind placebo-controlled ascending dose study. Typical again design for our Phase I, four weeks of dosing, six injections, weekly dosing ranging from 50 milligrams to 400 milligrams. One important thing to bring to your attention is these subjects normal volunteers were housed in a clinic and from day one to six and then again on day 22 and they were fed a fatty diet while they were in the clinic.
This summarizes the demographics for the patient population. I want to draw your attention to apoC-III and triglyceride levels, which were largely very low apoC-III levels in normal triglyceride levels and this is just breaking it down for each of the cohorts. These are small cohorts, we only dosed three volunteers in each of the subjects we had four in the placebo group.
So this is the key graphic, these are the medium levels of their apoC-III protein level circulating in blood. If you look at the placebo group, they kind of go up from day one to six and again on day 22, which is a consequence of they’re being fed the fatty diet and then even at 50 milligram, you start to see a reduction in both fasting and postprandial, but you see a dose dependent, a robust reduction at 100 milligrams, 200 milligrams, and 400 milligrams of not only their postprandial, but also their fasting apoC-III levels.
The great in areas are dosing period, so this is the post-dosing period you see a sustained reduction at the higher doses and statistically significant results at the 200 milligram and the 400 milligram level even with a small group of only three volunteers.
Importantly, here two of three of these subjects in the 400 milligram group went below the level of detection of the assay for apoC-III. So this likely well underestimates the level of reduction that we actually got at 400 milligrams. So what happened to the triglycerides they followed the same pattern.
Lipidology experts have told us when we go into human volunteers may be very difficult for lower triglycerides with an apoC-III drug in normal volunteers because the lipase activities are normal. They’ve got good clearance for the triglycerides. What we saw was the same effect dose dependent and significant reductions of triglycerides and with at the 200 milligram and the 400 milligram dose between 40% and 50% reduction in a normal person’s triglyceride levels.
And this was also sustained for a period of time and we also saw both the postprandial and the fasting triglyceride effects. Again the Lipidologists told us ideal to take down apoC-III along with triglyceride because of that nexus and it’s independent risk factor capability but also to take down both postprandial and fasting triglyceride is like the ideal and that’s exactly what we have with this drug.
This table summarizes the results in actual numbers, one week after the last dose. So this is a day 29 numbers and you can see the bold that Astra’s numbers are those that were statistically significant even with a group as small as three individuals with between 40% and 50% reductions in triglycerides.
Safety summary, very similar to what we saw with the Factor XI no [SAES], no significant adverse events and extremely low incidents of injection site reactions and they were very mild those that we’re seeing. Most patients did not exhibit injection site reactions and no subject exhibited flu-like symptoms even through the 400 milligram dose. Again, no significant changes in lab chemistries and very importantly no changes in liver enzymes, no elevations in liver enzymes even for those subjects for which we took their apoC-III levels to non-detect.
So, in summary, a robust dose dependent lowering of apoC-III protein on an individual basis, up to 89% reduction from baseline in just four weeks of treatment. A durable response was maintained at least four weeks following the last dose and associated with the dose dependent reduction in triglycerides and on an individual level up to 67% reduce from baseline.
And we expect larger reductions with patients who have restricted lipase activity because of an over production of apoC-III as we move toward phase II. And we saw in a study offer trends towards treatment related elevations in HDL even in only four weeks of treatment. There were trends to where this elevation which is very beneficial and no safety signals identified. So where do we go from here?
The initiating of Phase II trial in patients with severe high triglycerides greater than 500 milligram per deciliter projected for the first half of this year. The initial legislation path is going to be in patients who are at the highest risk of pancreatitis. Those are patients who have very high triglycerides greater than 500.
We are designing additional Phase II studies to expand and look into broader populations. But we are pursuing a stage development path much likely did with the mipomersen. Looking at those patients identifying those patients, who are greatest unmet medical need targeting that is our first population and then only after we’ve got experience, safety experience in that population moving to the broader population. Thank you very much and with that I’ll turn it over to Frank.
C Frank Bennett
Thank you, Richard. And thank you for your attention. I’d like to now turn your attention to ISIS-TTRRx, where I’m very pleased to share with you our Phase I data that we announced this morning. So just to emphasis again ISIS-TTRRx is our first choice to enter development for 2010 strategic alliance with GSK. I also like to highlight that when we began this alliance the ISIS-TTRRx drug is still in a drug discovery phase of our program or we are still screening (Inaudible) leads.
In the sort period of time since then we’ve been able to take the program from identifying leads duplication to tox to these to completion of the Phase I clinical trial really highlighting the efficiencies of antisense technology. To-date we’ve achieved $10 million of milestone of ISIS-TTRRx and have the potential to achieve additional milestone for a licensing to our partner.
One benefit of this program as Lynne has already mentioned is that ISIS controls the early development of this project ensuring that we get a very efficient and rapid advancement to clinic (Inaudible) value, at which point GSK has the opportunity to license the drug. And also recognized that GSK has been involved with the clinical trials to this point. So that when you do transition to them we have a very efficient process of transitioning to them. TTR amyloidosis is a fatal where, the genetic disease that affects about 50,000 patients worldwide.
It presents predominantly in two different forms, one form is the polyneuropathy in which you get the generation of peripheral nerves. And that's due to deposition of these TTR protein aggregate in nerve fibers either sensory nerves of autonomic nerves.
This results in a slowly progressive disease that leads to wasting and ultimately to death. There is another form of the disease that’s due to deposition of the TTR protein aggregates in heart tissue that ultimately leads to heart failure and death. And again this is a more, many more patients suffer from this form of the disease in the polyneuropathy. So, it's a tremendous opportunity for us.
TTR like the other two programs presented this morning is also expressed in liver and circulates in plasma. Therefore it makes an ideal antisense target. TTR amyloidosis is caused by an inherited mutation or there is multiple mutations that can occur in the TTR gene that lead to a abnormal protein. And one of the properties of this abnormal protein is that it becomes unstable and starts forming these deposits in tissue.
And that's exemplified by this histological section from a patient with TTR amyloidosis and polyneuropathy patient showing these amyloid deposits in the peripheral nerve tissue of this patient.
There are limited treatment options available for patients suffering from TTR amyloidosis. One option that's currently being practiced to a limited extent is liver transplantation. And this is only used for patients with early-stage polyneuropathy. In fact it's contraindicated in patients with a cardiomyopathy and that either has no affect on their disease or actually may accelerate their disease progression. And obviously with liver transplant, it's a major surgery that these patients have to go through, and has limited amount of donor tissue available for transplants, it does limit the application of this therapy for patients.
And also, it's important to recognize that with the liver transplant, you are replacing the abnormal form of the gene with a normal form of the gene that comes from the transplanted tissue, which still gets high levels of TTR being produced from the normal liver. These high levels of TTR continue to deposit in tissue and this is a histological slide from a patient with TTR amyloidosis, showing marked amyloid deposits and a continued degeneration of the nerves five years after the transplantation. So with liver transplants, what you do is you slow the progression of polyneuropathy, but you don't reverse it.
There are more traditional approaches or traditional drug approaches that one could envision for treating TTR amyloidosis. One approach that's being looked at in the research lab is looking for drugs that inhibit aggregation to protein, but there are no drugs currently in development that work through that process.
A second approach is to stabilize the tetramer that circulates in plasma so that tetramer doesn't dissociate into these amylogenic intermediates, and form these aggregates of forming tissue. There was a drug that's recently been approved that does stabilize the tetramers, that's Tafamidis that's been approved in Europe for early-stage FAP. It's not approved for the more severe forms of the disease, and it's yet to be tested for the cardiomyopathy patients, that’s unknown whether it'll benefit those patients.
The third approach, which is the approach we are taking, is to inhibit the synthesis of the TTR protein using our antisense-based drug. It has an advantage that it does reduce all known mutations associated with the TTR amyloidosis. And what we are doing is lowering the amount of substrate that's being produced from liver so that we lower the amount of substrates that is available for deposition and tissues, so we actually have the potential to reverse pre-existing disease by removing this substrate from those the former tissue, and also have substantial to be more effective in liver transplant in these patients.
We have done a number of preclinical studies with our TTRX drug. This is an example from a mouse model in which mice are engineered to express the human gene. So these are trenched in mice, and in this model we demonstrate a robust reduction of TTR messenger on a liver that correlates very nicely with the greater than 90% reduction of TTR of protein that circulates in plasma from these mice.
These studies have been extended to non-human primates where again we show a robust reduction of TTR messenger on a liver, robust reduction and certainly in TTR protein. Again, showing that we get very consistent effects across species with this drug. Based upon these studies, we have advanced the drug into Phase I clinical trial and this was and a healthy volunteers, you have already seen the outline of the trial, it’s very similar to what you saw for both Richards and Sanjay’s presentation, so not going to detail, just we looked at four different dose levels of the drug.
I’m very excited by the data. We again demonstrate a robust dose dependent reduction in TTR levels that are circulating in these patients, I should mention that this last cohort we’re still collecting data on these patients, so we expect this to continue to remain suppressed over longer period of time. And importantly in these patients, this high dose cohort, we did see one patient that TTR protein was global in its detection.
So in summary, we have shown that there is greater than 80% reduction in TTR levels in circulation for these patients with just four weeks of dosing. And that we have a very durable effect with the effects on TTR protein lasting for at least four weeks past the termination of the dosing in the high dose cohorts.
Importantly, the drug is very well tolerated. There were no SAEs and no significant AEs with just a very low instance of flu-like symptoms and injection side reactions. There were no changes in the clinical chemistries including liver enzymes.
So we feel that ISIS-TTRRx has a potential to be the best-in-class treatment for all forms of transthyretin-related amyloidosis. It should be effective for both the polyneuropathy patients as well as the cardiomyopathy patients, for patients that have a severe form of the disease as well as the patients that have a less severe form of the disease.
ISIS at our partners GSK are currently planning the clinical studies for the polyneuropathy patients; will start this year, with the objective to take this current drug into the market as quickly as possible.
And with that I will turn it over to Stan.
Stanley T Crooke
Thank you very much. And thanks for staying with us. I want to focus now on 2012; our agenda for 2012 remains as it has been, which is to advance the pipeline, to create us balanced portfolio of drug development and commercial opportunities as possible, and to increase the value of the pipeline and the technology.
In fact in 2009 at an R&D Day, I defined this agenda. I said we wanted to extend our pipeline, and what meant by that was to advance Mipomersen and OGX-011 to Phase III and beyond. To move more rapidly from development decision to initial clinical proof-of-value either in Phase I or Phase II trials, and to perform, when we did Phase II trials, more robust Phase II trials. We think we’ve accomplished all those objectives.
The second objective was to expand the pipeline. And by that, I meant to leverage the extraordinary efficiency of antisense to generate three to five new drugs a year to expand our pipeline, and we committed to making more interesting better drugs that we would add every year. In addition, we wanted to develop our programs through clinical proof-of-concept, which we’ve done, and of course develop and support our partner programs as we have with our Genzyme collaboration with mipomersen. So we think we have accomplished that.
We also wanted to balance the pipeline. I’m going to talk to you for a few minutes about what it means to have a balanced pipeline, but suffice it to say here we think we have accomplished that as well. And then finally, we wanted to maintain our current investments in our core therapeutic programs, which were cardiovascular and metabolic and enhance our investments in cancer and severe and rare diseases. And again, we think that’s been accomplished very, very well.
So now, I want to look more closely at what we’ve accomplished in the last year, 2011, and the first topic is has our pipeline advanced. And so what I begin with here is the pipeline that we had exactly a year ago, January of 2011, and of course we’re pleased to say that mipomersen has progressed from Phase III to registration, and as Paula described, we’re initiating the important additional trial that will get us to the much larger indication.
CRP completed Phase I and moved into a broad Phase II program. We’ve completed a successful Phase I program for our APOCIIIRx drug. Factor XI moved from development physician to a very positive outcome in the first-in-man trial. I am going to be describing a little more detail about that in a minute. And PCSK9, we will be talking about in detail toward the end of the presentation as well.
In addition, we’ve added Lp(a) or APOARx to our lipid franchise and that completes the strategy, which was to have an ISIS drug that could lower every estrogenic lipid contributor to cardiovascular disease. And we’ve added our second antithrombotic drug and our second-generation 2.5 drug, a Factor XII inhibitor.
Now on the metabolic side, we’ve already shown that PTP-1B reduction had the potential to be a much safer insulin sensitizer lowering glucose, lowering LDL and reducing weight. We’ve now found a more potent drug, move there from development decision to first-in-man. I am going to be describing the completion of the SGLT2 first-in-man study for you in just a little while, we are pleased with the data.
We’ve also advanced the glucocorticoid receptor drug from development decision to man, our glucagon receptor drug from development decision to first-in-man study. Our first peripherally acting anti-obesity agent FGFR4 has moved from development decision to first-in-man study and we’ve added a drug to treat NASH.
In cancer, of course, OGX-011 and our survivin drug and EIF4E and 427 have continued progressing in Phase II and Phase III trials. Our STAT3 drug, our first second generation 2.5 drug has moved from development decision and should be starting clinical trials in patients with cancer in the next very little bit.
We continue to progress with our SOD1 drug. We’ve moved our SMN drug from development decision to first-in-man or actually first-in-child trial in which we’re treating these little children with this terrible disease, our TTR drug has moved from development decision to a successful completion of first in man study. Our partners of ATL moved our growth hormone receptor drug from development decision to a successful completion in the first in man study and we’ve added alpha1 anti-trypsin, a second drug from our GSK collaboration.
Our partners at Atlantic had moved the animal formulation of Alicaforsen to a name patient named doctor supply situation in Europe and in fact we’re expecting to begin to get royalties from Alicaforsen in the near future. Our partners at Excaliard completed two – three positive Phase II trials and of course the company which recently bought by Pfizer and our partners at iCo took our drug for macular degeneration show very encouraging Phase I data and now have moved that into Phase II.
We think that’s a year of tremendous progress and we’re very proud of that. And of course advancing the drugs and development is only a piece of the equation to really increase value you need to pick the best drugs, you need to do the right clinical trials and you need to show that those drugs work and have the potential delivering value to significant groups of patients and we think we’ve done that.
Let’s look at Kynamro in 2011. In 2011 we started early in the year in January, telling you that we’d had our end of Phase III meeting that the FDA had told us our data were sufficient for homozygous FH and provided very clear guidance about a very manageable study that would support achieving the severe Heterozygous FH indication as you heard from Paula that study is getting underway.
We then reported a 100 milligrams per deciliter LDL reduction in patients with severe heterozygous FH, if you look at the data that alone should translate to greater than 6% reduction in cardiovascular risk in these patients. But of course we also reported the very broad lipid-lowering profile that mipomersen had shown in the homozygous FH study.
We then reported that 50% of patients at high risk could actually achieve LDL levels of 70 milligrams per deciliter or later and of course that number is tremendously important because at that level you are expecting to begin to regress pre-existing arthrosclerotic lesions. And remember even in this study most patients have had one and sometimes multiple cardiovascular events. We confirm that mipomersen is the only drug that robustly reduces Lp(a). If you talk to lipidologists, they’ll tell you the most exciting thing about mipomersen is it’s overall lipid-lowering profile, there is no drug, no drug that lowers all atherogenic lipids, triglyceride, apo-B, LDL, VLDL, IDL and now Lp(a).
We submitted for marketing approval in the EU, and we continue to report data from our long-term open label study. We’ve demonstrated that mipomersen efficacy continues, we now have a reasonable cohort of patients who have been treated three to four years. And they are continuing to show efficacy.
We demonstrated that tolerance and compliance actually improve with time and we showed continuing safety. And very importantly, we studied the small group of patients who had slight increases in liver fat with serial MRIs and we showed that in these subjects liver fat either plateaued or actually declined. So we recapitulated what we had in animals that showed that the liver (Inaudible) when you lower LDL dramatically and over time finds a new equilibrium that’s entirely safe for the liver. It’s great news.
We then reported that the drug works in statin intolerant patients, 47% reduction in LDL. Remember that about 12% of the patients who should take statin don’t because they’re intolerant. So that is another important long-term opportunity for Mipomersen that I should – that I don’t think should be ignored.
And finally we reported that we had special protocol approval for this 480 patient study that we call FOCUS FH, which will support the severe FH indication in the U.S. It’s sufficient and in Europe will be the core of the submission that gets us the larger indication in Europe. And so again that getting underway is great.
And as you heard from Paula, we’re thrilled with the progress that Genzyme is making and getting ready to commercialize Mipomersen, great year.
As (Inaudible) reported three positive Phase II trials, the most important in scar revision therapy for patients who scar badly, Lynne has already shown you this. They’re currently in Phase II trials and they should be very rapidly ready for Phase III and we expect that drug to progress very quickly to the market. We have significant milestones and royalties. We think this could be a really major, major product.
Our CRP drug was the first selective CRP to lower CRP in man. We showed 70% reduction of CRP in normal volunteers. That drug is in Phase II trial today in RA multiple myeloma and the atrial fibrillation study will begin very shortly.
You’ve seen the apoC-III data, this is the first selective apoC-III triglyceride lower that ever be shown to work in man. And remember that existing drugs for triglycerides are inadequately efficacious and they all have side effects. In fact there is talk about retiring niacin, I think, that’s premature but there is a desperate need for a better treatment for high triglyceride.
Again we’re recapitulating the development path that we chose for Mipomersen focusing initially on these patients for severe triglycerides problems and then moving beyond, just as we did with mipomersen.
Factor XI, this is I think the most exciting drug to come along in antithrombotics ever. This is a drug that clearly can reduce Factor XI and clouding and appears to be able to do that without any significant increase in bleeding even when you stress the system by performing surgeries as Sanjay showed, we did in the monkey.
Our partners at ATL have reported there is a growth hormone receptor drug lowered circulating levels of growth hormone receptor and all of the downstream consequences that you would expect from that. Those of you who know anything about the treatment of acromegaly know that a better, better tolerated safer treatment for acromegaly is desperately needed, our partners at ATL are progressing in Phase II program on this disease.
And as we reported today and Frank just showed you, our TTR drug again produced profound reductions and this was extraordinarily well tolerate. Again we think this is really quite a remarkable year. And a year in which the value of the pipeline and the value of the technology that supports this pipeline has been significantly enhanced by multiple exciting clinical data.
Now, I want to talk about balancing the pipeline. Since the pharmaceutical industry began one of the goals of all of the major companies is to have a balanced pipeline. And the reason for that is of course the drug discovery development is much more associated with disappointment and success. And you try to balance your portfolio in terms of opportunities and risk, so that the pipeline is sustainable and can take the failures that are inevitable or the disappointments that are inevitable in drug development.
In order to have a balanced portfolio, you need quite a few things. First, you need multiple drugs and balance the portfolio if you have two or three or one drug. And if you’re a small biotech company where you want and you want to have a reasonable cost structure, you have to have something likely [even venom] with antisense where the efficiency and versatility of the technology supports multiple drugs, reasonable cost and a broad range of therapeutic opportunities. And in a public world, you’d like to have multiple routes of delivery, so that you could balance systemic risk with the drug that was administered locally.
Now, when you at least when I think about balancing the portfolio, I begin by looking at the target. I ask, is the target validated and we benefit today from modern genetics and we benefit from the fact that antisense is the direct route from gene to patient. And so many of our targets as you’ve seen are genetically validated. So as a general rule, you’d like to have validated targets. But if you have only validated targets, you’ll miss the opportunity to hit the grand slam. Remember that cholesterol was not a validated target, it was very controversial.
HMG-CoA reductase was not a validated target and LDL receptors had not been discovered when people started developing statins. So yes, we are accepting some target risk when we focus on CRP, but we believe the opportunity that comes from lowering CRP and bringing benefit to such a wide range of diseases more than justifies that added risk of the investment in CRP.
As a general rule, we’d like to target the targets that are uniquely approachable by antisense. There is no reason for us to compete with small molecules as a general rule and as a general rule we choose not to.
In the present world of course you would like all your commercial opportunities to be blockbusters, but if they’re blockbusters, they’re chronic therapy, that means long-term development, high risk, limited tolerance for safety and tolerance issues. And so we try to balance that with smaller opportunities that are more niche that have more tolerance for safety issues and also have shorter and less costly development process.
Again you want to balance the types of safety risks and the tolerance for safety risk. We’re delighted that mipomersen is meeting the very stringent requirements for safety and tolerance that are associated with LDL reduction, but we don’t want to run that risk with every target in every drug that we’re developing.
In the present world you want entirely clear regulatory pass. But again, if you demand clear regulatory pass every time that would mean that you’re only travelling ground has been trod by others before. So yes, we don’t know exactly what the regulatory path for a Nash drug is today. But we’re confident based on our experience with mipomersen that we can easily demonstrate value with a relatively low-cost Phase II trial and when we do that there will be plenty of opportunities to license the drug and find an effective path to the market to treat Nash. Clearly Nash is a big worry today and getting worse.
You want to balance time and cost of registration and of course, we expect our drugs to bring very significant value and we expect therefore to be able to have significant value pricing and should we find ourselves in a position where we don’t think the pricing is supported, we probably (Inaudible) not be in there. So this is the pipeline today, we’ve invested heavily in cardiovascular and metabolic disease, we like it, there are a lot of – there are blockbuster opportunities. There is almost universal ability to show rapid proof of value with analytes that are really the target.
On the other hand, there are very high safety hurdles, very long-term costly development path. And we try to balance that in with enhanced investment in cancer and the severe and rare diseases, where we have smaller niche opportunities, lower safety hurdles, clearly significant pricing, flexibility, shorter-term development. And as you saw with TTR we’re working very hard to be able to create rapid proof of concept even in these rare diseases.
So this is possible because of the technology we invented and we control. And it is unique; it’s a unique platform discovery; it is a direct group from genes to drugs; it’s astonishingly efficient into drug discovery and early development level and we have virtually no failures in early development because we know what to ask these drugs to do and what not to ask them to do. Every investment can we amortized against the entire pipeline because these drugs all are chemically the same and that allows us then to evergreen our pipeline with three to five new drugs per year.
In this cycle that Lynne mentioned is the business cycle. And it really simple, invent, develop, license. And you’ve seen as invent, develop, license multiple times in our 20 years, 23 years of history. Biogen Idec is just the most recent; I can confidently tell you that it will not be the last.
Now, I want to focus on SGLT2Rx. It’s the exception to the rule, you’ll remember when we started our SGLT2 program there were small molecules that were well ahead and so we had long discussion in the company about whether we should develop an SGLT2 drug. We chose to develop the SGLT2 drug because we thought there was an opportunity to make a better drug.
And in the meantime of course the small molecules I think, has performed pretty well. I am pleased to tell you that our drug works. We’ve just completed the Phase I program. 13 weeks of treatment causes a steady increase in 24-hour urine glucose and then if you do an oral glucose tolerance test at the end of 13 weeks of treatment, it too shows very significant increase in urine glucose output.
So the good news is we have clear proof of concept and we have demonstrated that antisense drugs work in the kidney in man as they work in animals. However, I think the small molecule competition is significantly more advanced, and based on Phase I our SGA tier 2 profile isn’t better than a small molecule, maybe not as good. In order to answer that, we have to do a comparative Phase II trial and we don't think this drug merits the investment. So we are discontinuing our investment in this program.
The point of having a large pipeline and having a balanced pipeline is to force you to prioritize and pick the winners. It only works if you also make the decisions that nobody likes to make, which is determinate development, is this a drug that doesn’t deserve to be invested in by ISIS or not.
Now I’ll move onto PCSK9. PCSK9 is a unique target. It was discovered in the (Inaudible) work done at the – in the Texas heart program. And we took the data from that program and very rapidly identified the first PCSK9 inhibitor.
And you remember that we licensed PCSK9 very early to BMS. And in fact that’s the last early license we’ve done, it’s the last early license we’ll do, we are only going to consider these preferred partner transactions. And the reason for that is that BMS has been a great partner, but is just inevitable if you add a large company to ISIS development will slow. And in the meantime, we’ve lost our lead, we are not happy about that, the facts are we have lost our lead.
And in particular the Regeneron antibody is working really well. What’s happened very recently is that the FDA has written a letter to all IND holders of PCSK9 expressing very significant concerns about PCSK9 as a target. That concern is independent of the drug type whether it’s molecule antibody protein, antisense small molecules or what. And they have quite a number of concerns. I think many of them are, it’s hard to justify some of them, but they have also indicated that they are going to require, certainly requested in a strangerous way, a very substantial addition of studies. Some of these studies are going to be very difficult to do because they want them done in combination with statin.
They have also indicated that they want (Inaudible) studies done very early because they are very worried about potential malignancies and our read of it is that even for FH it’s not going to be possible to get approval even for FH without outcome studies. There is plenty of room for interpretation there, but that’s our interpretation.
As a consequence we are terminating development of our PCSK9 program as well. Now again, the bottom line is that we’re picking the winners. We are investing in opportunities like APOCIII, Factor XI, EIF4, CRP and so on. And with a sustainable deep broad pipeline, you can make the choice to invest only in drugs that really display strong efficacy, that where we can identify reasonable regulatory hurdles, ideally one of the stage development efforts, where we are, we have a clearly competitive profile. And in general, we want to be first. We want to be the leader, we want to be the only technology really that is amendable to the target.
So now I want to finish with the technology. Of course, everything we do has a technology component to it, and we continue everyday to invest in our technology. We’ve invented this and we continue to enhance it. We don’t know that second generation antisense drugs worked. This table shows 13 different targets to 13 different drugs to 13 different targets in which we have evidence, clinical evidence of antisense activity that is lowering the target.
So that’s multiple drugs, multiple targets, multiple tissues, multiple clinical trials, multiple analytes, and multiple partners. In fact, with Mipomersen as you’ve heard, we’ve actually completed 20 positive clinical trials. So we know that second generation antisense drugs are working, they are working broadly, and they’re working at doses that have this attractive safety and tolerance profiles.
In the meantime, as we’ve been developing and perfecting the technology, understanding of the RNA world has exploded. And so we sit at this unique moment in history in which we control the technology, the one significant technology and can be used for these newly reemerging RNA technologies. Regulus is a perfect example of that. Regulus is focused on microRNAs; that’s not a new technology, they’re using our technology antisense drugs to target new target Micronase, and there are thousands of those news targets. So we feel very privileged to be in the position where we are in at this time, and understanding how RNA behaves and the important roles that RNA play in the cell.
We know that our drugs work very broadly in the eye. Thanks to Excaliard, we know topical works, of course the liver, the colon, the long by aerosol, our partners at [Alteir] have shown that with our aerosol drug. In the kidney now, thanks to SGLT2, inset we showed target reduction in arthritic joints with our TNF-alpha Inhibitor long ago.
And in the last couple three years, we’ve made a lot of progress in understanding what we need to do to make our drugs for cancer work better. And we use to think antisense drugs didn’t get into muscle and didn’t work. We now know that’s not true. We have good activity in the muscle. And more importantly, we understand why we are getting activity today and why we didn’t see it earlier, broad activity.
We have multiple clinically proven routes of administration topical, aerosol, intravenous, subcutaneous, intrathecal now with administration for severe neurological disorders, intraocular, one drug on the market and another drug just in Phase II, even enema. alicaforsen enema has been given to patients with arthritis today.
And we’ve shown proof-of-concept with two different drugs with oral administration in man and we believe with generation 2.5, once we have the right target, the right disease, the right pricing opportunity, the right commercial opportunity, the technology, we will be ready to cross that final barrier oral administration of antisense drugs. So it’s exciting.
You remember that we invented the notion of screening multiple sites in RNA. And when we invented that, people said it was impossible.
We continue to advance our processes by which we screen for antisense growth. And the (Inaudible) that comes from small molecules, the more you screen, the better you screen, the better your drug applies to antisense just every bit as much as it does to small molecules.
What I'm showing you here is the effects of three different second-generation drugs. So, they’re all exactly the same chemistry. The only difference is the time it was, they were discovered and the advances that we made in deep screening. You can see with the first drug [P10], we had a reasonably active drug in the (Inaudible) with an ED50 of about 50 mg/kg.
Somewhat later drug that we discovered as a product of deeper screening had a 10 mg/kg activity, and then a more recent drug is down to around 2 mg/kg. So we are making more potent drugs with the same chemistry, because we know more about the technology and how to screen for productivity. And that’s translated demand.
This is a slide that compares the potency of a very good earlier second-generation antisense drug to the three drugs that you’ve seen today. Same exact trial, normal volunteers looking at each of the [analytes], four weeks of dosing, the potency of their earlier drug was very good. Clearly we're making much more potent drugs today, as a result of this enhanced deep screening.
And we've identified better and better ways to screen out the pro-inflammatory effects that produce these nuisance side effects and as a consequence you’re seeing very significantly less injection site reactions. Injection site reactions for the second-generation drugs are mild and they’re not really a big problem, but obviously the more we improve, the better they are. And we're seeing very, very real flu-like syndromes.
And of course we continue to add new chemistry, Generation 2.5 we expect to be 10 times more potent at least in Generation 2.0. If you think about Mipomersen working at 200 milligrams a week, that means 20 milligrams a week, 20 milligrams a week is significant improvement in every way including of course I think ISRs and flu-like symptoms will be I think in the past.
We continue to explore new mechanisms. We’ve just added the first drug in the clinic that all those splicing, but there are many other mechanisms that we’re understanding and using. We continue to improve tolerability. We’ve broaden therapeutic applications and we continue to work to enhance patient convenience. We think all of that is here now we’ve got the first two Generation 2.5 drugs that are progressing in the - toward the clinic as we speak.
So in 2012, we expect (Inaudible) to be approved and to begin to see commercial revenue from that drug at least being generated by the drug. We think our business strategy is successful. Biogen Idec is just the most recent example of that cycle of in depth developed license, there will be more we have a solid cash position and we have the efficiency of the technology to support broadening, expanding and maturing the pipeline. There will be multiple clinical data points this year as shown here, at least this year. And our first Generation 2.5 drug will go in demand. We will add three to five new drugs to the pipeline. And we expect those drugs to be better and more exciting than the really exciting drugs that we had in 2011.
With that I want to thank all of you for joining us. I know we’ve kept you here for two hours and want to thank everybody. And we will close now. Thanks very much.
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