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Isis Pharmaceuticals, Inc. (NASDAQ:ISIS)

ISIS-SMN Rx Phase 1 data Conference Call

March 21, 2013 10:30 AM ET

Executives

Stan Crooke - CEO and Chairman

Frank Bennett - Sr. VP Research

Richard Finkel - Division Chief, Division of Neurology, Department of Pediatrics, Nemours

Claudia Chiriboga - Associate Professor of Clinical Neurology & Clinical Pediatrics, Columbia University Medical Center

Karen Chen - CSO & COO, SMA Foundation

Jill Jarecki - Research Director for Families of SMA

Analysts

Alison Young - Barclays Capital

Stan Crooke

Good morning everyone and welcome. Thanks all – thanks to all of you for joining us and also welcome to the folks who are attending on the webcast. The purpose of the event today are to discuss the data that we presented yesterday by Dr. Chiriboga, at the American Academy of Neurology Meeting here, in San Diego. To put those data in appropriate context for you and then focus on the future and discuss the development plans that we have for SMNRx as we progress to control clinical trials that we define as value. The data that we presented yesterday derived from the study of SMNRx in children with spinal muscular atrophy.

SMNRx is our drug to treat spinal muscular atrophy and of course we are excited about what we are seeing and looking forward to continuing this develop. We will be of course making forward-looking statements. Obviously you should weight the risks as well as the opportunity of the SMNRx.

This is our agenda for today. I will introduce the participants and then discuss I think the critical message is that we hope you take home from today's presentation. Dr. Finkel will discuss the disease, SMA and the terrible mean that these children have, who have the disease and of course the terrible impact of this disease has on families. And then Frank Bennett will introduce you to the drug, SMNRx with the particular focus on the mechanism of action we think it is an elegant mechanism of action and that’s one of its attributes and strengths. And then with that background, Dr. Chiriboga will present the data from the Phase 1 study that she presented yesterday at the AAN.

Next Dr. Chen from the SMA Foundation will spent a couple of minutes discussing the efforts of the foundation to support clinical research in SMA and the work that they’re doing with regulatory bodies both in the U.S. and Europe, which we think is of central importance in assuring that the next clinical testing can be achieved and that if the drug is effective, approval will be prompt.

And then I will bring the proceedings to a close and we will open it up for questions. Now let me introduce the panel. Today we’re joined by Dr. Richard Finkel. Dr. Finkel is Chief of the Division of Neurology, at Nemours Children’s Hospital, in Orlando, Florida. He has just moved there. He was previously Director of the Neuromuscular Program at the Children’s Hospital, in Philadelphia and he has so moved to Orlando, he hasn’t decided yet whether he likes it in, he may not have been even to Disney World, I don’t know and that’s chance to check on that. Dr. Finkel is a pediatric neurologist. He is the key clinical investigator on SMA and he has contributed significantly to understanding of the disease, chose work on the natural history of SMA.

I think most of you know Frank Bennett. Well, he is responsible for research at Isis. But you may not know is that Frank and I’ve worked together for almost 30 years. So he is a good friend and a good colleague. He was the founder – part of the founding team of Isis 23 years ago. He created and led the Neuroscience Program and he personally led the discovery in early development of SMNRx. So Frank is very much a major reason that we’re in this room today.

Then Dr. Claudia Chiriboga, is Associate Professor of Clinical Neurology & Pediatrics, at Columbia University Medical Center. She is also Chief Pediatric Neurology at one of Columbia Universities affiliate hospital, the Harlem Hospital Center. Dr. Chiriboga has been treating children with SMA and other childhood neurological disorder for a number of years and has extensive experience in participating in clinical trials, and at evaluating a variety of drugs in the treatment of these disease.

And then finally we’re joined by Dr. Karen Chen, who is the Chief Scientific Officer and Chief operating Officer of SMA – of the SMA Foundation. And the SMA Foundation has been instrumental in driving development of treatments in patients with SMA and certainly a leading funder in SMA research worldwide and it has been responsible promoting extensive research and collaborative research on the disease. In addition Dr. Jill Jarecki, the Director of Research of Families of SMA is also attending the event. And the Families of SMA has been instrumental in reaching awareness of the disease and providing support for children with SMA.

So this is our agenda for the day. As I say, I'm going to introduce the participants, which I just did. I think there are three observations that derive from the study that are important. First, that we can give SMNRx directly in the spinal fluid of little children with Spinal Muscular Atrophy and SMNRx to-date has been extremely well tolerated. This is the first time we dose an antisense drug in children. And it is certainly the first time we dose an antisense drug directly in the spinal fluid of children, so the fact that we can say today that SMNRx was well tolerated and the procedure was well tolerated is great news.

The second key observation from the study is that based on the data that we have from this study coupled to the information that we have from preclinical models, we are optimistic that we will be able to dose variant frequently, perhaps every six to nine months. Again that is great news. Even though the lumbar puncture procedure is simple and was very well tolerated by these children. Certainly no one wants to have a lumbar function more frequently than necessary and no one wants to impose this procedure on these children more frequently than necessary. So, great news.

The third observation is that we have evidence of activity that is reasonably consistent and potentially very interesting and so obviously that's encouraging to us. But clearly in this disease like many other diseases there is a history of drug showing harmless in uncontrolled only trials and failing to show promptness to deliver that promptness in controlled clinical trials. So I would say, this is encouraging but it should be viewed very, very consciously.

My primary concern today is the children with SMA and their families. And further I would say the single most important lesson from this trial is that we are encouraged to move aggressively yet prudently through the controlled clinical trials that will determine whether this drug brings value to these children. We are certainly encouraged. So those are the main lessons that we take from the study today. As many of you know the SMA Program is a collaborative effort with Biogen Idec. In fact, early in 2012 it was when we completed the first transaction with Biogen Idec and it was focused on this drug.

We are very pleased to be a partner with Biogen Idec. They match our energy and commitment and they bring a great deal of expertise in developing drugs to treat severe neurological diseases. And we think that they have contributed to the rapid progress that we’re making and will contribute as we go forward to even greater progress.

SMA is a rare disease. It affects about 30,000 to 35,000 children in United States Europe, and Japan. But it is a very severe disease and as a consequence it is the number one genetic cause of death in infants. And least the disease is characterized by a failure to develop normal minor adjunctions, normal motor function than eventually atrophy of muscles and of course that progressive atrophy leads to a good many problems that these children have that are more mechanical and Dr. Finkel will describe some of that.

We understand the cause of the disease and we take advantage of understanding the cause of the disease to create SMNRx, which we think is an elegant solution built on the knowledge of what causes the disease. The disease is caused by a defect in gene called SMN1 that leads to a failure to produce an effective protein. We need that protein for normal neurological and neuromuscular development, and without it of course these disease ensues. Now SMA is currently it has – there is no treatment available for these children with SMA and so as Dr. Finkel will describe the need is truly desperate.

So with that, I think what I'll do now is turn the conversation over to Dr. Finkel, who will discuss the disease and the impact of this disease on their parent and families.

Richard Finkel

Good morning. Thank you Stan for the opportunity to comment, talk about SMA. It’s the condition that’s closest to my heart and something that I have struck with for now 30 years and I'm going to give you an overview and try to put a human picture on the unmet need in this condition and hopefully illustrates some of the wonderful opportunities that exist with SMNRx and how it fits into what this disease is all about.

So, this slide just tells you where I’m headed in the next 15 minutes or so, okay. So SMA is a protein deficiency disorder and we will get into the mechanism in a minute. As it’s a clinical spectrum and I'm going to first start with the most severe under the spectrum which is called SMA Type 1, or more classically Werdnig-Hoffmann Disease. And these are floppy babies, they never achieve independent sitting and the diagnosis is usually within the first six months of life and there is a fairly typical presentation as you will see in a moment in a video, but this is what the baby would look like in the more advanced stage, okay.

And because of progressive weakness, there is failure of the respiratory muscles leading to early death, typically within the first two years of life. Now this is a baby who is about five weeks old here. And the baby is moving, you can see lifting the leg up, lifting the arm, and certainly it’s weak, but it is still moving and breathing pretty well. And I want you to compare that to one month later. Now the baby is little over two months old and you will see paucity of movement in the arms and legs and the different breathing pattern. And the legs are split out and what's called a frog leg posture. So you can see how quickly this can progress, okay.

This slide illustrates the naturally history in what I’ll call the old days and this is a Kaplan-Meier curve, that shows that before the use of current treatment such as nutritional support with feeding tubes and breathing support BiPAP and as such. That there is a rapid decrease in survival over the first several months to year and then there is about a 20% or so that reach two years and a small group that actually live for several years, okay. But with the impact of better care, in fact the survival curves have improved quite a bit. So this is the same that I just showed you on this survival curve and with better supports you'll see that there is an improvement in survival, okay.

So now we're able to keep these babies living longer, but they’re still quite weak and needing a lot of support. And the type of care what we call the standard of care now involves mainly nutritional and breathing supports, we also had focus on orthopedic management, physical therapy and as such.

I am going to move now to SMA Type 2. Remember this is the continuum, so this is a little bit less severe. And this typically presents a little bit later 6 to 12 months of age and these children do achieve sitting, but not walking. And they often develop spinal curvature, they do develop some lung disease, but within a resting is they’re often are in a functional plateau phase for 5, 10 even 20 years where there is very little change in their motor function. So there is in an arrest of their development, meaning that they get to sitting and then things seem to stop. They fail to get to walking, but they stay that way and the way they’re at three is pretty much how they are going to be at 13, apart from Scoliosis and some of the consequences of the disease. And the longevity is quite a bit better than in Type 1 with the majority living into the adult years.

And this video shows a child who is at the stronger end of Type 2. So she's crawling, but you can tell that she's not crawling well. And this is a girl who never achieved walking, but she could pull herself up get caught on the chair. So this was the best she was able to achieve and unfortunately in the time since then she has lost some of the skills. So she is still sitting and she is very active, but she is not able to pull herself up to stand, okay. So this is just another patient of mine when she was a little girl and I just seen her now couple of times a year and she is a teenager and she looks the same, just bigger, but she is in her chair and she is very stable.

What are the impact this on the child? So this is from six year old girl with Type 2. I love my life. It is perfect for me. It is hard to be in a wheelchair. When I see children run I feel sad, I can't run, I can't tap and it is hard. So again this is the survival curve, the natural history for Type 2 and these are the majority of the children we see in the clinic. They comes again, they’re living a long time and they make up the majority of the children that we see year after year in the clinic. And you can see there is this survival curve is on a different timeline of 50 years and you can see the majority are really – almost all make it to 10 to 15 years and then there are some problems with some decrease in survival mainly due to some pulmonary disease. And because this is a continuum, there are some who are closer to the Type 1 into the spectrum and then there is some more robust ones like the little girl I showed you, it was almost walking, but didn’t quite get there.

And that brings us to Type 3, which is the mildest or Juvenile form of the disease. There is a Type 4, that’s seen in about 5% and that’s represented in adults, but I’m not going to focus on that today. And these children present even a little bit older, typically around 18 months of age and their early motor development is often normal, but and they do achieve walking, but they then seem to hit a developmental arrest, so they don’t become good runners and they’re limited in their motor activity. And the life expectancy is normal in this group. But about half of these children will loose ambulation by age 10 years, and these -- half of the children was early onset. So, they’re living a long time, but it is a progressive disorder, so as they’re growing and getting larger and heavier there maybe a decline in function. So here’s a little girl when she was walking, and this is like – so you can see that here gait pattern is not normal, but she can run.

[Video Playing]

Okay. And this is a girl who was walking, can no longer do that, but this -- she, we‘re trying to maintain some sense of mobility and it's just part of her exercise and physical therapy on the tricycle. So this girl was really the same as this girl just a few years prior. So the support of management for the SMA Type 2 and Type 3 are similar with nutritional and preliminary support, the scoliosis surgery is common in the Type 2. Okay, and we have to anticipate that they’re going to grow up and become adults and have normal sorts of issues and activities like other adults.

So I’m going to now move quickly into the basis of SMA. And as you heard from Stan, we do very clearly understand the biologic basis of SMA, and that has lead to this particular treatment strategy, so there’s a main gene called SMN1 which is on 5q and there’s a backup copy called SMN2 also in 5q. And humans are the only that -- animals that have this backup copy. And when you have the disease SMA, you have mutations in both copies of the SMN1 genes, and you’re relaying totally on the protein that’s being produced by this backup copy. And the treatment strategy you’re going to hear about today focuses on how to get more of the protein to be generated from this backup copy. Now there is, these two genes are not entirely the same. There are a small number of differences or single base pair changes in the D&A, and there’s one very critical one, which I’ll show here. And it's a C to T change that (indiscernible) tied to position age 40 and this single base pair change in exon 7 changes what's in exon splice enhancer site to a silencing site, and as such it prevents the inclusion of this exon 7 or this portion of the coding region into the transcript and you’ll see why that’s important in a minute.

So there are some flanking genes which we’re not going to talk about today. So in the normal situation you have the SMN1 gene that is making the full length transcript including exon 7. And you have a backup copy which in normal people we don’t really get concerned about this, we don’t need it. But when you have SMA you’re totally reliant on this backup SMN2 copy, because we’re not -- you don’t have the normal transcript from SMN1. So the consequence what generated from the SMN2 gene in about 90% of the cases excludes exon 7, you can see it's missing here and it creates an unstable protein that’s not functional. But because this is a splice site mutation it's a little bit leaky and it does allow approximately 10% of the transcripts to be generated with an inclusion of exon 7. And the identification of the biology here is what led to different strategies to try to say, how can we ramp this up? And that’s what you’re going to hear about today from SMNRx is how do we make more of this transcript which will generate more of the normal proteins. And what's different from some other antisense strategies is that you’ll notice that this makes a totally normal protein, that’s very important. So we’re just trying to make more of a deficient protein to help the motor neurons function better as opposed to let’s say an exon skipping strategy that uses antisense drugs where you’re not making a normal protein. You’re making a protein that functions to some degree and we welcome that of course, but this is an important difference to recognize.

So when we talk about these Types, 1, 2 and 3 that we probably mentioned. We do have clinical trials and there have been several studies to date that have tried to focus on; how do we best capture clinically meaningful events in these different populations? And the point of this slide is to show that, you cannot develop a clinical trial strategy that’s going to capture the full spectrum of the phenotype. So for a Type 1 child we’re going to -- the primary outcome measure in a clinical trial would be survival. Can we get a drug to get these kids to live longer and live longer free of ventilation support? Whereas in the Type 2 and Type 3 we’re looking at motor function skills, and the Hammersmith and its variants or what are typically being focused upon at the moment in clinical trials in SMA. So, and then we have secondary or support of outcome measures. So in additional to a motor function scale we can use Myometry which is the way to measure strength in individual muscles or muscle groups. We can look at what's called time testing, which is how long does it take for a child to lets say walk 10 meters or climb four stairs or do a six minute walk test, and that would be applicable to the Type 3 group obviously that’s walking, but not to the Type 2 group that is non-ambulatory. We look at preliminary function test measures, typically in children age 5 and up that are able to reliably perform these types of tests, and then quality of life measures that’s been developed that are specific for neuromuscular disease in children.

So this just summarizes what I said that, there is a clinical trial designed for Type 1. We look at survival, and then there are specific motor scales that have been developed for Type 1. We’re looking at biomarkers. The SMN protein in lymphocytes which may or may not reflect what's going on in the motor neuron, but it's something which can now be measured reliably using a new ELISA assay we can measure how much of the transcripts includes this exon 7 versus exclusion to show proof of concept of what the drug is doing. And there are Electrophysiology measures called CMAP and MUNE which can be done to it a varying degree in these different populations. We anticipate that these clinical trials will be 12 to 18 months, so they’re not going to be quick studies because of the nature of the disease. This summarizes what I’ve just said as well, that for Type 2 and 3 we’re looking at motor function scales and we have secondary outcome measures to include again the Electrophysiologic studies and importantly biomarkers.

So this slide summarizes that Hammersmith functional motor scale expanded. And it's expanded because there’s a basic 20 item which is highlighted here in brown, and this was originally designed for the Type 2 and our study group looked at adding some additional items which are highlighted in red which expanded it so they can now capture the skills that we’ve seen on Type 3 infants or child. And we do know from several studies now, natural history and intervention studies that, the Hammersmith scores are indeed stable over time so that they are we believe quite robust and responsive to change in this population, and I think that’s important. So, you will see if you look at the literature that some open-label studies which shows some change in the Hammersmith and then as you might expect when randomized control studies were performed in fact there was very little change over time in the placebo arm similar to some of the natural history studies. And our own study group looked at this over, this is 45 Type 2 and 3 patients ages 2 years up to age 45, and you can see how little the Hammersmith changes actually over a year. And we now have data that’s over a several year span.

So what's happened in the field of clinical trials and intervention efforts in SMA? I’m just going to focus on this upper part principally which are different drug’s that has looked at modulating that SMN2 gene to try to increase the inclusion of exon 7, as I showed on that earlier slide. And there’s some off the shelf drugs that has been repurposed and their HDAC inhibitors or that such that do show in vitro models some inclusion here, and unfortunately these are either open-label or randomized controlled studies. And to date none of these have shown any clinical benefit even though they did show some benefit in a vitro setting. There are other downstream pathways that are being looked at as well. And this slide just shows that on some of the survival data in an animal model for SMA and this is a more severe model for SMA, to the Type 1 so the mice typically live about 15 days and, so Trichostatin A and Sodium Butyrate have shown a very modest improvement in their survival curve here and here as compared to untreated controls. And if you -- and Frank will go over this in a bit, but I just want to highlight that after a single intracerebral dose of the SMNRx you can see a more substantial improvement in the survival curve here as compared to the others that I showed you. And also that you can see that in the animal studies that with different dosing given systemically to these animals that you can see a dose response curve here with improved survival at the higher doses. So as a clinician when we see this type of animal data we’re of course very enthusiastic about seeing what the prospects are moving us forward into the clinic.

So in conclusion, clinical trials can be performed in all forms of SMA, but there are different study designs that you need for Type 1 versus Type 2 versus Type 3. To date that none of the published intervention studies have shown any benefit. We have seen some improvement in the SMN proteins, and we do feel that having a very robust natural history data is important to the proper design and conduct of these studies. Because of the relative scarcity of these patients we feel that multi-center clinical trials will be necessary, and that we need to have harmonization of the outcome measures and standards of care of how these children are treated in the different clinical trials and that we need to have an effective coordination of the clinicians in the efficacy groups industry regulatory agency and the parents.

I will stop there for the sake of time, but would be happy to take questions later.

Frank Bennett

Thank you, Richard. That was a very good background. In the next couple of minutes what I plan on doing just providing a brief summary of the preclinical data for ISIS-SMNRx, and show that we have a very robust mechanistic basis for believing this drug should benefit that kids as well as supporting preclinical pharmacology data.

So, as Richard mentioned the diseases caused by a loss of this SMN1 gene either a loss or mutation the gene, so you no longer get a function of protein off the gene. And humans and only humans have a backup gene called SMN2 that differ by this critical nuclear type change here the C to T on the exon 7 that causes that exon to be skipped in a majority of cases. And skipping that exon results in production of a protein, but the protein is truncated and has a very short half life and this then really recapitulate all the functions of the SMN protein there. So with our drug what we’re coming in and fining to the pre messenger RNA for the SMN2 gene and cause that splicing to occur properly so that you get a fully functional protein of this second copy of the gene. And I should mention that the amino acid sequence from this full length protein is identical to the amino acid sequence that you should have gotten of the SMN1 gene. So we’re making a fully functional protein. We haven’t created new apiculture or modified the protein that’s authentic protein that’s being produced off this transcript.

And then finally just to mention that this drug works differently than our other antisense drugs in which those drugs are causing the reduction of a protein production. In this case what we’re actually doing is increasing the production of a protein that’s compensation for loss of the SMN1 genes in SMA patients. We published a large number of studies describing the preclinical pharmacology going from the test tube to cell culture to a variety of animal models. And we have a very consistent effect with the ISIS-SMNRx in all these studies and I’ll just show a couple of data points. So what we found is that the drug produces a dose dependant effect. So like all drugs this drug does produce drugs depending on pharmacology and this is an example in which we’re administering into these mice that express the human SMN2 genes so they’re transgenic mice. We can demonstrate when we deliver this into the cerebral spinal fluid of the mice, we get a very nice dose depending in increase in SMN exon 7 inclusion, and in fact we go from about 10% that baseline is Richard mentioned up to 95% of the transcripts being produced off the SMN2 genes will make the fully functional protein. And that correlates by showing that the protein is expressed in the right cell type. So, this is an example of immunostaining for the SMN protein. We see very nice bright staining and motor neurons of cells in animals that are treated with this drug.

The drug does have an affect on survival in mouse models of SMA. When we give the drug systemically as most of the other drugs that have been tested we have a very robust affect on survival with many of the animals surviving greater than a year. And with a single ICV injection, so an injection into the cerebral spinal fluid in these new born mice we have a robust effect on survival as well. I should caution, when you’re looking at data from these animal models that these are mice models and they’re not the human disease and in fact that what we’ve found is that the mice in the small severe mouse model will be not dying of a motor neuron disease. They have as you’ll see in a moment they have defects in the motor neurons, but they’re not dying of a motor neuron disease. They’re dying of effects like a Cardiomyopathy or more a systemic effects that occur. So, you’d have to be a little bit careful interpreting data from these mouse models. But when we do look mechanistically in the mice, we see that they do recapitulate some of the findings that you see in ischemic patients. And if you look at the motor neuron junction, so this is a immunostaining in which we’re stating for the presence the neurons shown in the green and then the red is staining for the acetylcholine receptor which is the receptor for the nerve transmitter released from the motor neurons on the skeleton muscle you see in the normal mouse you get good connection arborization of the nerve on to the motor neuron junction. Whereas in the SMA mice the neurons are still present, so we haven’t lost the neurons at least early in the disease, but they’re retracted of the muscle so you see these sort of convinced, collapsed nerve fibers and they’re really not making good contact and just simplistically if you put our cartoon together that I spent hours photographing myself showing that in a normal mouse you’re making good electrical connections whereas in the SMA mice the neuron is still there but it's just not making good contact with the muscle and you’re not getting good transmission of nerve impulses into the muscle to produce the muscle contraction. So when we treat with ISIS-SMNRx in these mice we do recover some of the morphology that you see in intact a lot of the motor neuron junctions have very normal looking motor neuron junctions, within a couple of weeks of treatment with the antisense drug. That correlates with a nice change in muscle pathology. So if you look in a SMA mice their muscle fibers – because they’re not getting innervations of atrophied and you see very small diameter of muscle fibers, it’ll be a little hard to see in the back. Whereas in wild-type you get very nice muscle fibers. When you treat with the ISIS-SMNRx we recover muscle fiber morphology it looks nice and clump like you see in wild-type mice, and if you made your muscle strengths we see a marked improvement in muscle strengths and almost bringing them up to what you see in wild-type animals with just a single injection of the drug in these mice.

A second point that I’d like to make is that the drug does have a long half life in CNF tissues. It's different, what we found is that our drugs have a relatively long half life in CNF tissues compared to peripheral tissues and this is an example in mice where we gave a single injection of the drug and you see the half life is on the order of six months. And our pharmacodynamic effect that is the splicing affects that we see on that order as well. So we have a very long tissue half life. We have similar data in prime mates. We can’t measure the pharmacodynamic effect but we can measure the tissue concentration in spinal cord and brain tissue in monkeys that we’ve treated with the drug and again see a very long half life in CNF tissues. So it's give us encouragement that we can dose this drug in frequently in patients.

And then finally just to show that the drug is getting to where we want it to go, this is a study that we’ve done in non-human primates where there is necessarily the single dose of the drug and you can easily see the brown staining here is stating for the drug and tissue that we get drug in motor neuron, since that motor neurons take up a lot of the drug that we see but you also see other supporting cells as well as other neurons in spinal cord tissues that tick up the drug. And the final point is that the single dose of the drug is achieving tissue concentration that’s based upon the mouse model we know should have very robust pharmacological effect. So those are one micrograms/g tissue is sufficient to cause about 50% of the splicing changes that we see in the mice, and a dose of 10 micrograms/g tissue is producing greater than 90% splicing changes. So that’s our target tissue concentration that we’re modeling for our human studies. And you can easily see that we’re achieving those tissue concentrations are greater than those tissue concentration in this market study with just a single injection of the drug.

So just to summarize – sorry ISIS-SMNRx is the first drug designed to correct the genetic defect in SMA to enter clinical trials. It has a very well characterized mechanism of action going from the test tube all the way through the mice. We have a very consistent story with the drug and very predictable affects in the all the different models that we’ve looked. We have a strong preclinical package that’s for testing this drug in patients. And as I mentioned the long half life in animals support that very infrequent administration in patients.

And with that I’ll turn the – turning over to Claudia to talk about the Phase 1 clinical trial. And I should before Claudia gets, just to acknowledge our (indiscernible) apologize for that, but I would love to give a special acknowledgement to our research contributors at Cold Spring Harbor, Dr. Adrian Krainer and Dr. Yimin Hua who really contributed immensely to this project and made it successful, and then the support that we’ve received from a families of SMA, the SMA Foundation, Muscular Dystrophy and University of Massachusetts for various aspects of the project and then our partners in the program at Biogen Idec. Thank you.

Claudia Chiriboga

Good morning. I am delighted to share with you the results of this open-label Phase 1 study and first of humans that you heard. And it's a safety trial open-label escalating dose to show the tolerability, safety and dose range of a single intrathecal dose of the ISIS-SMNRx in patients with SMA. You’ll note that it's a multi-site center. I am the site PI for New York, Kathryn Swoboda for Utah, Basil Darras for Boston and Susan Iannaccone for Texas.

I believe that this slide very much (indiscernible)so elegantly from Dr. Finkel about the severe neuromuscular disease, and how it will do to loss of the SMN1 gene. And you heard quite a bit about the SMN2 gene which is an identical copy that’s only missing from the C to T on exon 7 results in the improperly spliced truncated defective protein. What I don’t think you heard too much about was that humans do have the SMN2 genes in variable copy number, and dependant on the number of SMN2 copies you have will be a variable expression of the disease itself due to the variability in the SMN1 genes that is produced. ISIS-SMNRx modulates the splicing of SMN2 to increase normal SMN protein. You see here the SMNRx and it's a uniformly O-methoxyethyl modified antisense drug that results to correct the splicing disorder resulting in the production of the fully functional SMN protein. And the scene below shows how, when you have this SMN gene that exon 7 is skipped and that when ISIS-SMNRx is administered it allows that exon 7 that’s typically skipped to be included thus producing a fully functional protein.

For the study itself it's a Phase 1 study open-label and it's a single dose given. The objective of course was safety, tolerability and pharmacokinetics. And what was done is the single dose given as the Bolus injection and the population that was studied was going through with genetically confirmed SMA between the ages of 2 and 14 who were asked to be medically stated. The primary endpoints are safety and tolerability, CSF and plasma drug level pharmacokinetics and we also included some exploratory efficacy endpoints to get experience with these measures. The cohorts are listed here. There were four cohorts of increasing dosage, 1 milligram, 3 milligram, 6 milligram and 9 milligram. There were 6 patients in each of the first three cohorts, and 10 in the higher dose. This is a timeline showing a screening of 28 days and the injection in day one of a single dose. Patients were followed for 24 hours in house, and then they were followed over time. The first two cohorts, the lower doses they were followed for four weeks, and we followed for 12 weeks for higher dose, the 6 milligram and 9 milligram. There was final test performed at day seven in the majority of patients to assist pharmacokinetics and about half of the higher dose cohort has a spinal test at day 28.

Based on the case study outcomes on safety and tolerability, these are the usual suspects adverse events, neurological examination, CSF laboratory test including cytokines, vital signs for clinical laboratory tests, physical examination and weight in kgs and use of concomitant. The pharmacokinetic measures were the plasma levels of a drugs over 24 hours post dosing and at seven days, and the CSF drug at seven days post dose and as I said at 28 days in half of the 9 milligram dose group. The exploratory endpoints as you heard Dr. Finkel talk about the Hammersmith motor functions they’ll expanded and that’s what I will present to you today and in a very small group the 9 milligram higher dose we administered neurophysiology of CMAP and MUNE. These are the subject demographics, there were a total of 28 patients all of them completed the study. There were a bit more female’s than males as is the distribution of the disease in general. White patients formed the predominant number of patients. The mean age was 6.7 with a range of 2 to 14 obviously our criteria for entry, and the mean weight was 23.6 kilos. With regard to SMA disease characteristics and there were technically equal representation of Type 2, top 15 patients with SMA Type 2, and 13 with SMA Type 3. There were 18 non-ambulatory and 10 patients who were ambulatory. With regards to the SMN2 copy number, the majority had 25 had three copy SMN numbers and there were two with four copies, and there was one patient with five SMN2 copy numbers.

In terms of safety and tolerability, we were pleased to say that the ISIS-SMNRx was well tolerated with no significant safety findings when given as a single dose up to 9 milligram; specifically there were no serious adverse event’s for potential dose limiting toxicities. The worst events were either mild in about 93% that’s 67 out of 72, and moderate in 5 out of 72, which is about 7%. These adverse events were not related to the dose level and I’ll show you that in the table that follows. As there were no drug related changes on neurological exam. There were no changes in CSF safety labs or CSF cytokines either IL-6, TNF-alpha and MCP1 compared to pre dose, and that’s a day seven post dose for the first three cohorts and for cohort four at 7 or 28 days depending on when they have their follow up LP. The LP injection procedure was well tolerate each of with SMA and was shown to be feasible and the data suggested that the LP tolerability improved with the use of a small gauge needle that is a 24 or 25 gauge needle.

This table shows the treatment in merchant adverse effects, and you’ll note that the adverse event in the first column, the number, the percentage in number of patients in each of these adverse event categories and the final column is listed by order of increasing doses the 1 milligram, 3 milligram, 6 milligram and 9 milligram. You’ll note that to be honest with, with more than 5% about one patient and that none of these adverse events were considered to be study drug related. Call your attention to headache which was the most frequent seen in 11 patients in total. And there were four patients in the first cohort of 1 milligram and there four in the 9 milligram showing that there wasn’t the dose related adverse event response.

The Post-LP Syndrome was seen in 6 patients and again equally distributed across the cohorts and then back pain also related to the puncture site in about 5%. So were other less specific ones and some that clearly are like streptococcal infection as simply coincidental. The Post-LP headache rate of 6 events out of 55 LPs go through a rate of 11% which is entirely consistent with the rates of Post-LP seen in children. This table shows the CSF in the first graph and the plasma levels according to drug concentration. And as you can see there is a nice dose response seen in CSF at seven days post dose and plasma drug levels again in green is the 1 milligram, and in purple in the 9 milligram and it kind of peeks at two to four hours and rapidly declines over the next 24 hours. And these were, both in CSF and in plasma were reasonably consistent with those predicted in values in monkey and non-clinical studies.

This slide, I’ll just explain it a little bit. On the y-axis we have the change in baseline from the Hammersmith and the solid line of zero shows no change from baseline. These data show the Hammersmith scale for the first three cohorts, 1, 3 and 6, showing barely no change from baseline at day 29. And for 9 milligram dose the higher dose, there was a trend of increase from baseline. However when followed to day 85, call your attention to the 9 milligram dose that’s above the baseline and that, that at day 85 there was a 3.1 change in the baseline for a P of 0.02 which presents about a 17.6 change, incremental change. Of note, 6 out of these 10 patients had changes of greater than 4 points on the Hammersmith and because there’s a developmental trajectory where often times in younger patient between 2 and 4 the developmental trajectory can outpace in these mild to phenotype this disease so that you can see a little bit of increment just by natural growth in development. However out of these there were half that were over age 5.

We also performed, again in the subset of patients only those in the higher dose cohort CMAP a multipoint incremental unit at baseline in day 85 and again this was for feasibility issues, it was performed according to typical standards in the right ulnar nerve and of the Abductor Digiti Minimi. And as you can see the CMAP shows really not much change, it was quite stable and the MUNE had a slight increment that was seen. So conclusions and implications we found that the ISIS-SMNRx was well tolerated at all dose levels, and no safety or tolerability concerns were identified. We also found that the LP injection was feasible in children with SMA. But the CSF plasma drug concentrations were dose dependent and these observations were consistent with the preclinical data and that supported the infrequent administration that is about every 6 to 9 months.

We found the improvement in the Hammersmith expanded scores in the highest dose level, but as it has been noted we should not forget this is a Phase 1 study open-label with small number of patients which is very encouraging and certainly what it does is confirm the need for further study. We also did the Electrophysiology in the highest doses and found there’s a slight increase in MUNE with a stable CMAP and the data all supports the need for a further study and ongoing is the multiple dose study that will have additional endpoints and longer follow up to provide more data on safety and potential efficacy and obviously to establish efficacy what is needed as a controlled Phase 2, 3 study that is being planned for infants and children.

I do have many people to thank. The Columbia Group, the people in the University of Utah, all the folks over at Boston Children’s Hospital, University of Texas Southwest, the ISIS Daily Safety Management Board, all the folks at ISIS itself, Dawn McGuire of Biogen Idec, the SMA Foundation especially at Columbia, who’ve been very supportive, and the family of SMAs as well, and of course the patients and families who participated in the study.

And with that, I will pass over to Karen Chen.

Karen Chen

Thank you. I’ll just keep my remarks quite brief, because I think we want to get on to the question and answer period. I just wanted to thank ISIS for inviting me to participate in this meeting. I’m here on behalf of the Spinal Muscular Atrophy Foundation, who’s soul mission is to accelerate the development of therapeutics in SMA, and all of us actually come from a drug development background in pharma and biotech, so we certainly know what it takes to de-risk drug development in a rare neurological disease, and we have tried to reduce the barrier to entry for a pharmaceutical and biotech firms into this field. And towards that end since it's inception in 2003 the foundation has spent over $100 million supporting basic translation in clinical research in SMA. We have developed tools such as AMO models, cellular assays, set up standardized screening platforms both in vivo and in vitro, and in fact has screened over a 160 compounds in the severe mouse model that was described earlier.

I really wanted to focus my remarks on some of the clinical initiatives that we and others in the community have performed in this area. First of all, we have supported clinical infrastructure, supporting and funding clinical sites, and have established a clinical trial network the Pediatric Neuromuscular Clinical Research network. This PNCR network has established novel outcome measures such as the expanded Hammersmith scale that was described earlier and in conjunction with others in the community including Families of SMA, FightSMA, Muscular Dystrophy Association and SMA Europe. We are currently performing a statistical methodology called the Rasch Analysis to further refine some of these measurements including all the motor scales that are currently in use. Importantly this Rasch Analysis is highly endorsed by the FDA and they have both financially supported as well as encouraged drug developers to do a Rasch Analysis of the outcome measures in order to confirm that the scales are relevant and validated.

The PNCR network has also as well as others in the community have done a natural history study and currently over 200 patients have enrolled in this natural history study and up to, close to -- and for close to 8 years. This is a very important data base both in the design of clinical trials as well as in the assessment of any potential treatment and results as it was described earlier. Additionally the SMA foundation and others have engaged in biomarker development. I’m sure all of you know that biomarkers can really lead to speedy and efficient as well as successful trials. It was mentioned that there is an SMN live that’s commercially available now to allow the quantitative assessment of SMN protein levels in different tissues. I also wanted to quickly mention that there was a SMA pilot study done in which an unbiased study was performed including 18 sites throughout North America and as a result a panel of 27 plasma proteins was developed which predicts and is highly correlated with motor function. And subsequent studies have shown that this panel is, it may be predictive and currently follow up studies are being performed.

And lastly, I did really want to mention that we and others in the community have already engaged in dialogue with the FDA and EMA. The FDA is very familiar with SMA unlike some other rare diseases and has already funded and supported workshops in this area. The SMA foundation in conjunction with the NIH which has it's own internal SMA program and FDA are planning another workshop to be held at the end of September that’s really focused on clinical outcome measures and clinical design, and so a lot of the issues that have plagued other areas will be discussed and hopefully we’ll learn from the experience that others had in rare and neuromuscular diseases. So, I think that, I just really wanted to confine my remarks to just a introduction to the field and some of the work that’s been done by the community to make this an area in which clinical trials can be performed, and we like many others are highly encouraged by the data and results that Dr. Chiriboga described and we’re eagerly awaiting the next set of data from subsequent phases of the trial. Thanks.

Stan Crooke

Thanks, Karen, and also thanks for the panel. I think you can tell that everyone involved desperately, desperately wants to bring benefit to these patients and hope to their families. I certainly think that an antisense approach is the right approach, and in fact the only really sensibly targeted approach to this disease and the data that we’ve seen with SMNRx are certainly very encouraging. But to say it once again, this is an uncontrolled trial and all of the data should be viewed cautiously. I think the single most important point to make is all the lights are green, we have an exciting opportunity and the clinical trials designed to evaluate the performance of the drug are underway.

And what that really boils down to is, today we’re doing multiple dose studies in these children. I can tell you that trial was going well. The drug continues to be well tolerated and performed well. We’re certainly very encouraged by what we’re seeing there. The drug has been granted Orphan Drug Status in the U.S. and EU, it's been granted Fast-Track Status in the United States. And we plan two pivotal trials, either starting late this year or very early next year. The first is the study in infants with severe disease and in that study the end points will be survival or has surrogate time to the necessity for respiratory intervention. And then the childhood phase 2/3 study which will be very similar to the study that we just did, only a multiple-dose in control, in which the Hammersmith will be the principle measure of efficacy. We have strong support from the FDA and the EU. We have visited with them, discussed the plan, the protocols and as everyone has said I think they’re very much involved in the process and very supportive and so we look forward to working with regulatory agencies as we progress.

Again, just to acknowledge our partners and the groups that have contributed to the advancements that have been today, and with that I will bring us to a close and we will open up the floor for questions. Before I take the first question, I want to just take a moment to answer a question that was raised yesterday and that had to do with the plasma levels of the drug. Two parts for that question. Are you excited about the plasma levels that you are seeing with the drug and as it – where there any ALTs or sick liver signals? Absolutely not, there were no signage of liver toxicity. The main point I would make is these are trigger levels. These are while we’re showing a graph, these levels are dramatically lower than what you achieved with the systematically administered antisense drug. And the final piece of this is that the ALTs that we’ve seen with (indiscernible) are mechanism based. They’re driven by a reduction in apoB-100. We’ve more than 5,000 people now that are in our data – safety database with second generation ASOs and second generation ASOs do not cause increases in livery enzymes, unless the drug is working through a mechanism such as reduction in apoB-100. Ken?

Question-and-Answer Session

Unidentified Analyst

Thank you very much for the update and congratulations. That’s really astounding. Quick question for Dr. Chiriboga, if I may, I think this is just a matter of sampling, but and as the day 27 or day 29 point in the highest dose, where there only five samples taken in that way, that’s what you had with respect to the dataset and then add the 85, you have the full – all the children were sampled?

Claudia Chiriboga

No, let me clarify that a little bit. Everybody would – were administered the dose at day one. It’s when the PK value was done in that second follow-up LP. We’ve done in the majority of patients in seven, but they found the preclinical data showing that it remained in the central nervous system so much longer, we just have the 9 milligram group that follow-up LP we’ve done at day 29. But everybody received it at the same time.

Unidentified Analyst

Excellent. That’s really helpful. And then if I may too, Stan you’ve mentioned the roller in to the fees kind of this multi dose Phase 2a or whatever you want to call it. How many patients are in that study right now and tell us sort of what do you expect with respect to data rollout from that? Is there a data you’re hoping to achieve from that study still with respect to the planning of the Phase 2/3?

Stan Crooke

Thank you and I will answer the question on a number of patients. Yeah, the trial we have 24 patients in the study were enrolling the study as we’re speaking so, its progressing well. But ultimately its 24 patients.

And with regard to your expectations, the real goal is to gain the experience giving multiple doses in these children and what we’re looking for is continued tolerability, I think you can expect to see that. So far we’re very pleased with what we’re seeing and we will be looking in Hammersmith – again its an unblinded study, so we don’t have a comparer, but we will be looking at the muscle performs of these children and trying to get a fix on how long whatever benefit we seen by us and whether that benefit continues to be observed again with caution that we don’t have a control group to compare it too.

Frank Bennett

And the purpose of the trial, is only to get us into the control early as quick as possible, so that we want to have enough patients that we know the drug is safe and tolerated that give us a support for going into the control study.

Stan Crooke

And we’ve probably report data from that trial later this year, early next year. Over here.

Alison Young - Barclays Capital

Hi. This is Alison Young from Barclays Capital. Congratulations on the great results. I think one of the most impressive thing in the preclinical studies is the correlation between biology, chemistry with function phenotype is replicated by the studies in muscles and neuromuscular junction. Just wondering if you have similar data for other patients in the study, have you done for example a life of study the protein level of other MRA studies and how you see in correlation with function and secondly can you talk about distribution of Type 2 and Type 3 across the whole course because of the severity of function tends to be quite different? Thank you very much.

Stan Crooke

Let me answer the second question. There are two, three we distributed pretty evenly across the cohorts, the level of severity of the disease it was pretty evenly distributed and the age was reasonably evenly distributed too. So what you're looking at in the highest dose cohort is pretty representative of what we saw in terms of demographics throughout the study. Now Frank I suppose …

Frank Bennett

Yeah, so we do have some biomarkers built into the trial, they're still in process of being analyzed. So the [allies] that Karen and others have spoken about are majoring changes in SMN splicing and peripheral blood leukocyte because our drug is working essentially analyzing the facts and peripheral blood leukocytes early did makes sense. So we’re developing and modifying the assay to make some changes in SMN and cerebral spinal fluid as well as some other potential biomarkers.

Stan Crooke

I suppose it's fair to say we do know that SMA in protein can be measured in CSF today which we didn’t know a year-ago. But its way too early to know whether we have an assay that’s going to work in terms of estimating the pharmacology of the drug.

Frank Bennett

Yeah, the sensitivity is much lower, so we have to increase the sensitivity (indiscernible).

Stan Crooke

Well, the concentration is very low.

Frank Bennett

Yeah.

Stan Crooke

There was – before I move on, I think there have been a lot of questions about the meaning of the electro physiologic results and maybe I just ask Richard to comment on what these electro physiologic tests are and what to take away from that in the context of this study?

Richard Finkel

So the – I think the simple way to look at it is by contention or looking at the right on the nerve. So it’s a nerve at the wrist leading to a small hand muscle. So and this is derived from what’s been done in ALS. But it's not really particularly meaningful muscle when you think about SMA, but it’s where the field is. So when you look at the data for CMAP and MUNE, just keep in mind that you’re looking at distal muscle, not a proximal one that might be more clinically relevant.

But having said that, the testing for the CMAP is really quite simple. It just stimulate a nerve. In this case the on the nerve at the wrist and you’re recording and evolved response both are a muscle with a continues recording electrode, and it’s a summated response, which is the other thing. So you’re stimulating a bundle of nerves. In a normal situation it might be 250 nerves in that owner nerve fibers and the nerve bundle, And you get a summated response and that’s the CMAP. So the size of the CMAP, which is what is reflected on the slide here. We’re looking at the amplitude and the amplitude is proportionate to two things. It’s a number of nerve fibers that are conducting effectively to the muscle and generating a muscle response and its also reflecting how much muscle you have. So let's look at – from the point of view of SMA on a – you have a decreased number of nerve fibers because it is a motor known disease and results in muscle atrophy, Neurogenic atrophy. So there is – there are two reasons why the CMAP will be reduced, decreased number of nerve fibers, less muscles to contract.

The MUNE on the other hand, is a calculation. So its motor unit number estimates and don’t forget the E the estimate part. And it’s a calculation and it’s an effort to try to estimate how many actual nerve fibers are in that bundle, in that ulnar nerve, and how many nerve fibers are actually functionally conducting? So there are two different things that we’re measuring. And the MUNE, this calculation one of the things that’s dependent upon is the size of the CMAP. So, the MUNE and the CMAP are interdependent. The MUNE depends on the CMAP. So that’s the other thing.

So when we – now lets look at some of the point of view of SMA. If you do an intervention, let me step back, over time we know that the CMAP profile and the MUNE profile and that’s part of the natural history. So the question is what will happen with an intervention? If you increase the number of motor neurons which no one suggesting here, we don’t have a strategy to increase the number of motor neurons in the spinal cord. But if you did that then you would increase the number of nerve fibers and everything would go up. The MUNE would go up, the CMAP will go up. But if you take the pull of existing motor neurons, and that’s what we’re dealing with here. So you have the reduced number of motor neurons, because you have SMA and the question is if the drug is causing an improved fidelity where electrical transmission of those neuro fibers to the muscle, then over time, we will get an increase in the CMAP.

So, you will get and that’s assuming that the muscle stays healthy over time and that’s the question is what timeframe are we looking at? SMA is a slowly evolving process whereas the MUNE may actually respond more quickly to things because if you’re getting better, transmission of neuromuscular junction what you heard about from Dr. Chiriboga and from Frank, also that how the problem with SMA is, it is a motor neuron disease, but there are issue about the axon, the nerve fiber and in particular the neuromuscular junction. So I think we have to consider all those when we think about this type of data.

Stan Crooke

So just in summary, what we had seen in the SMA in the study with our drug to-date is more or less what you might expect, which is an increase, an improvement in MUNE and no perfect yet in CMAP. So you shouldn’t over interpret that information, the point is simply that it is consistent with the sort of pharmacology that the drug is designed to produce. Is that a fair statement?

Alison Young - Barclays Capital

Thank you. On the slide for the motor function task data, at 9 milligram and there are seven patients at 29 days, but they are 10 at 85, so what happens to the 30 patients at 29 days.

Claudia Chiriboga

What was the question again?

Stan Crooke

There is a difference in numbers seven versus 10 day, 29 versus …

Claudia Chiriboga

You’re talking about outcome, there were 10 patients total in cohort, four for the 9 milligrams, all of them we followed to date 85, all of them received the drug at day one, the only difference was when they had their follow-up LP. In terms of outcome improvement, six of them had improvements. And that was more than 4 points on the Hammersmith scale.

Alison Young - Barclays Capital

The question is on 29 days. There are only seven days in the motor function score data whereas I’d say 10 at 85 day.

Claudia Chiriboga

No, no they were 10. They were 10.

Frank Bennett

I think that is on top of each other.

Claudia Chiriboga

On top of each other. All right, all 10 of them.

Karen Chen

And in fact there are (indiscernible) as Dr. Chiriboga said, there were a small number of patients that we do LP on day 29 to get the additional CSF collected. Those four patients or three patients we did not do Hammersmith on the day 29.

Stan Crooke

Next question over here.

Unidentified Analyst

Hi. This is Kumar Raghav stepping in for (indiscernible). Congratulations on the data. So my question is, is it possible to use the biomarker as a surrogating point and is Isis planning to go for a break through designation with FDA and how onerous are this final injections?

Stan Crooke

The answer to the first question is no. We do not plan to use surrogates as an alternative end point. The end points are improved outcomes. So either improved survival for long time before needing to be put on the ventilator, and infant trial and improve muscle performance as measured by Hammersmith as the primary endpoint in the elder children trial. We’re continuing to evolve and trying to develop other surrogates and measures of the protein and so on. But in the end, the drug needs a very intangible benefit for these patients and that’s what we’re going to measure. Frank, do you want to add or subtract anything from that?

Frank Bennett

No, that’s it.

Unidentified Analyst

Thanks for taking my questions. Its (indiscernible). Just wanted to ask, there wasn't a lot of difference between the six and nine in terms of the CSF concentration, yet you saw the Hammersmith benefited nine and not at six. Was there any reason why you think that might have been given the same concentrations weren’t very different, (indiscernible) composition.

Stan Crooke

I think you’re just looking at the power and the danger of small numbers. Getting the CSF, getting the – evaluating the CSF is exactly the moment, there will be slight differences in time and so on and so on. I wouldn’t – I would really strongly caution trying to over analyze those dated to states, lets gets some more numbers.

Unidentified Analyst

You have any temptation to go higher than nine, because it seems like, it’s quite possible you could see even better results at the higher doses?

Stan Crooke

We certainly have in terms of safety experience in preclinical models. We have sufficient exposure that we can and margins that we could take the dose to higher levels. But for the moment we’re focused on six and nine, because we think we already have the evidence that those are – those are doses that would be – they have the potential to be active, its also consistent with predictions from animal models about the dose that we should require little bit to the concentration.

Unidentified Analyst

Thank you.

Stan Crooke

Other questions. Back here. And we will take just one or two more then we will bring it to a close.

Unidentified Analyst

What’s the status of the current efforts to implement prenatal screening for SMA?

Stan Crooke

I’m sorry?

Unidentified Analyst

What’s the status of the current efforts to implement prenatal screening maybe for Dr. Chen.

Karen Chen

There are efforts in the field for newborn screening and there was an attempt to add that to the National Panel of Drug and Diseases that were being screened. But the quandary is that there is a chicken and egg scenario in newborn screening in that, its often not placed on screening panels, if there is no effective treatment. And obviously in this disease area, the effective treatments especially if we believe in the Type 1, we need do treat very early on and thus diagnose very early on, since there is a very limited timeframe that it does hamstring drug development, but there are efforts in the field to move that forward.

Frank Bennett

I should mention our colleagues of families have estimate are really, (indiscernible) reinvesting and trying to develop a newborn screening panel, that it’s proved by the various state agencies.

Stan Crooke

It is a very common and perfectly rationale of identifying patients becomes meritorious when you have something you can offer them. And of course we can offer, I cant, but the courageous people who take care of these pediatric neurological diseases can offer appropriate care today, but the impetus for screening really changes when you got a drug that can bring benefit and we hope that’s what SMA will actually do. Right here and then we will get going.

Unidentified Analyst

A quick question. Did you follow on the low doses out past 29, did you follow up them till 85 and then a regulatory clinical question, when you look at your infant onset study I know you’re planning to run it as a single arm, why not run a controlling study of the Kaplan-Meier curve? We have no idea what the survival result is going to be, it could be 2.5 years, it could be 4 but without a control, how does the regulatory agency decide what (indiscernible)?

Frank Bennett

For the first questions, we did that follow below those group beyond 29, 28, 29, four weeks. Again, that’s the purpose of study was to collect some safety data as it very quickly move into multiple dose studies. The multiple dose studies again are focused on safety, but the pivotal trials as Stan mentioned will have a control arm especially with those trials. So we will be able to collect meaningful data on the natural history of these patients in the same cohort that we’re dosing in.

Richard Finkel

And it would be difficult to get through an IRB Phase 1 placebo controlled arm, because it’s more than minimal risk.

Stan Crooke

In the infant trial there will – pivotal study yes. But it will have a controlled one. Yes, now it’s not a classic placebo because its – but it’s a (indiscernible) LP injection. I think that’s correct, Frank?

Frank Bennett

Right.

Stan Crooke

So the book control on. Okay. One more here.

Unidentified Analyst

Thanks. Just one follow-up on the Hammersmith garter part just to be clear, so there were three patients right who didn’t get the day 29 Hammersmith assessment, so on an apples-to-apples basis between day 29 and day 85, is it possible for you to relook at the site, can you tell us which patients didn’t have it, just we get a sense to apples-to-apples what was the time dependant of that between 29 and 85 days?

Claudia Chiriboga

We can show it again, but I don’t think you will be to discern that from the table.

Frank Bennett

Right we …

Stan Crooke

I think the question you’re trying to ask is there any possibility today nine day, 89 day it could be skewed because of different from day 29 because difference in patients, no. And they did appear to be progression of improvement, if you look within individual patients.

Richard Finkel

Yes, so they were and the patients got better between 29 and 85.

Stan Crooke

Again, with all the caveats this is an uncontrolled trial.

Unidentified Analyst

Okay. Thanks.

Stan Crooke

Yeah. If there are no more questions, then – one more then we will quit. This is the absolute last one as I would say to my child taking – spoiling your child to the maximum limit that I can do on. I’m offering that to you.

Andrew Peters - UBS

Thanks. Congratulations on the data. It’s Andrew Peters from UBS. I guess, it’s a quick follow-up to raise question early on higher dosing. Is there any kind of downside to looking at higher doses given that the 9 milligram arm seem to be the best response and is there anything from a preclinical for safety perspective that gives you pause for dosing higher and is there kind of intra-patient variability in terms of plasma drug levels which could impact that as well.

Stan Crooke

So, let’s go from back to forward. What we see so far based on very limited numbers of these patients and inadequate sampling, is that the variability we’re seeing is very consistent with what we see typically for other adolescence drugs. That is everything cost us pretty well. And these – they appears to be very little patient to patient variability. Hence, that’s not surprising when you realize the drugs are not cleared by drug metabolizing enzymes and there is much more consistent behavior. With regard to the second question as I mentioned earlier, the preclinical studies do provide significant margins, so we can go to higher doses and in the context of the preclinical data. And there is nothing intrinsically wrong with going to higher doses, what obviously with the drug in early development, like we try to do is identify the minimum effective dose and perhaps its slightly higher dose of – because you don’t want to expose these young children to more drug than absolutely necessary. What we will do over time as we learn more about the drug as we may look at additional dose levels in other studies, but right now we’re focused on the 9 milligram as our primary dose that we think as the best chance to work and be well tolerated, okay.

Now that is the absolute last question. Again, I want to thank everyone for your interest and attention. I want to thank our panel, they did a wonderful job. And we stay pretty much on time. Thanks a lot.

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Source: Isis Pharmaceuticals' CEO Discusses the ISIS-SMN Rx Phase 1 data presented at the 2013 AAN Annual Meeting (Transcript)
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