Fourth Annual Friedreich's Ataxia Symposium

Transcript: Neurological Features of Friedreich's Ataxia

Transcripts in This Video Series
Neurological Features of Friedreich's Ataxia Diabetes in Friedreich's Ataxia Biochemical Mechanisms and Pathways Questions and Answers Session - Clinical Panel Research Topics and Discussion

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David Lynch: I get the privilege of starting today with some basic information. As most of you all know, Friedreich's ataxia is a rare genetic progressive degenerative disease of children, adolescents and adults. It affects about one out of every 50,000 people but it has affected in some way — not necessarily directly — all of us within this room.

Typically, we think about Friedreich's ataxia as a neurodegenerative disease. That's what you read in the textbooks. But really, as you all know, it's a multiple-system disorder. The neurologic dysfunction is simply the common denominator, perhaps the most visible sign.

Rob Wilson and Massimo Pandolfo will be talking a lot about the pathophysiology but in order to talk about a couple of things, which I'm going to mention in a minute, I have to remind people the genetic abnormality is an expansion of a naturally occurring GAA repeat in the intron which leads to deficiency of frataxin, difficulty with mitochondria and cellular dysfunction. Those things lead to neurologic dysfunction as well as all the other clinical features of the disorder.

So that's the amount of background I'm going to give in order to give my talk. So the other things which I'll mention are, since we don't have a cardiologist specifically speaking about the heart and Friedreich's ataxia today, though our cardiologist from the Children's Hospital Clinic, Kim Lin, will be here with us for the question-and-answer session on clinical matters just after lunch. I'll remind people the heart is affected in Friedreich's ataxia both with cardiomyopathy, what we call degenerating or abnormal heart essentially, as well as giving rise to funny heart rhythms. The word we use being arrhythmia.

Remember that as physicians and scientists, we like to make up lots of words for the simple purpose of confusing you. It's a talent they teach us in school.

In most individuals, the cardiomyopathy is of a hypertrophic nature where the heart grows in size, the muscle becomes thick, and that can lead to difficulties as well as long-term changes and it is the most common cause of mortality long term now, is what we've even studied recently. People do have EKG abnormalities which don't necessarily mean anything, but will look like a person's having a heart attack when they go to the Emergency Room even though they're not, and, but people can have the funny heart rhythms called arrhythmias which can lead to difficulties.

Our second speaker Steve Willi will talk a lot about insulin resistance in diabetes and the results of studies we've done recently. And then as many people know curvature of the spine, scoliosis, is present and can affect, require surgery in about 50 percent of people in some studies.

So that's our background. That's what I think, most people knew before they came today from the textbooks. I get the task of talking about neurological issues.

Now while we talk about cardiac disease as the cause of mortality, the long-term disability is mainly caused by the neurological dysfunction. You can go to any neurology textbook or Wikipedia or whatever, and you can probably read about the classical form of it.

Well, we want to rethink things a little bit here because with the past 10 years, we've entered a different era, an era where we have new potential treatments and our job is to try and treat things to make them better. So we have to sort of think about [this] in a very different perspective and think about what our goals might be. Normally we use neurologic function to diagnose, but now this is a different era. We want to think about treating it, treatment and greater understanding so that we can move forward.

So I'm going to review a little bit about the neurology and nervous system of all of this and then we're going to consider some new questions.

So I'll start at the beginning. Most of you know that we talk about the brain and your nervous system as a computer and this computer is composed of two types of processes, let's say: a cell body, you might say the chip; and then a long wire called the axon. And these are connected together to give rise to the computer which is your brain. And of course I've diagrammed it as two neurons here. Your brain has about 10 million neurons so it's a bit more complex that I can ever draw without making an absolute mess of everything. But this is the prototype of what we talk about.

So what, if you read a textbook, what do you see? What you see in a textbook is that what happens in Friedreich's ataxia is a slowly, progressive loss of the large sensory neurons, particularly the ones which are concerned with what we call proprioception, where your limbs and body is in space. That is, the signal is not getting to your brain where your hands are or where your feet are. Now that's a crucial component of balance.

In addition, there's a loss of a long pathway, a wire, which we call the spinocerebellar tract. Now again we like to make up words but I'm going to make a bet that most people figured out that this is the tract which goes from your spinal cord to your cerebellum. And actually where the cerebellum is where it makes that comparison between what you want to do and what your limbs tell you you are doing so that's a particularly important tract, albeit, I'll show you in a minute, it is impressively small.

There's also to a more modest degree, loss of the motor tracts which start in your brain and go down to your spinal cord to tell you to move, giving the rise to some loss of motor control but less weakness than we see in terms of balance.

There's also a very small area within the brain called the dentate nucleus of the cerebellum. Dentate, it looks like a tooth on sections I think that's why they named it that way. So it's lost in FA but tends to be lost somewhat later and then a few other sights, you know? It's not like the brain is entirely abnormal. That's important. The cortex of the cerebellum as well as the cerebral cortex, that area which we all use to think, to speak, to do the things that make us us, for lack of a better phrase, is largely intact.

If you were to add this all up, it's probably maybe two percent of the neurons in the brain, some small number of like that, and maybe 10 percent of the long wires.

Now, that's not that much. That's important because when we talk about the therapies we're going to talk about, the question is always, "Well how much will recover?" Well, we don't know but, we know that we'd much prefer to start with 98% of the normal neurons still being there and 90% of the tracts and anything else. So the potential for recovery is there once we figure out how to slow or stop disease progression. So one step at a time, but we know that potential is there.

So what does this mean? The loss of the large sensory neuron gives rise to a loss of balance because you don't know where your limbs are. For those people who are electrical engineers, the cerebellum can be thought of about as a differential amplifier and where you compare the movement you want to make with the movement you are making. Essentially, if you don't have the information coming in on what you're doing, you're going to lose your balance.

That same thing is coded in those very small, spinocerebellar tracts. Once you get into the cerebellum, that back portion of the brain itself, which I'll show you in a minute, there you have some other issues, speech difficulty, some eye movement abnormalities and probably some other features later on. And then a very few other sites. A few people know that vision and hearing could be affected particularly later. Those are those few other sites which we mentioned. But remember, people's cognition as you would know from me, is largely spared. You know that because you're holding your jobs well, you're doing all the things you did 15 years ago but just superimposed with a motor burden on top.

So this is — I have to show a picture — this is a picture of a spinal cord, obviously at autopsy. The one on the left is out of a textbook. It's quite normal except it's been colored yellow and green, you know? Most of our spinal cords aren't yellow and green. The one on the right has Friedreich's ataxia. This area right here, the blue area, is normal. Over here, the black area is normal. This area here the cell body is, that's normal.

What actually happens in Friedreich's ataxia is the cells, the cells that are lost, are these right here which sit right outside the spinal cord, called the dorsal root ganglia, where the sensory neurons are, particularly the large ones which are concerned with where your limbs are in space. The others tend to be more spared. They send a branch, a wire, into the spinal cord such that, into this area right here. What you see goes away over time in Friedreich's ataxia.

The only other things that you see that might be missing here is, there is a little bit of the motor tract loss right there which carry the deep, the fibers going down to control muscle and this little "ditzel", as I like to call it, right there which is the spinocerebellar tract. It's a very small pathway but it's crucially important to clinical manifestations.

So this is what the spinal cord might look like. This gives rise to that loss of sensory information and that sense of balance. So, and we look at the anatomy and what's really going on, the things which are going on are just these two small things here at the spinal cord level. Not a whole lot. Think about, that's the most affected area in the central nervous system in FA and still it's not everything that's affected there.

The other place — did I? — there we are. This is a section through a brain which we've cut down the middle. We call it sagittal for those who are — And if you look at it here — where's my pointer — This is the cerebral cortex. It's all the area that you think with; that you speak with; that you see with, after the eyes; that you hear with, after the ears. That's a fiber pathway there. This is the cerebellum which is concerned with balance back here. And if you were to go just past the midline and make a little dot about the size of a half of a small marble, you would find the nucleus called the dentate nucleus. That would go away over time in Friedreich's ataxia but basically the rest of the brain at first glance, and as we look at it classically, would be normal.

So the message I'm, and what that gives rise to, oops, I'm going to go back. What that gives rise to is perhaps the loss of speech and the speech dysarthria as well as some of the true cerebellar components of the disease. So if you really want to understand this, we need to look at the simplified wiring diagram of the cerebellum. Here we are. We'll be having a test on this in just a very few minutes. Massimo and I will be passing it out. We'll see how the people at the first table do. So no you don't need to know it in this much detail. In fact, do we need to know it in that much detail? That's an interesting question but we can look at this very simply.

Think about this in Friedreich's ataxia as opposed to the other ataxias you may meet people with in support group. You lose the input coming from your joint receptors where your limbs are in space so you have difficulty making that actual comparison. You also lose some of the dentate nucleus down at the bottom so you lose part of the outflow, particularly later. But, it's a relatively simple scenario.

What does this mean to you? When we see people with Friedreich's ataxia, a lot of it is going to be dependent on knowing where your limbs are in space and if you don't have those joint receptors, you don't have that sensation, you're going to use your eyes to do so. As you know as well as I do, the balance difficulty will be very dependent on visual input. Yes, there are other features, but that's something that you can remember in everyday life to help you walk better, is simply to use your eyes and use your brain. Your brain's intact, it can help you out a whole lot. I wish I knew people who remembered that. So the neural anatomy is actually very simple, you can read this in a textbook.

Why do we think about it? Well our job now is not simply to recite this, as we can do quite well, but we want to try and figure out how to make people better and really improve them with a new generation of drugs which we'll talk about in a few minutes. Well I think it's common sense but often forgotten that if you want to make someone better, you have to prove it. And how do you prove it? Well you have to be able to measure it.

How do we do that? So let me see, probably about half the people here have come to see either myself or Dr. Pandolfo or one of the other neurologists and you'll see us go through an exam with you. And you'll notice that I'll call out some numbers to Sean or Carla or Lauren, sometimes I'll even flash them behind my back like a catcher making signals. You know, we, that's a faster way although I shouldn't bring a baseball in front of such (unintelligible).

What are we doing? We're doing a very standardized neurological exam where we're looking at very specific things and how far a person shakes in a certain amount. How accurately they touch the top target. How long they can stand for us. Where they can bring out reflexes. How long they feel a tuning fork. So that we can quantify our neurological exam. Does that seem like a good way to measure the disease? I don't know. It's what we do, it's what neurologists do but many people know that neurologists are basically useless. I'm a neurologist, I can say that.

So is that really a good thing? And that's actually an issue. We call this exam the Friedreich's Ataxia Rating Scale or the FARS for short because it takes a lot, entirely too much time to say Friedreich's Ataxia Rating Scale. We call it the FARS for short and we've done studies that validate that we can make neurologists pretty similar if we really instruct them, but there are issues with this. I think as you all well know, not every neurologist, no matter how much training you do, is going to be the same. That's just what we'll call human nature. If Susan Perlman and I and Massimo rate the same patient, or the same series of patient, I bet we have the same rank order of it in what the numbers are, but the numbers no matter how much training we do may not be exactly the same.

What does that give rise to? Variability. And when you're trying to rate how someone is doing and make them better, variability is your enemy. You want things as uniform as possible. So if we were to clone Massimo and pass him out to seven different sites, it would be quite easy to do a seven-site trial, but you know, we're not against that, we're not going to do that. Other questions about doing these things, besides the fact that it's semi-subjective, will never be quite the same.

You can give me an honest opinion here. When we do these tests on you, do you think this has any bearing on your day-to-day life? "No" is a perfectly acceptable answer. And that's a very good point. Our goal is not to make neurologic exams better, it's to make people better. And while we may use the neurologic exam as a measure of that, our goal is really to make an individual with Friedreich's ataxia better. So there's certain aspects which may not be relevant. It's important for you to ask us but it's also important for another matter. This is what the FDA asks us.

They'll take these exam scales but really they would like us to prove that it means something in people's lives. To a certain extent, that's why we ask all those other questions about your life and how you're doing all these different things so that we can correlate it. But the FDA would really like us to really prove that people were better in a way which is relevant to their life.

And the final thing is, all these things give rise to what I'll call a lack of sensitivity. Ideally, you'd like to be able to do a study with the minimum number of patients which you need. Why? I think everyone would give me that's it's a lot more expensive to do a study with 100 patients than it is with 50 patients in terms of effort, money, time, travel, things like that. If you could have the most reliable measures, you'd be able to do the studies with fewer and fewer individuals. Or in other ways, as the drugs get better and better, you'd be able to show add-on effects of one drug on top of the other with smaller numbers of people.

That's why we keep doing these things every year when you come back to see us and visit us and that's why we'll be seeing 20 people between yesterday, Thursday and Monday, to help evaluate that. This is how we learn, how we make better measures. It's important to you because when you come for clinical trials and notice I use the word "when." This is what we'll be doing and this is what we'll be doing to measure these things so that you understand exactly why we're doing things.

Is there another way that gets around this exam-based problem? Well maybe we should just have people do some tasks. Or torture as we sometimes call it. We call these performance tests. Timed measures where you get rid of the neurologist, always a worthwhile thing in most people's mind. No neurologist to be subjective. You just see how fast people put things in a pegboard, how fast they walk, whether they can read a vision chart, how fast they can speak a certain set of words. Some people can speak a little faster than others and it has nothing to do with disease. These are ways we can time and no one's going to argue about [results]. We set up the rules on how we time them, you know, there's no interpretation, they're objective. They're relative to lives because, you know, people care about how fast they walk, people care about whether they can do fine finger movements, though, not necessarily putting pegs in a pegboard. Maybe we should have like a typing test but I'd lose that one so badly. People care about whether they can read and whether they can speak.

These are very real, in fact the FDA likes these a lot better than neurological exams. So I can leave now and, the neurologist isn't necessary. The issues are, these tests tend to be, work over a narrow range. For example, a timed walk isn't useful in people who are having sufficient difficulty walking where they don't walk well. The pegboards are only used with certain points. The vision is a later stage feature of FA. If we combine these together statistically, we can make a composite which works over the disease but this is somewhat a new concept that is only now being accepted. So that's one issue with these nice, highly-quantifiable, timed measures.

In addition, suppose you break your hand. That is going to affect how you do a pegboard even though I might be able to account for that in a neurologic exam. So there's some confounders there and certain random events might be going on. Suppose you trip while you're doing the walk and you fall. That's really just something that happens every once in a while but we don't really have a good way to account for that so random events can intervene. So which one do we want to use?

The answer is, each study that you do neurologically is a different experiment. And I want to come back to the fact that every time we do a clinical research study, whether it's a natural history study, or a drug study, or a blood study, it is an experiment. You want to use the one which is best for that particular experiment. Wow, they sent me to school to think about that. Oh my gosh, what a waste of society's money.

So, in fact, that's why you see us doing all these, even within the same event and you want to be sure that they at least all go in parallel, even if within a given study we have to take one and call it the primary measure, and it's the one we're really going to count.

So, this is the reason we think about the neurology and we do timed exams and performance measures which work on, look at those neuroanatomical components I said before.

So now, I am going to go forward and talk about the three trials, actually four trials we have participated in here for neurologic function. And in the question-and-answer session later you're perfectly welcome to corner Dr. Pandolfo and those he's participated in as well. You love me, don't you? You were expecting it.

When you read about clinical trials because now this is the information era, you will see the abstracts, you might see the full paper. You'll want to understand what you're reading, not just trust us. The things you'll want to notice: What does each stage do for participants? How effective? Was it only ambulatory people or did it include everyone? Was it only children? These were things which affect the results and affect the interpretation, both good and bad. There will also be something about, who did they get to come for the trial, you know? Does it say 50 people showed for trial but 20 of them dropped out. You know? You would wonder about the meaning when that occurs. What happened to the other 20 people and why did they drop out? That's an important thing to understand because it might skew the results.

How long did the trial go on, the trial duration? This is a particularly important component. Let's suppose something works if we give it to someone for a month and people get better. What happens if you give it to them for six months? Do they keep getting better still? Or even better? Or do you just get that little bump you saw at one month? Or is the body smart enough to realize that whenever we give someone a drug, we're trying to trick the body. And the body is smart enough to recover its abilities and go back to the abnormal state six months later? How do you figure these things out? You do the experiment. And if you don't do the trial, you can't figure out what happens or you can sit up here and wonder what happens at one month versus six months, and you can never be wrong but, you'll never be right.

So let's talk about the four trials we have done in the past four years. Now remember one thing, as we talk about this, that's four more than we're talking about in most other disorders that we take care of, so these are the first steps toward that eventual goal.

The drug called Idebenone. A series of studies performed in recent years, I guess if we add them all together, it's probably eight to ten studies. The ones I'll mention very briefly here are the so-called NIH Phase II study which was done around 2005 and then the American Phase III Study which we did at CHOP and UCLA. The NIH was called Nicosia if you remember that, the Phase III Study here was called Ionia. That's because Santhera names all their trials after cities in Greece. I don't know. You know, someone has to know those things.

In any case, they're very similar. Both are six-month studies, similar doses of drug, though not exactly identical. The Phase II had four doses. We only had three doses, one of which was placebo in each. Now, they gave different results. Why?

Well let's take a look at those data. Okay, now what I have here, and this slide was given to me by Thomas Meier of Santhera though it's publicly available data, he did give me the slide. And what I'm looking at here, if you go up — because my pointer is burning out a little bit — up is bad, down is good. And looking at the difference in people's exam scores done with an ICARS rather than a FARS but that's not important here, it's very similar. People get the two doses and they get better when they do it at the NIH. When they go to UCLA or Philadelphia, the blue is the placebo group here, the placebo group gets a little better and the people on drug, get a little more better, if that's appropriate English.

So what happened? Why are they different? Well you never know those things so you have to think about this sort of stuff. We don't know exactly what but I'll come back to those in a minute. So now let's do something else. So that's trial number one.

There's actually a second trial and what we did, and this is new since we talked last a year ago. We took the people who got in that Phase III study and we put them all on drug for one year. And I know some people in the audience participated or their children participated in this. And then you compare on how people would have been expected to do had they just been living out in the community, what we'll call a natural history control group.

So what happens? This is what happens and I'll take you through this. Again, prepared by Thomas out of convenience. Again, the data is being published. I think it comes out probably next month. It's already available online. This is the start of everything and as you saw people on average, even including the placebo, got better but just a little bit in that six-month study. And then you keep giving them Idebenone and what happens? Well, they get a little bit worse but they're not back to where they were when they started the [trial]18 months earlier.

So that's really good evidence that Idebenone is a great drug, right? No. There's no placebo group here. How do we know that we just didn't take some people who were really uncomfortable with people who talk really fast and bring them to the office, and by the time they got to the end of the trial, they were really comfortable with people like me? It's possible this is entirely practice as we had them do their pegboards and we had them do these complicated exams. You know, you wouldn't want to see it go the other way where people got worse, but you can't use this as great evidence that it does work.

So again, we have the quandary of, "Does it work one day and not work the next?" Don't know. And it does give us to a problem. So how do you actually interpret this? Because in the end, we don't care as much what happens on those slides as what happens in real life. And because Idebenone is generally available over the Internet, there actually is a question here. Do you take it or not? And I'm not going to take a position while I'm up here right now, but it's a really good question. Are the side effects less or better, are the potential side effect less or better than the potential benefit? I do have an opinion, particularly based on the fact that it has very few side effects, but you can't sit up here and say that is has been shown to work. You think it might, but you're not sure why. Well why might it have been different between the different studies? Well the observers change. I mentioned those exam-based rating scales.

In the second study, it's Susan Perlman and I rating who have seen, probably, with the exception of Dr. Pandolfo, more individuals with Friedreich's ataxia than any in the world. Our exams are very practiced in. The individual in the NIH study was naive to Friedreich's ataxia. They will rate perfectly fine and perfectly consistent but they will rate different than we do. Who's right? Neither is right. They're both internally consistent, but things will happen as you do these studies. Not everything will be a clean result. The other catch is the first one is one site. That person is almost by definition internally consistent. Instead if you take it to two sites, you're going to see more variability. I remind you of this for things which I might show in a later slide. When you go from one sight to more you will see more variability. Count on it. Maybe it's different selection criteria. In the first NIH, they took anyone who was a child. We were required to recruit ambulatory children. So, different group. Maybe they're not perfectly comparable on that basis. And you know that people differ in other ways that we don't even know. So as we select people, we may not even be selecting for the group that we thought we had. So we get to this quandary, "Does it work or not?" The good news is I don't think we'll ever do another study because we have better things.

Third clinical trial we're involved in which hasn't been talked about much is Varenicline. I think most people have forgotten about it. You will recall in the literature there were case reports of which I was an author, of individuals who carry a single-point mutation and in conjunction with expanded allele who responded dramatically in response to Varenicline. As well as some people with some other ataxias, all well documented. But that's only two people so let's see what happens when you give it to a bigger group and the original target enrollment was 32 individuals, 16 for drug, 16 for placebo. So it's a double-blind study. I don't know what the person's on, my co-investigator doesn't know what the person's on, the people, the subject, patients don't know what they're on. Two sites, here and the University of South Florida. Our outcome measure was that exam-based measure that we're doing everything. We only enrolled a total of 26 subjects, 17 people actually completed getting the drug. Why? Because when you oversee a study, there's always a safety monitoring board, the DSMB was looking at the data. They got to know what everyone was on and they discovered that a large number of people were dropping out and getting worse who were on active agent. So the study was stopped after 26 patients due to increased ambulation imbalance in subjects who were on drug and increased number of adverse events in the treated group as well as the fact that it didn't seem to be working. So the DSMB stepped in and stopped it. Good, because we were not helping people. It was statistically shown that we were making people worse and that is the time we have neutral people stop it.

So if you actually look at the adverse events, it's a little small. Drug is on that middle column there. Placebo is over here. One particular thing to note: This is the total number of adverse events. We give you a questionnaire and say, "What's going wrong?" There are 64 adverse events in the placebo group, okay. You wouldn't expect that taking sugar pills, I forget what the actual placebo group was, would cause adverse events, but if we ask you a bunch of questions, people will find things which might be adverse events. And the number actually in the drug-treated group were not that much more.

But where it comes down to is, when you look at the relationship of adverse events to study drug. When you tell us about something that is going wrong, the investigator or safety monitor is asked, "Do you think that came from drug or not?" And if you do it based on when it happens, things like that. It was felt that the adverse events in the drug group were related to study drug were very few and much less than the placebo group. So this was giving it rise to too many adverse events. And if you look at the bottom, this one right here, imbalance and really almost loss of the ability to walk in people who were previously ambulatory, only appears on the Varenicline side and on the placebo. So this study was stopped because of that reason.

But remember we started this study for a very good reason that we saw people getting better when they took the drug. So is this a failed study? I will argue that no, this is not a failed study. It's a failed drug, we showed that it didn't work. But this trial did succeed in accomplishing the outcome of figuring out whether this is a good drug for people on average to take. And the answer is clearly no but sometimes the answer that is right and is correct and that you get is just not the one you wanted. Protecting people is equally important to making people better. So I will argue that this is a successful study because it showed how the process can go through and get us to the right answer.

So now, we have one more study which the results were shown at the ANA meetings in San Diego a week ago. A0001. What is A0001? It's a modified form of Idebenone / Vitamin E, sort of looks like you put them together. It's alpha-tocopheryl quinone. It's actually found in your bodies all the time to a very small amount. It's more potent than Idebenone. The slide I've taken here on the right is the dose response curve. I have to show a little science. This is from Rob Wilson's group done in collaboration with Amale Hawi and Tom Sciascia from Penwest. On the right is Idebenone, on the left is A0001. They're looking at the number of fiber blasts using a model developed by Halam Perchio up here at the front table, die in response to challenge and how much A0001 versus Idebenone can protect him.

And basically what you see is that A0001 is about one order of magnitude, about a factor of 10 better, than Idebenone at protecting him from that oxidative challenge.
In addition, A0001 is absorbed much, much better.

Now you do have to do some things, like eat fat, and when I was talking to one of the individuals from the trial the other day, I remember him saying how much fat, he asked the question, "How much fat are you required to eat to absorb A0001?" And the answer was, "As much as possible." So there are some adverse events, but maybe it doesn't, you know, but it's a trial, you have to do what we ask you to do. We get to make the rules here, guys.

We call this trial FRDo2, no named after Greek cities. It was done by Penwest Pharmaceutical with us as a trial. It's double-blind, placebo-controlled, medium and high doses of A0001, 31 total subjects. We got to replace one drop out. It is a one-month treatment. The primary outcome measures those people who participated knows we do this glucose tolerance test on you where we shoot you full of a lot of glucose and we shoot you up with a lot of insulin. We measure of these diabetic measures. Now that's the primary outcome but then we measure the neurological things as well. It's a reasonably tough protocol and I'll note we're measuring the neurological outcome measures after we have put these people through these various IV treatments. Remember that when we come to generalizability.

So what does it actually show? Well, the glucose outcome measure just didn't sort of work. They were very noisy and we couldn't establish anything. However, the individuals on A0001 had a significant improvement in their FARS score. People on placebo got about two units better. People on low dose got about five points better. People on high dose got 6.1 units better. These are statistically significant, very high levels. It worked across all aspects of that neurologic exam. In addition and this goes to the bottom point, it actually happened in just about every subject. So it was very uniform. This change wasn't driven by a couple people getting a huge amount better. It's actually every individual, except for maybe one or two, getting better out of the 10. The improvement, this amount of improvement, yes. Well how does that mean? It's about the, six points is about what people change in one to two years. So this would meet the definition of clinically significant. So great outcome. What are the problems with this?

Let's go back one. The problems, it's one month, you know? I brought it up earlier. What happens at six months? There's only one way to find out and that's do the experiment. Yes, these were not the things we meant to measure as our primary measure to begin with, we just found that they were better. You always have to be cautious in interpreting such things. Maybe it only happens after we give people an IV glucose tolerance test and challenge and fatigue them with that. Don't know. If that's true, it's not so generalizable. That said, this is a very nice result. It's a reason to keep moving forward with this drug without doubt. And the question is what happens if we give it to people for six months or a year? We'll see.

So this is, I've stolen from my good friends at Santhera the pipeline slide again. I think I copied this a while back but I've added something over here to emphasize a new announcement, right here at the corner, this thing called OX1, this is a new drug for which safety data is available in adults, which is now been licensed to ViroPharma for trials in Friedreich's ataxia. Now the one good thing about this is Jen and I might fly all around the country to visit various drug companies. They're local, we don't have to fly anywhere. So we can save some of our time which is always a nice thing and we can get back to more work for you. Works for me.

Notice though, in particular, the real emphasis here is not so much, is on OX1, but all the things on this list. That I mentioned A0001 but there's lots of other shots coming as well and that's why I want you to know about all the details about these clinical trials so that you could be active participants. And there's some things that we ask you to realize in clinical trials. Clinical trials are experiments. There are rules. Oh my gosh, Dave has to enforce a rule. We call them, in some cases, inclusion/exclusion criteria that we write the study so that we can do the best, most generalizable experiment at the safest scenario for people.

Sometimes we'll want to look at the individuals who are likely to be at the most responsive window so that we can get the most reliable result. Sometimes we will exclude people in whom we are worried that they are more likely to have a safety event. That would be drug dependent, as sometimes well as not drug dependent. We do this because we need to do it right.

That said, they are largely inflexible. A few of them have interpretational components and usually it's the principal investigator who gets to make those interpretations. So if you get excluded, it's unfortunately part of the game. If you get included, it carries that much more responsibility to do the right thing as you're there.

There are also personal practicality issues. We set the visit schedule so that we can do the experiment right. For example, Massimo emphasizes this from the Phase II, the Deferiprone trial which we were almost involved in many years ago. The first, because the adverse events potential with that drug, the first four weeks involve six visits to the Children's Hospital of Philadelphia. Now, I don't even like to go to Children's Hospital of Philadelphia six visits in a month. I'd prefer to stay at home and work, but in any case, it's a rugged schedule for particularly people coming out of town but it was necessary for safety reasons and it was non-negotiable. And the other thing was cost. It does cost money to get to the Children's Hospital of Philadelphia, or to UCLA, or to Iowa, or Chicago or Minnesota or Emory or the other places I'm forgetting, Toronto or Melbourne or Brisbane. And I know I forgot some, what did I forget? University of South Florida, University of Florida. So it costs money to get there.

I will compliment my friends at Santhera for in their trial because they had such tight recruitment criteria. They actually covered the cost of everyone coming to CHOP for nine visits over the course of a year and a half, which if you calculated out, is about $700,000. It's not a trivial amount of money. Companies are not required to do that. It may affect their recruitment, their ability to move forward in a trial, but it's not a requirement.

So as we move forward, the Varenicline study covered only a minimal travel expense, A0001 had travel expense covered after the first screening visit. These are all things that you will have to consider as these announcements come up.

So if you want to participate, what do you do? You sign up on the registry for the Friedreich's ataxia Research Alliance so when that trial is announced, you will get an e-mail.

So I started this as a talk about neurologic dysfunction and the things we are going to measure. So what's the upshot with clinical trials at this moment with that very encouraging result? There's reason to be optimistic, you know? We've done some trials. We have one, some that is neutral. One we have shown that the drug didn't work and one which at first glance, emphasis first glance, showed that the drug may well be efficacious. Let's see what happens long term.

But I think the other thing which I wish to emphasize is the only way to truly move forward with a systematic approach and getting the answers. I think we've gotten the right answers and the right answers are the ones in which actually protect people as well as help people out long term. So at this point, I get to stop and we'll go from there. Thanks.